PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of brainInstructions to AuthorsSubcribeAboutFree EditorialsBrain
 
Brain. 2009 December; 132(12): 3199–3230.
Published online 2009 November 20. doi:  10.1093/brain/awp247
PMCID: PMC2792369

A developmental and genetic classification for midbrain-hindbrain malformations

Abstract

Advances in neuroimaging, developmental biology and molecular genetics have increased the understanding of developmental disorders affecting the midbrain and hindbrain, both as isolated anomalies and as part of larger malformation syndromes. However, the understanding of these malformations and their relationships with other malformations, within the central nervous system and in the rest of the body, remains limited. A new classification system is proposed, based wherever possible, upon embryology and genetics. Proposed categories include: (i) malformations secondary to early anteroposterior and dorsoventral patterning defects, or to misspecification of mid-hindbrain germinal zones; (ii) malformations associated with later generalized developmental disorders that significantly affect the brainstem and cerebellum (and have a pathogenesis that is at least partly understood); (iii) localized brain malformations that significantly affect the brain stem and cerebellum (pathogenesis partly or largely understood, includes local proliferation, cell specification, migration and axonal guidance); and (iv) combined hypoplasia and atrophy of putative prenatal onset degenerative disorders. Pertinent embryology is discussed and the classification is justified. This classification will prove useful for both physicians who diagnose and treat patients with these disorders and for clinical scientists who wish to understand better the perturbations of developmental processes that produce them. Importantly, both the classification and its framework remain flexible enough to be easily modified when new embryologic processes are described or new malformations discovered.

Keywords: cerebellum, brain stem, malformations, development

Introduction

Recent advances in developmental biology, molecular genetics and neuroimaging have led to an increased interest in and understanding of developmental disorders of the embryonic midbrain and hindbrain that grow into the adult brainstem and cerebellum. Malformations of the brainstem and cerebellum often occur as the only recognized malformation in individuals with mental retardation or autism (Soto-Ares et al., 2003; Courchesne et al., 2005). However, they have also been increasingly recognized in patients with malformations of the cerebrum such as lissencephaly (Ross et al., 2001; Poirier et al., 2007), cobblestone malformations (Aida et al., 1994; Barkovich, 1998; Triki et al., 2003; van Reeuwijk et al., 2006) or callosal anomalies (Barkovich et al., 2007); and in patients with developmental disorders of other organ systems such as the kidneys or skin (Brocks et al., 2000; Gleeson et al., 2004; Tan et al., 2005; Valente et al., 2005).

The number and complexity of recognized malformations of the brainstem and cerebellum has been steadily increasing. While the practical ‘every day’ approach to a patient with a midbrain-hindbrain malformation is still based mainly on the neuroimaging ‘pattern recognition’ approach, a system by which these disorders can be clearly identified and compared is badly needed. A few classification systems have been proposed (Patel and Barkovich, 2002; Parisi and Dobyns, 2003), but none are comprehensive or widely used. Here we take advantage of a combination of large clinical practices and an expanding knowledge base regarding neuroembryology and developmental biology, structural imaging and molecular genetics to present a comprehensive, yet flexible, system of classification for these collectively common disorders.

This classification system (Table 1) relies most heavily on embryology and genetics, as these comprise the bodies of knowledge that most easily allow relationships among a large group of disorders to be clarified. A similar classification system for malformations of cortical development (Barkovich et al., 2005) has proven useful for both physicians who diagnose and treat patients with these disorders and for clinical scientists who wish to understand better the perturbations of developmental processes that produce them. Importantly, both the classification and its framework remain flexible enough to be easily modified when new embryologic processes are described or new malformations discovered (Barkovich et al., 2005).

Table 1
Overview of developmental and genetic classification of mid-hindbrain malformations

Overview of midbrain and hindbrain development

The central nervous system derives from the dorsal epiblast of the vertebrate embryo, and is induced by a combination of signals originating in the region of Hensen's node at the posterior margin of the early embryo (Wurst and Bally-Cuif, 2001). After many steps, a neural tube is formed that subsequently develops a series of vesicles at its anterior (rostral) end. These three vesicles are designated the prosencephalon or forebrain (which soon divides into diencephalon and telencephalon), the mesencephalon (midbrain), and the rhombencephalon (hindbrain), which divides into the rostral metencephalon (pons and cerebellum) and caudal myelencephalon (medulla oblongata). This differentiation along the anteroposterior axis (also called the rostral-caudal axis) is called patterning, a name given to the early differentiation of the neural tube (Lumsden and Krumlauf, 1996).

The mechanisms that result in early anteroposterior patterning are partially understood (Chambers et al., 2009) and, other than the formation of the diencephalic-mesencephalic boundary and the midbrain-hindbrain boundary (MHB), are beyond the scope of this manuscript. In murine and chick models, the diencephalic-mesencephalic boundary appears to form, at least in part, from interactions between the Pax6, Pax2, En1 and En2 genes. Pax6 confers diencephalic fate by repressing both Pax2 and En1, while En1 represses Pax6 expression in the mesencephalon (Lim and Golden, 2007). Changes in expression of these genes will shift the diencephalic-mesencephalic boundary caudally (more Pax6) or rostrally (more Pax2/En1). Similarly, the location of the MHB is determined by the expression of Otx2 in the caudal midbrain and Gbx2 in the rostral hindbrain; increase or posterior shifts in the expression of Otx2 or decrease in Gbx2 shift the MHB caudally, while decrease in Otx2 or increase or anterior shift in Gbx2 shifts the MHB rostrally (Nakamura et al., 2005). The interaction of Otx2 and Gbx2 also specifies the location of the isthmus organizer (Fig. 1), a critical structure located at the MHB that functions via secreted Wnt and fibroblast growth factor signalling molecules to organize expression of genes and specify cell type (Broccoli et al., 1999; Wurst and Bally-Cuif, 2001): it is essential for normal brainstem and cerebellar development (Sotelo, 2004).

Figure 1
Mid-hindbrain embryonic development. (A) Early neural tube development—e9.5 mouse embryo stained for Lmx1b expression—a transcription factor expressed in many places of the embryo including the isthmic organizer (IsO) a signalling center ...

At the same time that anteroposterior patterning is taking place, an analogous process is occurring along the dorsoventral axis (Fig. 1). Dorsoventral patterning depends on the relative amounts of dorsalizing and ventralizing factors. The most important dorsalizing factors are proteins belonging to the bone morphogenic protein family that are produced by the non-neural ectoderm of the roof plate, while the most important ventralizing factor is sonic hedgehog (Shh) a signalling molecule that emanates from the prechordal plate and floor plate (Tanabe and Jessell, 1996; Wurst and Bally-Cuif, 2001). Along the dorsoventral axis, the mesencephalon is divided into the tegmentum (ventral region) and tectum (dorsal region) while the rostral hindbrain is divided into the pons (ventral region) and the cerebellum (dorsal region). The neuronal subtypes produced in these regions are specified by expression of local Hox genes and other transcription factors (Gaufo et al., 2004) and their targets (Chambers et al., 2009), as well as graded doses of signalling molecules, such as Shh and bone morphogenic protein from the floor and roof plates (Wurst and Bally-Cuif, 2001), all influenced by local organizers especially the isthmic organizer (Fig. 1) (Ye et al., 1998; Chizhikov et al., 2006b; Canning et al., 2007).

Although several of the genes involved in generation of mid- and hindbrain neurons have been discovered (Wang and Zoghbi, 2001; Wang et al., 2005; Sieber et al., 2007), the forces controlling neuronal progenitor proliferation are not as well understood as the timing and location of the proliferation. Many neurons in the posterior fossa are generated in the ventricular zone of the hindbrain, while far more are generated in the rhombic lips, the dorsal-most portion of the hindbrain proliferative neuroepithelium (Fig 1B) (Wingate and Hatten, 1999; Sotelo, 2004). The rhombic lips are separated into the upper (cerebellar) rhombic lip, located at the level of rhombomere 1, and the lower (hindbrain) rhombic lip, located at rhombomeres 2–8 (Fig. 1C) (Landsberg et al., 2005). Some of the neurons produced in the ventricular zone, such as the cerebellar Purkinje cells and other gamma-aminobutyric acid (GABA)-ergic cerebellar neurons, migrate radially in a relatively straightforward manner to their final location (Wang and Zoghbi, 2001). Many rhombic lip derivatives, however, such as the cerebellar granule cells and the so-called ‘precerebellar nuclei’ of the brain stem (i.e. inferior olive, lateral reticular and external cuneate nuclei) migrate along complex pathways, often tangential to the radial neuraxis and sometimes over considerable distances, guided by adhesion molecules, neurotrophins, and repulsive molecules that may be on the surface of cells or in the interstitium (Bourrat and Sotelo, 1990; Wingate and Hatten, 1999; Sotelo, 2004; Bloch-Gallego et al., 2005; Kawauchi et al., 2006; Yamada et al., 2007). Of interest, specific cell types seem to originate from distinct neuroepithelial domains (Fig. 1C). For example, Ptf1a+ domains generate the GABAergic cerebellar Purkinje cells and mossy fibre neurons of the pontine nuclei, lateral reticular nuclei, and external cuneate nuclei (Bermingham et al., 2001), whereas Atoh1+ (also called Math1) domains produce the glutamatergic cerebellar granule cells and climbing fiber neurons of the inferior olivary nuclei (Yamada et al., 2007). It was accepted for many years that deep cerebellar nuclear projection neurons (from the dentate, fastigial, globiform, and emboliform nuclei) are produced in the ventricular zone along with Purkinje cells (for review, see Wang and Zoghbi, 2001), migrating first outward to form a nuclear transitory zone, where they start to differentiate, and then entering a phase of inward migration that takes them to their ultimate position (Altman and Bayer, 1978; 1985). However, recent work suggests that glutamatergic deep cerebellar nuclear projection neurons arise from the rhombic lip, and then migrate rostrally in a subpial stream to the nuclear transitory zone (Fig. 1C) (Wang et al., 2005; Fink et al., 2006). Moreover, recent analysis suggests that all glutamatergic cerebellar neurons (deep nuclear projection neurons, in addition to granule cells, and unipolar brush cells) are produced in the rhombic lips, whereas all GABAergic cerebellar neurons (Purkinje cells and inhibitory interneurons) are produced in the cerebellar ventricular zone (Englund et al., 2006; Fink et al., 2006).

As in the cerebrum, the final destination of migrating neurons in the developing cerebellar cortex, and their specific neuronal cell fate, depend upon many factors: (i) genetic programming; (ii) disengagement signals at the end of migration; (iii) molecular signals received from the surrounding cellular milieu after termination of migration; and (iv) the establishment of distant and local axonal connections (Sotelo, 2004; Chizhikov et al., 2006b; Englund et al., 2006; Kawauchi et al., 2006; Leto et al., 2006; Porcionatto, 2006; Weisheit et al., 2006). The later parts of this process, including final positioning within the cortex, development of (axons and) dendrites and synapses, and other changes to form a functionally mature neuron, are termed ‘cortical organization’; this process probably begins during neuronal migration, as the distances are shorter and the pathfinding easier in the less mature brain. Axons of the same pathways can later navigate more simply, by detecting signals emanating from these pioneer axons, a process known as fasciculation (Tessier-Lavigne and Goodman, 1996). As for neuronal migration, pathway selection by axons is oriented by a large variety of short and long range guidance cues distributed along the entire pathway, to which different axons respond differently (Richards et al., 2004). Indeed, the growth cone on the leading process of a migrating neuron in many ways resembles that of a pathfinding axon and the mechanisms of pathfinding are likely to be similar (Hatten, 2002; Gomez and Zheng, 2006; Round and Stein, 2007). Neurons of brain stem nuclei also migrate to their final location. With the exception of the oculomotor (third nerve) nuclei, which derive from the mesencephalon, cranial nerve nuclei are derived from rhombencephalic (hindbrain) neuronal precursors: the fourth nerve from rhombomere 1, fifth nerve from rhombomeres 2–3, sixth nerve from rhombomeres 5–6, and seventh nerve from rhombomeres 4–5 (Trabousli, 2004). Due to their compartmental identity, the neuronal progenitors display programmed migratory behaviors and send axons along defined trajectories to their peripheral targets. While the position of the neural cell progenitors along the anteroposterior axis determines the identity of the nucleus, its sensory or motor function is determined by its position along the dorsoventral axis. Graded expression of Shh, together with Pax6 and Nkx.2.2, along the dorsoventral axis appears to generate domains conducive to either motor (ventral) or sensory (dorsal) cell fate (Trabousli, 2004). Downstream cell fate decisions are regulated by yet other genes. For example, the paired-like homeodomain protein Phox2b is required for the formation of all branchial and visceral, but not somatic, motor neurons in the hindbrain (Pattyn et al., 2000b). Mice lacking Phox2b have early disruption of motor neuron differentiation, with precursors dying in the neuroepithelium or not switching on postmitotic markers that allow later differentiation (Pattyn et al., 2000b). The last stages of cortical organization continue into the postnatal period; indeed, the last migrations of granule cells from the transient external granular layer into the definitive granular layer of the cerebellar cortex do not occur until the middle of the second postnatal year in humans (Donkelaar et al., 2003). Therefore, a greater overlap of the migration and cortical organization phases occurs in the cerebellum than in the cerebrum, and some anomalies of the cerebellar cortex may develop quite late in gestation or even, possibly, after birth. From a conceptual point of view, it is useful to keep these two phases of cerebellar development separate even though they are not (yet) separated in the classification system.

Framework of the classification

In constructing this classification, we used known embryologic, genetic, imaging, and pathophysiologic information from the literature plus information acquired from our own patients and laboratory work. Whenever the genetics/embryology of the disorder was well enough understood, we have classified disorders primarily by genotype (ultimately, we would hope that the entire classification will be arranged this way); when the genetics/embryology was incomplete, we classified by clinico-radiologic phenotype. Recognizing that humans have differences from other animals in all of these areas, we have specified when using chick, murine, or zebra fish-derived data in both our tables and in the text. The first step was to use fundamental embryology in order to separate localized MHB malformations due to early defects in anteroposterior and dorsoventral patterning or mis-specification of cell proliferation zones in the MHB, from malformations that result from later events such as axonal pathfinding and neuronal migration (or disruptions). We next considered existing knowledge regarding MHB malformations associated with more widespread developmental disorders affecting forebrain structures and those restricted to regions derived from the midbrain or hindbrain; we separated these two large groups and then classified them according to the underlying processes involved. When the associated genes and proteins, or their functions, were known, this information was included and used as part of the classification process. Recognizing that we have only limited knowledge regarding the pathogenesis of many brainstem and cerebellar malformations, among which are some of the most common and best known, the malformations were classified in the most likely category according to our current knowledge. The flexibility of the system allows the disorders to be reclassified as our knowledge of underlying genetics and embryology progresses. This leaves a few rare disorders with evidence for both prenatal origin and disease progression, which we place in the last group. On the basis of these considerations, we propose to separate midbrain-hindbrain malformations into the following four major groups.

  1. Malformations secondary to early anteroposterior and dorsoventral patterning defects, or to misspecification of mid-hindbrain germinal zones.
  2. Malformations associated with later generalized developmental disorders that significantly affect the brainstem and cerebellum (and have a pathogenesis that is at least partly understood).
  3. Localized brain malformations that significantly affect the brain stem and cerebellum (pathogenesis partly or largely understood, includes local proliferation, migration and axonal guidance).
  4. Combined hypoplasia and atrophy in putative prenatal onset degenerative disorders.

These groups will form the framework of the new classification and, wherever possible, will contain those disorders known, or expected to, result from developmental aberrations during a particular process. These groups differ substantially from those used in previously proposed classifications of cerebellar malformations (including ours), which were largely based on the anatomic regions involved (Parisi and Dobyns, 2003) or the end result morphologic appearance of the malformation (Patel and Barkovich, 2002). They also differ from classifications of cortical malformations based on embryology and genetics (Barkovich et al., 2005), largely because the embryology of the midbrain and hindbrain, and the morphologic consequences of disturbing the normal embryologic processes, are currently not as well defined. As with previous classifications based on embryology and genetics, this classification integrates previous and novel findings, provides a comprehensive view of all major midbrain and hindbrain structures, and has the possibility to expand to accommodate new discoveries. Additional strengths of this system are its flexibility and the understanding it renders to those using it. There is flexibility both in the framework of the classification and in the distribution of malformations within each group: either can be changed as our knowledge of the malformation, its cause, or of the processes involved in midbrain-hindbrain development, change. Ultimately, as in a similar genetic/embryologic classification of malformations of cortical development (Barkovich et al., 2005), we expect that this classification will evolve into a system that almost exclusively uses embryology and genetics as the bases for classification, with clinical phenotypes as subcategories listed under the major categories that are the causative genes and the pathways or networks in which their protein products participate.

Justification of classification

Group I. Malformations secondary to early patterning defects

Malformations secondary to early patterning defects include those with abnormalities of anteroposterior or dorsoventral segmentation of the brainstem (Table 2), and are often associated with cerebellar anomalies. Malformations isolated to the cerebellum are not included here, as (in concept) the malformations in this group involve processes that predate formation of the cerebellar anlage. Malformations of this type are well known in animal models, and have been suspected in humans. However, techniques of brain imaging have only recently advanced to a point where thin section, high resolution volumetric data can be acquired in clinically feasible time slots. This has allowed high quality images of the brainstem to be produced in multiple planes and greatly facilitates the identification of morphologic abnormalities. In addition, improvements in diffusion tensor imaging have allowed production of colour fractional anisotropy maps of the brain stem, giving information about the morphology and location of the larger axonal pathways (Sicotte et al., 2006; Widjaja et al., 2006; Jissendi-Tchofo et al., 2009). With the advantage of these tools, malformations are more easily identified; many were reviewed in a recent publication (Barkovich et al., 2007).

Table 2
Group I. Malformations secondary to early anteroposterior and dorsoventral patterning defects, or to misspecification of mid-hindbrain germinal zones

The first subgroup of Group I is composed of disorders of anteroposterior segmentation, in which there is gain, loss, or transformation of segments at boundaries between sections of the neural tube, such as the diencephalic-midbrain boundary (Group I.A.1) or midbrain-rhombomere 1 boundary (Group I.A.2). For example, the combination of a shortened midbrain and enlarged pons associated with enlarged anterior vermis (Fig. 2) presumably results from either loss of midbrain, gain of rhombomere 1, or both. Similar rostral displacement of the MHB results from increased Gbx2 expression or reduced Otx2 expression in mouse and chick models (Nakamura and Watanabe, 2005; Waters and Lewandoski 2006), producing an enlarged rhombomere 1, especially anteriorly, and consequently an enlarged anterior vermis (Sgaier et al., 2005). Elongation of the medulla with shortening of the pons (Fig. 3) is postulated to result from mixed gains and losses of pons or medulla (I.A.3.c) or a segmental shift (I.A.3.d). Similar abnormalities result from murine embryo exposure to retinoic acid, which causes a dose-dependent anterior to posterior transformation of cell fate in which the hindbrain is expanded at the expense of the midbrain and forebrain (Lumsden, 2004). Lesser changes in retinoic acid gradient or other regionalizing molecules could result in transformations of the middle rhombomeres from pontine to medullary fate.

Figure 2
Defect of anteroposterior patterning. Sagittal T1-weighted magnetic resonance image shows a short midbrain and elongated pons. Note the enlarged superior cerebellar vermis (arrows). These findings suggest alteration of caudal mesencephalon to rostral ...
Figure 3
Elongation of the medulla with shortening of the pons. Sagittal T1-weighted image shows a long midbrain and shortened pons. The tectum is dysmorphic and the cerebellum is dysmorphic and small. These findings suggest alteration of rostral rhombencephalon ...

The authors have observed several malformations in humans that suggest a posterior to anterior transformation at the diencephalon-mesencephalon junction. Shortening and thickening of the midbrain with midline (mesencephalic) cleft has been described as a malformation of unknown cause (Barkovich et al., 2007). But close inspection of imaging studies shows extension of the third ventricle and other diencephalic features into the upper part of the thickened midbrain (Fig. 4). This is interpreted as a putative posterior to anterior transformation of mesencephalon into diencephalon that results in caudal expansion of the diencephalon (I.A.1.c). A similar malformation has been described in mouse models with overexpression of Pax6 in the diencephalon and underexpression of En1/Pax2 in the anterior mesencephalon (Nakamura and Watanabe, 2005; Lim and Golden, 2007). Other patients have been described with elongated midbrain and medulla with short pons (Barkovich et al., 2007); classification is difficult in such cases. Further understanding of such patients awaits identification of genes and animal models.

Figure 4
Abnormality of diencephalic-mesencephalic junction. (A) Sagittal T1-weighted image shows a thick midbrain (arrows) and a poorly-defined junction between the midbrain and the diencephalon. (B) Axial T2-weighted image shows that the hypothalamus and midbrain ...

Defects in dorsoventral patterning are herein postulated to result in abnormal development or function of specific mid-hindbrain ventricular zones and structures derived from them, including abnormal formation of brain stem nuclei, cranial nerves, or any cerebellar structures (Section I.B). For example, abnormal development of the superior rhombic lip may cause diffuse granule cell hypoplasia (Group I.B.2.b) while abnormal development of the cerebellar ventricular zone due to mutation of the PTF1A gene causes cerebellar (and pancreatic) agenesis (Group I.B.2.c) (Sellick et al., 2004; Hoshino et al., 2005) and defects of the basal ventricular zone result in defects of specific cranial nerve nuclei such as the abducens and facial nerves (Section II.B.3.b) (Al-Baradie et al., 2002; Michielse et al., 2006). [Note that diffuse granule cell hypoplasia may, in fact be better classified as congenital disorder of glycosylation (CDG) type 1a (IV.B), as suggested by Pascual-Castroviejo et al. (2006). It is temporarily included in both categories.] The Ptf1a gene encodes a basic helix-loop-helix transcription factor that has been shown to be expressed in progenitor cells in the ventricular zone of the dorsal aspect or rhombomere 1; the protein product is required for the generation of GABAergic cells (Purkinje cells and interneurons) in the cerebellum (Hoshino et al., 2005), neurons of the inferior olivary nuclei (Yamada et al., 2007), and specification of dorsal interneurons in the spinal cord (Glasgow et al., 2005). [It is also necessary for the specification and formation of the pancreas (Hoshino et al., 2005).] The number of granule cells generated is extremely reduced when Purkinje cells are not located in their normal position and in normal numbers (Wetts and Herrup, 1982; Sotelo, 2004). In animal models, Purkinje cells regulate proliferation of granule cell precursors via secretion of Shh, perhaps by upregulation of Nmyc (Wallace, 1999; Kenney et al., 2003; Hoshino, 2006). Granule cells are reduced in number by any process that reduces the number of viable Purkinje cells. Thus, just as accentuated apoptosis can cause cerebral hypoplasia, it causes cerebellar hypoplasia, as well (Kaindl et al., 2006; Takano et al., 2006). In humans, mutations of PTF1A result in profound cerebellar hypoplasia (Fig. 5) (Sellick et al., 2004; Hoshino et al., 2005). It will probably take time for all of the precise causes of cerebellar hypoplasia to become fully elucidated; as these causes become better understood, this classification can be appropriately modified.

Figure 5
Profound cerebellar hypoplasia due to PTF1A mutation. (A) Sagittal T1-weighted image shows an extremely small cerebellar vermis (small arrow) and small posterior fossa with low tentorium (arrows) and occipital lobes. (B) Axial T2-weighted image shows ...

Several reports have described seven patients in whom the superior portion of the brain stem is connected to the inferior portion of the brain stem by a thin cord of tissue (Mamourian and Miller, 1994; Sarnat et al., 2002; Bednarek et al., 2005; McCann et al., 2005; Poretti et al., 2007b; Barth et al., 2008); these have been referred to as brain stem ‘disconnection syndromes’. In three of the patients, the disconnection was in the lower midbrain/upper pons (I.A.2.b) and in four it was in the lower pons/upper medulla (I.A.3.b, Fig. 6). Neuropathological analysis of two cases by Sarnat et al. (2002) showed a thin midline cord passing from the upper segment to the lower segment with hypoplasia of the cerebellar vermis and hemispheres and an anomalous basilar artery. Histological investigation revealed a poorly organized mixture of neurons in the tegmentum, but no evidence of any gliotic lesions to suggest hypoxia or ischaemia; this was interpreted as providing evidence in favour of a brain stem malformation, rather than a disruption (Sarnat et al., 2002). In contrast, Barth et al. (2008) found central cavitation that they interpreted as more of a syrinx and postulated a vascular cause. It is, indeed, possible that some ‘disconnection’ syndromes might be described as examples of segmental dysgenesis in which segments of the midbrain and hindbrain do not develop normally, perhaps as a result of malexpression of the genes that are responsible for segmentation. One of the authors has seen a case of disconnection syndrome associated with periventricular nodular heterotopia, a finding that supports a genetic aetiology. In avian and murine models, the formation of the rhombomeres is closely related to expression of Hox genes, a set of chromosomally clustered genes whose close relatives are known to specify positional values along the main body axis of the fly embryo (Lumsden, 2004). In avian models, the loss of Hoxa1 function, for example, results in deletion of rhombomere 5, reduction of rhombomere 4, and loss of specific neuronal nuclei (I.A.3.c.) (Mark et al., 1993). Another possibility is that disruption of the upstream modulators of Hox genes, such as Krox20 and Mafb, may be responsible for these disconnections (Lumsden, 2004). However, in animal models, deletion of a rhombomere results in a shortened brain stem, but not in a ‘gap’ within the brain stem (Lumsden, 2004). In addition, it is important to remember that early vascular disruptions in the brain result in tissue liquefaction without glial response. Thus, gliosis would not be expected from an early segmental injury, and so an early vascular or toxic injury to the brain stem might be more likely. Further work with animal models or identification of families with these malformations may help to further elucidate these mechanisms.

Figure 6
Hindbrain disconnection syndrome. Sagittal T2-weighted image shows nearly complete absence of the medulla, with only a few fibres (arrows) appearing to connect the somewhat small pons to the spinal cord. Controversy exists concerning the cause (genetic ...

In mouse models, absence of several cranial nerves has resulted from abnormal expression of anteroposterior patterning genes (I.A.3.c), including Wnt1 (trigeminal nerve), Gbx2 (trigeminal nerve), Hoxb1 (loss of facial motoneurons, absent facial nerve), Hoxb2 (absent facial nerve), and Hoxa3 (hypoplasia of IXth cranial ganglia) (Cordes, 2001; ten Donkelaar et al., 2006). In Krox20−/− mice, rhombomeres 3 and 5 do not develop, the abducens nucleus and the visceromotor component of the facial nerve are absent, and the axons of trigeminal motoneurons join the facial nerve and enter the second pharyngeal arch (Schneider-Maunoury et al., 1997). These axons do not find the muscles of mastication (their proper targets), so the parent motoneurons undergo apoptosis (Schneider-Maunoury et al., 1997). It is likely that some mutations of the corresponding human genes will eventually be found in patients with congenital cranial neuropathies.

Segmental shifts in the brain stem are also present in humans with Athabaskan brainstem dysgenesis syndrome (seen in Native American tribes) and Bosley-Salih-Alorainy syndrome (observed in Saudi and Turkish families), both caused by homozygosity for mutations of Hoxa1 (Bosley et al., 2008), resulting in horizontal gaze abnormalities, hearing loss, facial weakness, hypoventilation, mental retardation and autism spectrum disorder (Tischfield et al., 2005). Anomalies of the vascular system and the inner ear may be seen as well (Tischfield et al., 2005).

Group II. Generalized brain malformations that significantly affect the brain stem and cerebellum

Malformations in Group II are best classified as generalized brain disorders but involvement of the midbrain and hindbrain is so significant that they need to be included in this classification. Some of these disorders affect cell proliferation, others are believed to primarily affect cell migration, while still others are associated with defects in ciliary proteins and, therefore, probably affect cell migration, axon navigation, and possibly other aspects of brain development.

The first group in this section (Group II.A, Table 3) is mid-hindbrain malformations in association with developmental encephalopathies, a term used to describe mental retardation, autism-spectrum disorders, Rett syndrome, and other similar disorders. For example, a number of families with mental retardation or autism and nonprogressive cerebellar hypoplasia (Illarioshkin et al., 1996; Illarioshkin et al., 1999; Gardner et al., 2001; Tsao et al., 2006; Ventura et al., 2006) or isolated vermian hypoplasia (Courchesne et al., 1988; Carper and Courchesne, 2000; Bergmann et al., 2003; Philip et al., 2003; van Amelsvoort et al., 2004; Zinkstok and van Amelsvoort, 2005; Bish et al., 2006; Boland et al., 2007; Hill et al., 2007; Poot et al., 2007; van Bon et al., 2008; Webb et al., 2009) have been described, including some with mutations of oligophrenin 1 (OPHN1) (Zanni et al., 2005) and one found to have a locus in Xp11.21-q24 (Illarioshkin et al., 1999).

Table 3
Group II.A. Developmental encephalopathies associated with mid-hindbrain malformations (these include mental retardation, autism spectrum disorders, schizophrenia, Rett-like disorders and others)

An important, and only recently described, group is mesenchymal-neuroepithelial signalling defects (Group II.B, Table 4). Work in Forkhead box C1 (Foxc1) knock-out mice has shown that, even though the gene is expressed only in the posterior fossa mesenchyme overlying the cerebellum, absence of Foxc1 deficiency results in cerebellar hypoplasia (Aldinger et al., 2009). In humans, mutations of FOXC1 cause a range of posterior fossa anomalies ranging from vermis predominant cerebellar hypoplasia to mega cisterna magna to Dandy–Walker malformation (Aldinger et al., 2009). Similar ranges of posterior fossa anomalies (Fig. 7) have been described with deletion of 3q24 (loss of ZIC1-ZIC4) (Grinberg and Millen, 2005), duplication of 9p (Melaragno et al., 1992; Cazorla Calleja et al., 2003; Chen et al., 2005), deletion of 13q2 (McCormack et al., 2003; Ballarati et al., 2007), and deletion of 2q36.1 (Jalali et al., 2008), as well as in neurocutaneous melanosis (Kadonaga et al., 1992; Barkovich et al., 1994; Acosta Jr et al., 2005) and PHACES (Posterior fossa malformations, Haemangioma, Arterial anomalies, Cardiac abnormalities/aortic coartation, Eye abnormalities, Sternal cleft defects) syndrome (Frieden et al., 1996; Metry et al., 2001), raising the possibility of significant effects of the developing leptomeninges upon MB-HB development. The finding of malformations of the leptomeninges (arachnoid cysts, mega cisternae magnae, meningoceles), which are derived from cranial mesenchyme, in some of the same families suggests that these malformations belong within the same group (II.B.2).

Figure 7
Dandy–Walker malformations with multiple associated genetic/clinical disorders. All show a small cerebellum and a CSF containing structure that expands the posterior fossa; these seem to result from mutations of genes that affect both leptomeningeal ...
Table 4
Group II.B. Mesenchymal-neurepithelial signalling defects associated with mid-hindbrain malformations

A number of malformations are proposed to result from abnormal cell proliferation (Group II.C, Table 5); these include decreased proliferation, increased proliferation, and proliferation of dysplastic cells. Increased proliferation (Group II.C.2) is very uncommon; it is mainly seen in the macrocephaly-capillary malformation syndrome (Conway et al., 2007), which has many similarities to the megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome and is likely to be closely related to it (Gripp et al., 2009). Both have overgrowth of cerebral and cerebellar hemispheres that often result in cerebellar tonsillar herniation and sometimes Chiari 1 malformation. Proliferation of abnormal cells (Group II.C.1) predominantly results in focal areas of overgrowth containing dysplastic cells. Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease) and cerebellar cortical hamartomas (of tuberous sclerosis) are both mass-like disorders that are composed of dysplastic, rather than neoplastic, cells and are, therefore, included in this section. Lhermitte-Duclos is characterized pathologically by enlarged, circumscribed cerebellar folia containing large ganglion cells in the granular cell layer and prominent myelinated tracts in the outer molecular layer. However, the histology is variable, ranging from a recognizable granular cell layer containing occasional large dysplastic neuronal cell bodies, to an unrecognizable granular layer occupied by a population of large nerve cell bodies between the molecular layer and internal white matter (Ambler et al., 1969). The hypertrophic granule cells express neurofilament protein in a manner similar to Purkinje cells, and it has been postulated that the increased expression of neurofilament proteins by the cerebellar granule cells may account for their hypertrophy and subsequent axonal enlargement leading to myelination within the molecular layer of the cerebellar cortex (Yachnis et al., 1988). Nearly 50% of cases are associated with Cowden syndrome, an autosomal dominant syndrome caused by mutations of the PTEN gene at 10q23.31, and characterized by multiple hamartomas throughout the body (Marsh et al., 1999). Cortical tubers of tuberous sclerosis, caused by mutations of either the TSC1 (at 9q34) or TSC2 (at 16p13) gene are composed of a coarse subpial gliosis, abnormal cortical lamination with many large, abnormal, often multinucleated cells, and multiple heterotopic subcortical neurons (Norman et al., 1995); the finding of cerebellar tubers is common (Eluvathingal et al., 2006). The effect of these cerebellar lesions upon outcome is not understood. Hemimegalencephaly is a poorly understood malformation of cerebral cortical development, composed of dysmorphic cells (both neuronal and glial) that are often in abnormal locations (Robain and Gelot, 1996; Flores-Sarnat, 2002; Flores-Sarnat et al., 2003). This most often occurs as an isolated malformation, but may be associated with epidermal nevus (linear nevus sebaceous of Jadasohn) or other neurocutaneous syndromes (Peserico et al., 1988; Pavone et al., 1991; Pelayo et al., 1994; Griffiths et al., 1994), or with tuberous sclerosis (Griffiths et al., 1998; Galluzzi et al., 2002) or other phakomatoses (Cusmai et al., 1990; Dhamecha and Edwards-Brown, 2001). The reason for the presence of ipsilateral cerebellar hemispheric enlargement and dysplasia in some cases (Sener, 1997) is even more poorly understood.

Table 5
Group II.C. Malformations of neuronal and glial proliferation that prominently affect the brainstem and cerebellum

Microcephalies with (disproportionately) decreased cerebellar cell proliferation (Group II.C.3) mostly have autosomal recessive inheritance (Albrecht et al., 1993; Sztriha et al., 1998; Hashimoto et al., 1998; Rajab et al., 2003) [although CASK mutations cause microcephaly with disproportionate cerebellar hypoplasia via X-linked inheritance (Najm et al., 2008)]. Many patients with developmental microcephaly (in contrast to those with acquired microcephaly) have cerebella that are proportionally small when compared to the cerebrum (Fig. 8) (Barkovich et al., 1998; Bellini et al., 2002; Kelley et al., 2002; Sheen et al., 2004; Chandler et al., 2006), suggesting that many of the same processes controlling cell proliferation or apoptosis apply in both the supra- and infratentorial compartments. Other patients with microcephaly (Hoveyda et al., 1999; Hoshino et al., 2005; Sztriha et al., 2005; Sztriha and Johansen, 2005) and some with normal head size (Patel and Barkovich, 2002) have disproportionately small cerebella, suggesting that developmental processes differ in the supra- and infratentorial compartments.

Figure 8
Microcephaly with disproportionate midbrain-hindbrain hypoplasia. Sagittal T1-weighted image in a microcephalic neonate shows disproportionately small brainstem and cerebellum.

Many other malformations of cortical development are associated with MB-HB developmental abnormalities (Table 6), including lissencephalies (Group II.D.1), cerebral heterotopia (Group II.D.2), cerebral polymicrogyria (Group II.D.3), and cobblestone-like malformations with defects of the pial basement membrane (Group II.D.4). The association of cerebellar hypoplasia with cerebral heterotopia and polymicrogyria is not understood. The reason for cerebellar hypoplasia associated with lissencephaly (Ross et al., 2001), even when head size is normal, is not always known; as discussed in the previous section, some pathways and processes that are more involved in cerebellar than cerebral development are affected in these cases. Alternatively, the cerebellar hypoplasia may result from associated Purkinje cell involvement, or failure of connection of Purkinje cells with granule cells, causing subsequent apoptosis of the granule cells. In DCX and LIS1 mutations, the cerebellar hypoplasia is inconsistent and, when present, is rather mild (Ross et al., 2001). It is more consistently seen in DCX mutations rather than in LIS1 mutations (unpublished results), and is severe in a significant number of patients with TUBA1A mutations (Bahi-Buisson et al., 2008; Fallet-Bianco et al., 2008; Morris-Rosendahl et al., 2008). The mid-hindbrain is particularly severely affected in patients with RELN and VLDLR associated cortical malformations (Group II.D.1.b), in which the brain stem shows malpositioning of neurons (Nishikawa et al., 2003) and the cerebellum is extraordinarily small and smooth (nearly afoliar, Fig. 9) (Hong et al., 2000; Boycott et al., 2005). Reelin is a secreted glycoprotein that regulates neuronal positioning in cortical brain structures and the migration of neurons along the radial glial fibre network by binding to lipoprotein receptors VLDLR (very low density lipoprotein receptor) and APOER2 (apolipoprotein E receptor 2, or low density lipoprotein receptor-related protein 8) and the adapter protein disabled-1 (DAB1) (Hiesberger et al., 1999). In the cerebellum, Reelin regulates Purkinje cell alignment (Miyata et al., 1997) and granule cell proliferation (Wechsler-Reya and Scott, 1999), which are necessary for the formation of a normal sized cerebellum, as well as a well-defined cortical plate through which granule cells migrate to form the internal granular layer (Rakic and Sidman, 1970). Although both protein products function in the same pathway, RELN mutations seem to have a more severe effect than VLDLR mutations on both the cerebral and cerebellar malformations. The reason for the difference is not known at this time, although it is probably related to the fact that reelin has multiple other receptors, including ApoER2, that result in different downstream effects and that these effects differ in the mid- and hindbrain compared to the forebrain (Gressens, 2006; Hack et al., 2007).

Figure 9
Cerebellar and pontine hypoplasia secondary to VLDLR mutation. Sagittal T1-weighted image shows cerebral pachygyria and a very small, smooth cerebellum (arrows), characteristic of mutations involving the RELN pathway. The pons is always small with developmental ...
Table 6
Group II.D. Malformation of neuronal migration that prominently affect the brainstem and cerebellum

The so-called dystroglycanopathies (Group II.D.4), believed to be caused by impaired O-mannosylation of α-dystroglycan (Moore et al., 2002; Beltran-Valero de Bernabe et al., 2004; van Reeuwijk et al., 2005; Kanagawa and Toda, 2006; Saito et al., 2006; Martin, 2007), are associated with congenital muscular dystrophy and variable eye and brain anomalies. The brain abnormalities are sometimes called cobblestone malformation and involve the cerebrum, brain stem, and cerebellum. In these disorders, abnormal O-glycosylation of α-dystroglycan in the basal lamina of the pial basement membrane is postulated to result in abnormal fusion of the endfeet of radial glial cells with the basal lamina and gaps in the pial basement membrane; migrating neurons do not receive proper ‘stop’ signals and overmigrate into the subpial space (van Reeuwijk et al., 2005, 2006; Kanagawa and Toda, 2006; Saito et al., 2006; Martin, 2007). In the cerebellum, affected patients have variable degrees of dysmorphism, ranging from abnormal cortical foliation with a few cortical/subcortical cysts (Fig. 10) to profound cerebellar hypoplasia and dysmorphism with greater involvement of the vermis than the hemispheres (Fig. 11). The malformation may be related to disturbances in the external granule cell layer (Henion et al., 2003). The brain stem is affected in nearly all patients, manifesting enlarged quadrigeminal plates, fusion of the colliculi, and hypoplasia of the pons, often with a longitudinal ventral midline pontine cleft (Figs 10 and and11)11) (Barkovich et al., 2007). The small pons with midline cleft may be caused by hypoplasia of the middle cerebellar peduncles resulting in hypoplasia of their decussation; another component of the pontine hypoplasia may relate to impaired tangential migration of pontine nuclear neurons as shown in murine models of Large mutations (Qu et al., 2006). Thus, as in the cerebral hemispheres, the midbrain-hindbrain disorder appears to be the result of both abnormal neuronal migration and abnormal formation of white matter tracts. We know of several similar malformations associated with subtle differences in both the glycosylation defects and the clinical phenotype (Group II.D.4.b), including those due to mutations of GPR56 [often called bilateral frontoparietal polymicrogyria (Chang et al., 2003)], ATP6V0A2 [associated with Debré type cutis laxa (Kornak et al., 2008; Van Maldergem et al., 2008)], and SNAP29 [which is associated with cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma (CEDNIK) syndrome (Sprecher et al., 2005)]. Recent work shows that G protein-coupled receptor (GPR) 56 has a role in the organization of the pial basement membrane and in the regulation of anchorage of radial glial endfeet (Li et al., 2008). GPR56 mutations affect cerebral cortical development by causing breaches in the pial basement membrane, thus allowing overmigration of neurons into the subpial space and resulting in a cobblestone-like malformation (Li et al., 2008). In the cerebellum, mouse models demonstrate that granule cells show loss of adhesion to extracellular matrix molecules of the pial basement membrane (Koirala et al., 2009). Both of these mechanisms are similar to what is seen in the dystroglycanopathies.

Figure 10
Midbrain and hindbrain malformations in mild dystroglycanopathy (muscle-eye-brain phenotype) due to POMT1 mutation. (A) Sagittal T1-weighted image shows abnormal vermian foliation, large, abnormally rounded quadrigeminal plate (small arrows) and flattened ...
Figure 11
Midbrain and hindbrain malformations in severe dystroglycanopathy (Walker-Warburg phenotype). (A). Sagittal T1-weighted image shows massive hydrocephalus, a very small, dysplastic vermis (small arrowheads), large, round tectum (small arrows) and small, ...

Group II.E consists of disorders known as Joubert syndrome and related disorders [JSRD; see Table 7 (Joubert et al., 1969; Boltshauser and Isler, 1977; Gleeson et al., 2004; Zaki et al., 2007), also called molar tooth malformations (Quisling et al., 1999)]. These disorders have abnormalities of white matter tracts in the brain stem and abnormal superior cerebellar peduncles (Fig. 12) as well as dysplasia of the cerebellar vermis and, often, accompanying abnormalities of the eyes (retinal dysplasia or colobomas), kidneys (nephronophthisis), limbs (preaxial, mesaxial, or postaxial polydactyly), liver (fibrosis), orofacial deformities, and other central nervous system anomalies (including occipital encephaloceles and cerebral polymicrogyria) (Zaki et al., 2007). Zaki et al. (2008) have suggested a classification of these disorders based upon the associated anomalies, which we have adopted. JSRD seem to be caused by mutations of genes encoding ciliary and centrosomal proteins (Keeler et al., 2003; Valente et al., 2003; 2006a, b; Gleeson et al., 2004; Parisi et al., 2004; Louie and Gleeson, 2005; Badano et al., 2006; Sayer et al., 2006; Brancati et al., 2007; 2008; 2009; Baala et al., 2007b; Delous et al., 2007; Frank et al., 2008; Gorden et al., 2008). A consistent overlap between JSRD and Meckel-Gruber syndrome—an autosomal recessive and genetically heterogeneous lethal disorder characterized by a combination of renal cysts and other variable features including developmental anomalies of the central nervous system (typically occipital encephalocele), hepatic ductal dysplasia and cysts, and polydactyly (Baala et al., 2007b; Delous et al., 2007; Frank et al., 2008)—has been recognized, which is supported by discovery of mutations in several of the same genes. Thus, the two disorders represent different points along a single spectrum of malformations (Baala et al., 2007b; Delous et al., 2007; Frank et al., 2008). Although the precise mechanisms by which these mutations affect brain development are only starting to be elucidated (Arts et al., 2007; Chizhikov et al., 2007; Delous et al., 2007; Frank et al., 2008), it has been postulated that ciliary and centrosomal proteins may interact to respond to extracellular signalling or modulatory cues in renal and retinal homeostasis and in neuronal development (Louie and Gleeson, 2005; Badano et al., 2006; Valente et al., 2006b). Alteration of centrosomal dynamics can alter neuronal migration (Sapir et al., 2008), which may explain the severe vermian hypoplasia seen in affected patients (Quisling et al., 1999; Yachnis and Rorke, 1999). As growth cones of migrating neurons and pathfinding axons are similar, defective ciliary and centrosomal function could explain the aberrant axonal pathways in the midbrain and hindbrain in affected patients (Yachnis and Rorke, 1999; Widjaja et al., 2006; Poretti et al., 2007a).

Figure 12
Molar tooth malformation in patient with ataxia, developmental delay, and nephronophthisis. (A) Sagittal T1-weighted image shows a thin isthmus (large arrows) and a small vermis (small arrows) with abnormal foliation. (B) Axial T2-weighted image shows ...
Table 7
Group II.E. Diffuse molar tooth type dysplasias associated with defects in ciliary proteins

Group III. Regional developmental defects (localized brain malformations that significantly affect the brainstem and cerebellum, pathogenesis partly or largely understood)

Patients in this group (Table 8) have malformations of the brain stem or cerebellum that are localized and manifest clinically with neurological signs that are attributable to one anatomofunctional system rather than diffuse. Most are present from the time of birth, although some may not become evident until childhood.

Table 8
Group III. Localized brain malformations that significantly affect the brainstem and cerebellum (pathogenesis partly or largely understood, includes local proliferation, cell specification, cell migration and axonal guidance)

Developmental clefts are included in this group. These may be seen in the dorsal or ventral midline surface of the pons, particularly in patients with cerebellar hypoplasia or dysplasia, but also in patients with normal cerebella (Barkovich et al., 2007). These are believed to result from impaired pathfinding of axons in the developing brain stem. The most common clefts are ventral longitudinal and midline, involving the pons. These are likely to be due to absence of the decussation of the middle cerebellar peduncles and possibly the transverse pontine axons migrating from the cerebellar cortex to the pontine nuclei. They are often associated with cerebellar hypoplasia, although they are also reported as a manifestation of generalized axonal midline crossing defects; when the midline-crossing defect is more generalized, the corpus callosum is often abnormal (Barkovich et al., 2007). Midline dorsal clefts are thought to result from abnormal development of the median longitudinal fasciculus and the tectospinal tract (Barkovich et al., 2007). The best studied of these is the condition known as horizontal gaze palsy with progressive scoliosis (Group III.A) (Thomsen et al., 1996; Trabousli, 2004; Bosley et al., 2005), a condition caused by mutations of the ROBO3 gene, which codes for a netrin receptor that is required for midline crossing of hindbrain axons (Jen et al., 2004). Affected patients have congenital horizontal gaze palsy and MRI shows quite characteristic brain-stem hypoplasia with absence of the facial colliculi, presence of a deep midline dorsal pontine cleft (split pons sign), and a ‘butterfly’ configuration of the medulla (Fig. 13) (Rossi et al., 2004). Diffusion tensor tractography shows more extensive white matter abnormalities including absence of major pontine crossing axons and absence of decussation of the superior cerebellar peduncles in addition to reduced volume of dorsal longitudinal tracts in the pontine tegmentum (Sicotte et al., 2006), the latter being consistent with reduced volume or absence of the medial lemniscus and median longitudinal fasciculus. A dorsal longitudinal cleft in the midbrain (Group III.B) has been seen by one of the authors in a patient with trisomy 14 (AJB, unpublished observation). Several other brain stem disorders purportedly secondary to abnormal axonal pathfinding have been described (Barkovich et al., 2007). These include the recently reported pontine tegmental cap dysplasia, a malformation in which the ventral pons is hypoplastic due to absence of normal ventral decussation of the middle cerebellar peduncles while a band of horizontally oriented axons is present, instead, along the dorsal surface of the pons (Fig. 14) (Barth et al., 2007b; Jissendi-Tchofo et al., 2009). Other disorders that are presumably due the white matter guidance disruptions in the brain stem have been described recently (Barkovich et al., 2007) and the authors continue to find more, as yet unpublished, brain stem malformations. It is likely that an increasing number will be discovered as the quality of brain imaging improves, with higher field strength magnetic resonance scanners and as diffusion tensor tractographic methods become more robust.

Figure 13
Horizontal gaze palsy with progressive scoliosis secondary to ROBO3 mutation. Axial T2-weighted image shows midline pontine dorsoventral cleft (arrows) caused by lack of midline crossing of axons.
Figure 14
Pontine tegmental cap dysplasia. Sagittal T1-weighted image shows a small ventral pons and a dorsal tegmental ‘cap’ (arrow) that is characteristic of the malformation. Diffusion tensor imaging studies show that the cap is composed of highly ...

Also included in this group are disorders caused by localized abnormalities of cell specification, such as the Duane retraction syndrome [a congenital sixth cranial nerve paralysis caused by deletion of CHN1 (Al-Baradie et al., 2002)], Okihiro syndrome [Duane retraction syndrome with radial ray anomalies and deafness, caused by mutations of SALL4 (Al-Baradie et al., 2002; Kohlhase et al., 2005; Sakaki-Yumoto et al., 2006)], and congenital fibrosis of the extraocular muscles [caused by mutations of PHOX2A (Nakano et al., 2001; Bosley et al., 2006)].

Disorders of cerebellar foliation are poorly understood. They appear to be clinically asymptomatic when minor (abnormal orientation of vermian fissures) but may be associated with developmental delay when more extensive (Demaerel, 2002). Another disorder included in this group is cerebellar heterotopia, formed of clusters of neurons that typically lie within the white matter of a cerebellar hemisphere (Friede, 1989; Norman et al., 1995; Patel and Barkovich, 2002). These are most commonly seen in syndromes (especially trisomy 13) and in association with cerebellar cortical dysplasia (heterotaxias or clefts, see Group IV), but may be seen as isolated anomalies and therefore are included in Group III rather than Group IV.

Group IV. Defects secondary to combined hypoplasia and atrophy in putative prenatal onset degenerative disorders

The final group of defects is composed of progressive disorders in which the cerebellum is already small at birth and subsequently undergoes further atrophy (Table 9). The two best known disorders that fall into this category are the pontocerebellar hypoplasias (PCH) (Barth et al., 1990, 1993; Rajab et al., 2003; Patel et al., 2006; Barth 2007a; Hevner, 2007; Leroy et al., 2007; ) and the congenital disorders of glycosylation (CDG), especially CDG type 1a (CDG1a, formerly known as carbohydrate deficient glycoprotein syndrome) (Kier et al., 1999; de Lonlay et al., 2001; Drouin-Garraud et al., 2001; Freeze, 2001; Miossec-Chauvet et al., 2003; Giurgea et al., 2005). Five types of PCH have been described in the literature, although it now appears that types 2 and 4 may lie along the same continuum, with type 4 having more serious clinical and pathological manifestations (Barth et al., 2007a; Hevner, 2007). All have a small brain stem and cerebellum from birth (Fig. 15), with the vermis relatively less affected than cerebellar hemispheres. Type 1 has spinal motor neuron loss; type 2 is characterized pathologically by normal spinal motor neurons and clinically by chorea/dystonia; type 3 has absence of dyskinesias, optic atrophy, and linkage to chromosome 7q11-21; types 4 and 5 have C-shaped inferior olivary nuclei with relative vermian sparing in type 4 (Hevner, 2007). Although the cerebellar malformation in both PCH and CDG1a are commonly referred to as ‘hypoplasia’, pathologic studies have shown the cerebellum to exhibit a combination of hypoplasia and atrophy (Norman et al., 1995; Pascual-Castroviejo et al., 2006; Barth et al., 2007a). This observation suggests that the causative gene(s) are important both for cerebellar neuronal development and for postmitotic neuronal survival (Hevner, 2007). In support of this concept, the authors have seen sequential MRI studies of several affected patients with PCH and CDG1a in whom the cerebellum was small at birth and underwent further atrophy postnatally. Thus, these disorders are classified in group V.

Figure 15
Pontocerebellar hypoplasia type 1. Sagittal T1-weighted image shows very small brain stem and cerebellum in this hypotonic, encephalopathic neonate. Note prominent cerebellar fissures (arrows), suggesting atrophy that started prenatally.
Table 9
Group IV. Combined hypoplasia and atrophy in putative prenatal onset degenerative disorders

The other major disorders in this group are unilateral cerebellar hypoplasia and cerebellar cortical dysplasia [also called cerebellar polymicrogyria and cerebellar heterotaxia (Friede, 1989; Norman et al., 1995; Soto-Ares et al., 2002; 2004)]. Both disorders are most often detected incidentally on neuroimaging studies for patients with unrelated complaints (Fig. 16) (Boltshauser et al., 1996; Patel and Barkovich, 2002; Kilickesmez et al., 2004; Poretti et al., 2009). If assessed carefully, these patients typically have abnormal foliation (Soto-Ares et al., 2004) or clefts (Poretti et al., 2008) in the affected hemisphere; thus these conditions are considered together. Affected patients are typically asymptomatic or minimally symptomatic and, typically, no associated abnormalities are found elsewhere in the brain (Friede, 1989; Norman et al., 1995; Soto-Ares et al., 2004; Poretti et al., 2008). Familial cases have not been reported and some patients have been found to have associated destructive lesions such as schizencephaly (Poretti et al., 2008). Many authors, therefore, have postulated that these are the result of prenatal injury (Friede, 1989; Norman et al., 1995; Boltshauser et al., 1996; Kilickesmez et al., 2004; Poretti et al., 2008, 2009). In support of this concept, the authors have been referred several cases in which focal cerebellar cortical dysplasia, usually associated with hypoplasia of the affected hemisphere, developed after a second trimester or early third trimester prenatal cerebellar haemorrhage that was detected on routine obstetrical sonography and confirmed by foetal MRI.

Figure 16
Unilateral cerebellar hypoplasia/dysplasia. Axial T1-weighted image shows a small right cerebellar hemisphere with a large cleft (arrows) and abnormal folial pattern. Such lesions are often associated with prenatal cerebral and cerebellar injuries and, ...

Discussion

This classification organizes malformations of the midbrain and hindbrain into a logical system based, as much as possible, upon known embryological events and genetic mutations from work in humans and animal models. As the genetics and embryology of mid-hindbrain development are still being elucidated, this classification is far from complete. Nonetheless, it brings some order to a very difficult and confusing group of malformations and can continue to be used as a framework as our knowledge of developmental process and genetics evolves.

This classification might be criticized for some of the assumptions that have been made in the categories selected. Why are some groups based upon known embryologic processes while others are based upon whether the processes are well localized or not? The answer is that this method of grouping gives maximum flexibility to the classification. As understanding of general processes in hindbrain development increases, the categories can be modified, and as understanding of the pathophysiology of individual disorders increases, those disorders can be moved to more appropriate groups. Why propose a classification now, instead of waiting until the processes are better understood? We contend that the presence of a logical classification is essential to the investigation of disorders. Classifications, even early ones, bring groups of disorders from the realm of chaos, where every case differs from every other case, to science, where the complexity of nature is reduced to a more comprehensible form. Placing a malformation in a certain group will elicit testing to see whether it belongs in that category; if not, the classification is flexible enough that it can be moved to a more appropriate one.

This classification may also be criticized for some of its details, such as the categories to which certain malformations are assigned. Why are some cerebellar hypoplasias included in Group I, while others are in Groups IV? Cerebellar hypoplasia can be the result of many different processes, starting with patterning of the developing neural tube and progressing all the way to increased apoptosis due to abnormal late migration of granule cells [granule cells undergo apoptosis if Purkinje cells have not migrated normally to their end location (Wetts and Herrup, 1982; Wallace, 1999; Kenney et al., 2003; Hoshino, 2006)]. In order to treat the potential causes, malformations with cerebellar hypoplasia need to be ‘split’ based upon the pathophysiology of the hypoplasia. By separating the different types of this disorder, we take the first step in making this complex diagnosis more comprehensible.

How can the authors justify the assumptions they have made in creating this classification? Any useful model is based upon some assumptions. Indeed, Sarnat uses a number of assumptions in assigning malformations to his molecular genetic classification of malformations (Sarnat, 2000). The authors do not claim that this version of the classification system is the last. Undoubtedly, new discoveries in the future will show that some of the disorders included in this classification should be reclassified into another group or, perhaps, a new group. Indeed, 5 years ago no one would have suggested classifying Joubert syndrome as one of a group of multisystemic disorders caused by defects in ciliary proteins. Some disorders that are listed separately may have to be combined, while others that are listed as a single disorder may have to be divided into multiple groups. Discoveries may result in the creation of new groups and elimination of others. Indeed, the framework of the classification will probably need modification as new aspects of mid-hindbrain development are discovered. The strength of this classification system is that it has to flexibility to allow changes in both its framework and its listings with periodic updates as new discoveries necessitate change.

Why do the authors classify some disorders by genotype and others by phenotype? Ultimately, we hope that all malformations will be classified by genotype or disrupted embryologic step. Currently, however, our understanding of the genetic/embryologic causes of many of these disorders is not advanced enough to create such a sophisticated classification. Therefore, we have classified by genotype/embryology those malformations for which the cause is adequately understood; the more poorly understood malformations are classified by clinicoradiologic phenotype. We anticipate that number classified by genotype will increase in subsequent revisions.

Other classification systems of mid-hindbrain or cerebellar malformations have been proposed (Patel and Barkovich, 2002; Parisi and Dobyns, 2003), but have not been widely accepted by practicing neurologists and geneticists, possibly because there was no unifying thread tying together disorders within the same group. This classification attempts to rectify that problem by classifying the malformations according to the underlying processes affected. This allows the classification to grow with the knowledge of embryology and genetics that is the source of its structure. The multitude of recent advances in this understanding has brought the state of the art to the point where this genetic-embryological classification is now feasible.

This classification is not restricted to malformations restricted to the midbrain-hindbrain. To do so would be unrealistic as the developmental processes in the forebrain and mid-hindbrain share so many genes and gene products that it is nearly inevitable that the supratentorial compartment or other organs will be affected in some way when an infratentorial structures develops abnormally. Indeed, in many of these disorders, the supratentorial malformation may be the first one discovered, with the infratentorial malformation only being identified later. Discovery of the infratentorial malformation may allow a more refined classification of the overall malformation complex, however. Indeed, discovery of cerebellar abnormalities similar to those in dystroglycanopathies in patients with GPR56 mutations led to the suggestion that the mutant protein is associated with glycosylation defects (Ke et al., 2008).

In summary, a developmentally based classification of midbrain-hindbrain malformations is proposed in this manuscript in an attempt to organize these disorders for better clinical understanding and guidance of future research. It is hoped that this classification helps to clarify what is known (and what is not) about normal and abnormal development of these structures and that it may help to guide future studies.

Funding

NIH R01 NS058721, R01 NS46432 and R37 NS35129 (to A.J.B.); NIH NS050386 and R56 NS050386 (to K.J.M.); and NIH R01-NS050375 and R01-NS058721 (to W.B.D).

Acknowledgements

The authors would like to thank their many colleagues who shared cases, MRIs, and ideas, thus contributing to the concepts presented in this review.

Glossary

Abbreviations

CDG
congenital disorders of glycosylation
FOXC1
Forkhead box C
GABA
gamma-aminobutyric acid
GPR
G protein-coupled receptor
JSRD
Joubert syndrome and related disorders
LCH
lissencephaly with cerebellar hypoplasia
MHB
midbrain-hindbrain boundary
OPHN
oligophrenin
PCH
pontocerebellar hypoplasias
Shh
sonic hedgehog signalling molecule

References

  • Acosta FL, Jr, Binder DK, Barkovich AJ, Frieden IJ, Gupta N. Neurocutaneous melanosis presenting with hydrocephalus. Case report and review of the literature. J Neurosurg. 2005;102(Suppl 1):96–100. [PubMed]
  • Aicardi J. Aicardi syndrome. Brain Dev. 2005;27:164–71. [PubMed]
  • Aicardi J, Lefebre J, Lerrique-Koechlin A. A new syndrome: spasm in flexion, callosal agenesis, ocular abnormalities. Electroencephalogr Clin Neurophysiol. 1965;19:609–10.
  • Aida N, Yagishita A, Takada K, Katsumata Y. Cerebellar MR in Fukuyama congenital muscular dystrophy: polymicrogyria with cystic lesions. AJNR Am J Neuroradiol. 1994;15:1755–9. [PubMed]
  • Akasaka-Manya K, Manya H, Endo T. Mutations of the POMT1 gene found in patients with Walker-Warburg syndrome lead to a defect of protein O-mannosylation. Biochem Biophys Res Commun. 2004;325:75–9. [PubMed]
  • Al-Baradie R, Yamada K, St Hilaire C, Chan WM, Andrews C, McIntosh N, et al. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet. 2002;71:1195–9. [PubMed]
  • Albrecht S, Schneider MC, Belmont J, Armstrong DL. Fatal infantile encephalopathy with olivopontocerebellar hypoplasia and micrencephaly. Report of three siblings. Acta Neuropathol. 1993;85:394–9. [PubMed]
  • Aldinger KA, Lehmann OJ, Hudgins L, Chizhikov VV, Bassuk AG, Ades LC, et al. FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation. Nat Genet. 2009;41:1037–42. [PMC free article] [PubMed]
  • Altman J, Bayer SA. Prenatal development of the cerebellar system in the rat. I. Cytogenesis and histogenesis of the deep nuclei and the cortex of the cerebellum. J Comp Neurol. 1978;179:23–48. [PubMed]
  • Altman J, Bayer SA. Embryonic development of the rat cerebellum. II. Translocation and regional distribution of the deep neurons. J Comp Neurol. 1985;231:27–41. [PubMed]
  • Ambler M, Pogacar S, Sidman R. Lhermitte-Duclos disease (granule cell hypertrophy of the cerebellum): pathological analysis of the first familial case. J Neuropathol Exp Neurol. 1969;28:622–47. [PubMed]
  • Amiel J, Laudier B, Attie-Bitach T, Trang H, de Pontual L, Gener B, et al. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet. 2003;33:459–61. [PubMed]
  • Aronica E, van Kempen AAMW, van der Heide M, Poll-The BT, van Slooten HJ, Troost D, et al. Congenital disorder of glycosylation type Ia: a clinicopathological report of a newborn infant with cerebellar pathology. Acta Neuropathologica. 2005;109:433–42. [PubMed]
  • Arts HH, Doherty D, van Beersum SEC, Parisi MA, Letteboer SJF, Gorden NT, et al. Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome. Nat Genet. 2007;39:882–8. [PubMed]
  • Baala L, Briault S, Etchevers HC, Laumonnier F, Natiq A, Amiel J, et al. Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis. Nat Genet. 2007;39:454–6. [PubMed]
  • Baala L, Romano S, Khaddour R, Saunier S, Smith UM, Audollent S, et al. The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am J Hum Genet. 2007;80:186–94. [PubMed]
  • Bachetti T, Matera I, Borghini S, Di Duca M, Ravazzolo R, Ceccherini I. Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome. Hum Mol Genet. 2005;14:1815–24. [PubMed]
  • Backman SA, Stambolic V, Suzuki A, Haight J, Elia A, Pretorius J, et al. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet. 2001;29:396–403. [PubMed]
  • Badano JL, Mitsuma N, Beales PL, Katsanis N. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet. 2006;7:125–48. [PubMed]
  • Bahi-Buisson N, Poirier K, Boddaert N, Saillour Y, Castelnau L, Philip N, et al. Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations. J Med Genet. 2008;45:647–53. [PubMed]
  • Ballarati L, Rossi E, Bonati MT, Gimelli S, Maraschio P, Finelli P, et al. 13q Deletion and central nervous system anomalies: further insights from karyotype-phenotype analyses of 14 patients. J Med Genet. 2007;44:e60. [PMC free article] [PubMed]
  • Barkovich A, Frieden I, Williams M. MR of neurocutaneous melanosis. AJNR Am J Neuroradiol. 1994;15:859–67. [PubMed]
  • Barkovich AJ. Neuroimaging manifestations and classification of congenital muscular dystrophies. AJNR Am J Neuroradiol. 1998;19:1389–96. [PubMed]
  • Barkovich AJ. Morphologic characteristics of subcortical heterotopia: MR imaging study. AJNR Am J Neuroradiol. 2000;21:290–5. [PubMed]
  • Barkovich AJ, Millen KJ, Dobyns WB. A developmental classification of malformations of the brainstem. Annals of Neurology. 2007;62:625–39. [PubMed]
  • Barkovich AJ, Kjos BO, Norman D, Edwards MSB. Revised classification of posterior fossa cysts and cyst-like malformations based on results of multiplanar MR imaging. AJNR Am J Neuroradiol. 1989;10:977–88. [PubMed]
  • Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB. A developmental and genetic classification for malformations of cortical development. Neurology. 2005;65:1873–87. [PubMed]
  • Barkovich AJ, Ferriero DM, Barr RM, Gressens P, Dobyns WB, Truwit CL, et al. Microlissencephaly: a heterogeneous malformation of cortical development. Neuropediatrics. 1998;29:113–9. [PubMed]
  • Barth PG. Pontocerebellar hypoplasias: an overview of a group of inherited neurodegenerative disorders with fetal onset. Brain Dev. 1993;15:411–22. [PubMed]
  • Barth PG. Pontocerebellar hypoplasia–how many types? Eur J Paediatr Neurol. 2000;4:161–2. [PubMed]
  • Barth PG, de Vries L, Nikkels PG, Troost D. Congenital brainstem disconnection associated with a syrinx of the brainstem. Neuropediatrics. 2008;39:1–7. [PubMed]
  • Barth PG, Vrensen GF, Uylings HB, Oorthuys JW, Stam FC. Inherited syndrome of microcephaly, dyskinesia and pontocerebellar hypoplasia: a systemic atrophy with early onset. J Neurol Sci. 1990;97:25–42. [PubMed]
  • Barth PG, Blennow G, Lenard H-G, Begeer JH, van der Kley JM, Hanefeld F, et al. The syndrome of autosomal recessive pontocerebellar hypoplasia, microcephaly and extrapyramidal dyskinesia (pontocerebellar hypoplasia type 2): compiled data from 10 pedigrees. Neurology. 1995;45:311–7. [PubMed]
  • Barth PG, Aronica E, de Vries L, Nikkels P, Scheper W, Hoozemans J, et al. Pontocerebellar hypoplasia type 2: a neuropathological update. Acta Neuropathologica. 2007;114:373–86. [PMC free article] [PubMed]
  • Barth PG, Majoie CB, Caan MWA, Weterman MAJ, Kyllerman M, Smit LME, et al. Pontine tegmental cap dysplasia: a novel brain malformation with a defect in axonal guidance. Brain. 2007;130:2258–66. [PubMed]
  • Bednarek N, Scavarda D, Mesmin F, Sabouraud P, Motte J, Morville P. Midbrain disconnection: an aetiology of severe central neonatal hypotonia. Eur J Paediatr Neurol. 2005;9:419–22. [PubMed]
  • Bellini C, Mazzella M, Arioni C, Fondelli MP, Serra G. 'Apple-peel' intestinal atresia, ocular anomalies, and microcephaly syndrome: brain magnetic resonance imaging study. Am J Med Genet. 2002;110:176–8. [PubMed]
  • Beltran-Valero de Bernabe D, van Bokhoven H, van Beusekom E, Van den Akker W, Kant S, Dobyns WB, et al. A homozygous nonsense mutation in the fukutin gene causes a Walker-Warburg syndrome phenotype. J Med Genet. 2003;40:845–8. [PMC free article] [PubMed]
  • Beltran-Valero de Bernabe D, Voit T, Longman C, Steinbrecher A, Straub V, Yuva Y, et al. Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome. J Med Genet. 2004;41:e61. [PMC free article] [PubMed]
  • Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, Celli J, van Beusekom E, van der Zwaag B, et al. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet. 2002;71:1033–43. [PubMed]
  • Ben-Arie N, Bellen HJ, Armstrong DL, McCall AE, Gordadze PR, Guo Q, et al. Math1 is essential for genesis of cerebellar granule neurons. Nature. 1997;390:169–72. [PubMed]
  • Bergmann C, Zerres K, Senderek J, Rudnik-Schoneborn S, Eggermann T, Hausler M, et al. Oligophrenin 1 (OPHN1) gene mutation causes syndromic X-linked mental retardation with epilepsy, rostral ventricular enlargement and cerebellar hypoplasia. Brain. 2003;126(Pt 7):1537–44. [PubMed]
  • Bermingham NA, Hassan BA, Wang VY, Fernandez M, Banfi S, Bellen HJ, et al. Proprioceptor Pathway Development Is Dependent on MATH1. Neuron. 2001;30:411–22. [PubMed]
  • Bhattacharya JJ, Luo CB, Alvarez H, Rodesch G, Pongpech S, Lasjaunias PL. PHACES syndrome: a review of eight previously unreported cases with late arterial occlusions. Neuroradiology. 2004;46:227–33. [PubMed]
  • Bish JP, Pendyal A, Ding L, Ferrante H, Nguyen V, McDonald-McGinn D, et al. Specific cerebellar reductions in children with chromosome 22q11.2 deletion syndrome. Neurosci Lett. 2006;399:245–8. [PubMed]
  • Blaess S, Graus-Porta D, Belvindrah R, Radakovits R, Pons S, Littlewood-Evans A, et al. Beta1-integrins are critical for cerebellar granule cell precursor proliferation. J Neurosci. 2004;24:3402–12. [PMC free article] [PubMed]
  • Bloch-Gallego E, Causeret F, Ezan F, Backer S, Hidalgo-Sanchez M. Development of precerebellar nuclei: instructive factors and intracellular mediators in neuronal migration, survival and axon pathfinding. Brain Res Rev. 2005;49:253–66. [PubMed]
  • Boland E, Clayton-Smith J, Woo VG, McKee S, Manson FD, Medne L, et al. Mapping of deletion and translocation breakpoints in 1q44 implicates the serine/threonine kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum. Am J Hum Genet. 2007;81:292–303. [PubMed]
  • Boltshauser E, Isler W. Joubert syndrome: episodic hyperpnea, abnormal eye movements, retardation and ataxia associated with dysplasia of the cerebellar vermis. Neuropadiatrie. 1977;8:57–66. [PubMed]
  • Boltshauser E, Steinlin M, Martin E, Deonna T. Unilateral cerebellar aplasia. Neuropediatrics. 1996;27:50–3. [PubMed]
  • Bosley TM, Oystreck DT, Robertson RL, Al Awad A, Abu-Amero K, Engle EC. Neurological features of congenital fibrosis of the extraocular muscles type 2 with mutations in PHOX2A. Brain. 2006;129:2363–74. [PubMed]
  • Bosley TM, Alorainy IA, Salih MA, Aldhalaan HM, Abu-Amero KK, Oystreck DT, et al. The clinical spectrum of homozygous HOXA1 mutations. Am J Med Genet A. 2008;146A:1235–40. [PMC free article] [PubMed]
  • Bosley TM, Salih MAM, Jen JC, Lin DDM, Oystreck D, Abu-Amero KK, et al. Neurologic features of horizontal gaze palsy and progressive scoliosis with mutations in ROBO3. Neurology. 2005;64:1196–203. [PubMed]
  • Bourrat F, Sotelo C. Early development of the rat precerebellar system: migratory routes, selective aggregation and neuritic differentiation of the inferior olive and lateral reticular nucleus neurons. An overview. Arch Ital Biol. 1990;128:151–70. [PubMed]
  • Boycott KM, Flavelle S, Bureau A, Glass HC, Fujiwara TM, Wirrell E, et al. Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification. Am J Hum Genet. 2005;77:477–83. [PubMed]
  • Brancati F, Travaglini L, Zablocka D, Boltshauser E, Accorsi P, Montagna G, et al. RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders. Clin Genet. 2008;74:164–70. [PMC free article] [PubMed]
  • Brancati F, Iannicelli M, Travaglini L, Mazzotta A, Bertini E, Boltshauser E, et al. MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement. Hum Mutat. 2009;30:E432–42. [PMC free article] [PubMed]
  • Brancati F, Barrano G, Silhavy JL, Marsh SE, Travaglini L, Bielas SL, et al. CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders. Am J Hum Genet. 2007;81:104–13. [PubMed]
  • Broccoli V, Boncinelli E, Wurst W. The caudal limit of Otx2 expression positions the isthmic organizer. Nature. 1999;401:164–8. [PubMed]
  • Brocks D, Irons M, Sadeghi-Najad A, McCauley R, Wheeler P. Gomez-Lopez-Hernandez syndrome: expansion of the phenotype. Am J Med Genet. 2000;94:405–8. [PubMed]
  • Budde BS, Namavar Y, Barth PG, Poll-The BT, Nurnberg G, Becker C, et al. tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat Genet. 2008;40:1113–8. [PubMed]
  • Canning CA, Lee L, Irving C, Mason I, Jones CM. Sustained interactive Wnt and FGF signaling is required to maintain isthmic identity. Dev Biol. 2007;305:276–86. [PubMed]
  • Cantagrel V, Silhavy J, Bielas S, Swistun D, Marsh S, Bertrand J, et al. Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. Am J Hum Genet. 2008;83:170–9. [PubMed]
  • Cardoso C, Leventer RJ, Ward HL, Toyo-Oka K, Chung J, Gross A, et al. Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet. 2003;72:918–30. [PubMed]
  • Carper RA, Courchesne E. Inverse correlation between frontal lobe and cerebellum sizes in children with autism. Brain. 2000;123(Pt 4):836–44. [PubMed]
  • Cazorla Calleja MR, Verdu A, Felix V. Dandy-Walker malformation in an infant with tetrasomy 9p. Brain Dev. 2003;25:220–3. [PubMed]
  • Chambers D, Wilson L, Alfonsi F, Hunter E, Saxena U, Blanc E, et al. Rhombomere-specific analysis reveals the repertoire of genetic cues expressed across the developing hindbrain. Neural Dev. 2009;4:6. [PMC free article] [PubMed]
  • Chan WM, Traboulsi EI, Arthur B, Friedman N, Andrews C, Engle EC. Horizontal gaze palsy with progressive scoliosis can result from compound heterozygous mutations in ROBO3. J Med Genet. 2006;43:e11. [PMC free article] [PubMed]
  • Chandler KE, Del Rio A, Rakshi K, Springell K, Williams DK, Stoodley N, et al. Leucodysplasia, microcephaly, cerebral malformation (LMC): a novel recessive disorder linked to 2p16. Brain. 2006;129:272–7. [PubMed]
  • Chang B, Piao X, Bodell A, Basel-Vanagaite L, Straussberg R, Dobyns W, et al. Bilateral frontoparietal polymicrogyria: clinical and radiological features in 10 families with linkage to chromosome 16. Ann Neurol. 2003;53:596–606. [PubMed]
  • Chang BS, Duzcan F, Kim S, Cinbis M, Aggarwal A, Apse KA, et al. The role of RELN in lissencephaly and neuropsychiatric disease. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:58–63. [PubMed]
  • Chaves-Vischer V, Pizzolato G-P, Hanquinet S, Maret A, Bottani A, Haenggeli C-A. Early fatal pontocerebellar hypoplasia in premature twin sisters. Eur J Paediatr Neurol. 2000;4:171–6. [PubMed]
  • Chen CP, Chen CP, Shih JC. Association of partial trisomy 9p and the Dandy-Walker malformation. Am J Med Genet A. 2005;132A:111–2. [PubMed]
  • Chizhikov V, Millen KJ. Development and malformations of the cerebellum in mice. Mol Genet Metab. 2003;80:54–65. [PubMed]
  • Chizhikov VV, Lindgren AG, Currle D, Rose M, Monuki ES, Millen KJ. The roof plate regulates cerebellar cell-type specification and proliferation. Development. 2006;133:2793–804. [PubMed]
  • Chizhikov VV, Steshina E, Roberts R, Ilkin Y, Washburn L, Millen KJ. Molecular definition of an allelic series of mutations disrupting the mouse Lmx1a (dreher) gene. Mamm Genome. 2006;17:1025–32. [PubMed]
  • Chizhikov VV, Davenport J, Zhang Q, Shih EK, Cabello OA, Fuchs JL, et al. Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool. J Neurosci. 2007;27:9780–9. [PubMed]
  • Conway RL, Pressman BD, Dobyns WB, Danielpour M, Lee J, Sanchez-Lara PA, et al. Neuroimaging findings in macrocephaly-capillary malformation: a longitudinal study of 17 patients. Am J Med Genet A. 2007;143A:2981–3008. [PubMed]
  • Cordes SP. Molecular genetics of cranial nerve development in mouse. Nat Rev Neurosci. 2001;2:611–23. [PubMed]
  • Courchesne E, Redcay E, Morgan J, Kennedy D. Autism at the beginning: microstructural and growth abnormalities underlying the cognitive and behavioral phenotype of autism. Dev Psychopathol. 2005;17:577–97. [PubMed]
  • Courchesne E, Yeung-Courchesne R, Press GA, Hesselink JR, Jernigan TL. Hypoplasia of the cerebellar vermal lobules VI and VII in autism. N Eng J Med. 1988;318:1349–54. [PubMed]
  • Cross SH, Morgan JE, Pattyn A, West K, McKie L, Hart A, et al. Haploinsufficiency for Phox2b in mice causes dilated pupils and atrophy of the ciliary ganglion: mechanistic insights into human congenital central hypoventilation syndrome. Hum Mol Genet. 2004;13:1433–9. [PubMed]
  • Cusmai R, Curatolo P, Mangano S, Cheminal R, Echenne B. Hemimegalencephaly and neurofibromatosis. Neuropediatrics. 1990;21:179–82. [PubMed]
  • de Koning TJ, de Vries LS, Groenendaal F, Ruitenbeek W, Jansen GH, Poll-The BT, et al. Pontocerebellar hypoplasia associated with respiratory-chain defects. Neuropediatrics. 1999;30:93–5. [PubMed]
  • de Lonlay P, Seta N, Barrot S, Chabrol B, Drouin V, Gabriel BM, et al. A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases. J Med Genet. 2001;38:14–9. [PMC free article] [PubMed]
  • Delous M, Baala L, Salomon R, Laclef C, Vierkotten J, Tory K, et al. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet. 2007;39:875–81. [PubMed]
  • Demaerel P. Abnormalities of cerebellar foliation and fissuration: classification, neurogenetics and clinicoradiological correlations. Neuroradiology. 2002;44:639–46. [PubMed]
  • Dhamecha RD, Edwards-Brown MK. Klippel-Trenaunay-Weber syndrome with hemimegalencephaly. J Craniofac Surg. 2001;12:194–6. [PubMed]
  • Dixon-Salazar T, Silhavy JL, Marsh SE, Louie CM, Scott LC, Gururaj A, et al. Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet. 2004;75:979–87. [PubMed]
  • Donkelaar HJ, Lammens M, Wesseling P, Thijssen HO, Renier WO. Development and developmental disorders of the human cerebellum. J Neurol. 2003;250:1025–36. [PubMed]
  • Drouin-Garraud V, Belgrand M, Grunewald S, Seta N, Dacher JN, Henocq A, et al. Neurological presentation of a congenital disorder of glycosylation CDG-Ia: implications for diagnosis and genetic counseling. Am J Med Genet. 2001;101:46–9. [PubMed]
  • Dubeau F, Tampieri D, Lee N, Andermann E, Carpenter S, Leblanc R, et al. Periventricular and subcortical nodular heterotopia: a study of 33 patients. Brain. 1995:1273–87. [PubMed]
  • Edvardson S, Shaag A, Kolesnikova O, Gomori JM, Tarassov I, Einbinder T, et al. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet. 2007;81:857–62. [PubMed]
  • Eluvathingal T, Behen M, Chugani H, Janisse J, Bernardi B, Chakraborty P, et al. Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates. J Child Neurol. 2006;21:846–51. [PubMed]
  • Eng C, Murday V, Seal S, Mohammed S, Hodgson S, Chaudary M, et al. Cowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy? J Med Genet. 1994;31:458–61. [PMC free article] [PubMed]
  • Engle EC, Andrews C, Law K, Demer JL. Two pedigrees segregating Duane's retraction syndrome as a dominant trait map to the DURS2 genetic locus. Invest Ophthalmol Vis Sci. 2007;48:189–93. [PMC free article] [PubMed]
  • Englund C, Kowalczyk T, Daza RAM, Dagan A, Lau C, Rose MF, et al. Unipolar brush cells of the cerebellum are produced in the rhombic lip and migrate through developing white matter. J Neurosci. 2006;26:9184–95. [PubMed]
  • Ericson J, Muhr J, Jessell TM, Edlund T. Sonic hedgehog: a common signal for ventral patterning along the rostrocaudal axis of the neural tube. Int J Dev Biol. 1995;39:809–16. [PubMed]
  • Ericson J, Briscoe J, Rashbass P, van Heyningen V, Jessell TM. Graded sonic hedgehog signaling and the specification of cell fate in the ventral neural tube. Cold Spring Harb Symp Quant Biol. 1997;62:451–66. [PubMed]
  • Fallet-Bianco C, Loeuillet L, Poirier K, Loget P, Chapon F, Pasquier L, et al. Neuropathological phenotype of a distinct form of lissencephaly associated with mutations in TUBA1A. Brain. 2008;131:2304–20. [PubMed]
  • Ferland RJ, Eyaid W, Collura RV, Tully LD, Hill RS, Al-Nouri D, et al. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet. 2004;36:1008–13. [PubMed]
  • Ferrer I, Cusi MV, Liarte A, Campistol J. A Golgi study of the polymicrogyric cortex in Aicardi syndrome. Brain Dev. 1986;8:518–25. [PubMed]
  • Fink AJ, Englund C, Daza RA, Pham D, Lau C, Nivison M, et al. Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip. J Neurosci. 2006;26:3066–76. [PubMed]
  • Flores-Sarnat L. Hemimegalencephaly. I. Genetic, clinical, and imaging aspects. J Child Neurol. 2002;17:373–84. [PubMed]
  • Flores-Sarnat L, Sarnat H, Davila-Gutierrez G, Alvarez A. Hemimegalencephaly: part 2. Neuropathology suggests a disorder of cellular lineage. J Child Neurol. 2003;18:776–85. [PubMed]
  • Forman MS, Squier W, Dobyns WB, Golden JA. Genotypically defined lissencephalies show distinct pathologies. J Neuropathol Exp Neurol. 2005;64:847–57. [PubMed]
  • Frank V, Hollander AId, Brüchle NO, Zonneveld MN, Nürnberg G, Becker C, et al. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome. Hum Mutat. 2008;29:45–52. [PubMed]
  • Freeze HH. Update and perspectives on congenital disorders of glycosylation. Glycobiology. 2001;11:129R–43R. [PubMed]
  • Friede RL. Developmental neuropathology. Berlin: Springer-Verlag; 1989. 2nd ed.
  • Frieden IJ, Reese V, Cohen D. PHACE syndrome. The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol. 1996;132:307–11. [PubMed]
  • Galluzzi P, Cerase A, Strambi M, Buoni S, Fois A, Venturi C. Hemimegalencephaly in tuberous sclerosis complex. J Child Neurol. 2002;17:677–80. [PubMed]
  • Gardner RJM, Colemen LT, Mitchell LA, Smith LJ, Harvey AS, Scheffer IE, et al. Near total absence of the cerebellum. Neuropediatrics. 2001;32:62–8. [PubMed]
  • Gaufo GO, Wu S, Capecchi MR. Contribution of Hox genes to the diversity of the hindbrain sensory system. Development. 2004;131:1259–66. [PubMed]
  • Gavalas A, Ruhrberg C, Livet J, Henderson CE, Krumlauf R. Neuronal defects in the hindbrain of Hoxa1, Hoxb1 and Hoxb2 mutants reflect regulatory interactions among these Hox genes. Development. 2003;130:5663–79. [PubMed]
  • Gavalas A, Studer M, Lumsden A, Rijli FM, Krumlauf R, Chambon P. Hoxa1 and Hoxb1 synergize in patterning the hindbrain, cranial nerves and second pharyngeal arch. Development. 1998;125:1123–36. [PubMed]
  • Giurgea I, Michel A, Le Merrer M, Seta N, de Lonlay P. Underdiagnosis of mild congenital disorders of glycosylation type Ia. Pediatr Neurol. 2005;32:121–3. [PubMed]
  • Glasgow S, Henke R, Macdonald R, Wright C, Johnson J. Ptf1a determines GABAergic over glutamatergic neuronal cell fate in the spinal cord dorsal horn. Development. 2005;132:5461–9. [PubMed]
  • Gleeson J, Keeler L, Parisi M, Marsh S, Chance P, Glass I, et al. Molar tooth sign of the midbrain junction: occurence in multiple distinct syndromes. Am J Med Genet. 2004;125A:125–34. [PubMed]
  • Goddard JM, Rossel M, Manley NR, Capecchi MR. Mice with targeted disruption of Hoxb-1 fail to form the motor nucleus of the VIIth nerve. Development. 1996;122:3217–28. [PubMed]
  • Godfrey C, Clement E, Mein R, Brockington M, Smith J, Talim B, et al. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain. 2007;130(Pt 10):2725–35. [PubMed]
  • Gold DA, Gent PM, Hamilton BA. ROR alpha in genetic control of cerebellum development: 50 staggering years. Brain Res. 2007;1140:19–25. [PubMed]
  • Gomez TM, Zheng JQ. The molecular basis for calcium-dependent axon pathfinding. Nat Rev Neurosci. 2006;7:115–25. [PubMed]
  • Gorden NT, Arts HH, Parisi MA, Coene KL, Letteboer SJ, van Beersum SE, et al. CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. Am J Hum Genet. 2008;83:559–71. [PubMed]
  • Goutieres F, Aicardi J, Farkas E. Anterior horn cell disease associated with pontocerebellar hypoplasia in infants. J Neurol Neurosurg Psychiatry. 1977;40:370–8. [PMC free article] [PubMed]
  • Grellner W, Rohde K, Wilske J. Fatal outcome in a case of pontocerebellar hypoplasia type 2. Forensic Sci Int. 2000;113:165–72. [PubMed]
  • Gressens P. Pathogenesis of migration disorders. Curr Opin Neurol. 2006;19:135–40. [PubMed]
  • Griffiths PD, Welch R, Gardner-Medwin D, Gholkar A, McAllister V. The radiological features of hemimegalencephaly including three cases associated with Proteus syndrome. Neuropediatrics. 1994;25:140–4. [PubMed]
  • Griffiths PD, Gardner S-A, Smith M, Rittey C, Powell T. Hemimegalencephaly and focal megalencephaly in tuberous sclerosis complex. AJNR Am J Neuroradiol. 1998;19:1935–8. [PubMed]
  • Grinberg I, Millen KJ. The ZIC gene family in development and disease. Clin Genet. 2005;67:290–6. [PubMed]
  • Grinberg I, Northrup H, Ardinger H, Prasad C, Dobyns WB, Millen KJ. Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation. Nat Genet. 2004;36:1053–5. [PubMed]
  • Gripp KW, Hopkins E, Vinkler C, Lev D, Malinger G, Lerman-Sagie T, et al. Significant overlap and possible identity of macrocephaly capillary malformation and megalencephaly polymicrogyria-polydactyly hydrocephalus syndromes. Am J Med Genet A. 2009;149A:868–76. [PubMed]
  • Hack I, Hellwig S, Junghans D, Brunne B, Bock HH, Zhao S, et al. Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons. Development. 2007;134:3883–91. [PubMed]
  • Hansske B, Thiel C, Lubke T, Hasilik M, Honing S, Peters V, et al. Deficiency of UDP-galactose: N-acetylglucosamine beta-1,4-galactosyltransferase I causes the congenital disorder of glycosylation type IId. J Clin Invest. 2002;109:725–33. [PMC free article] [PubMed]
  • Hashimoto K, Takeuchi Y, Kida Y, Hisaya H, Kantake M, Sasaki A, et al. Three siblings of fatal infantile encephalopathy with olivopontocerebellar hypoplasia and microcephaly. Brain Develop. 1998;20:169–74. [PubMed]
  • Hatten ME. New directions in neuronal migration. Science. 2002;297:1660–3. [PubMed]
  • Henion TR, Qu Q, Smith FI. Expression of dystroglycan, fukutin and POMGnT1 during mouse cerebellar development. Mol Brain Res. 2003;112:177–81. [PubMed]
  • Hevner R. Progress on pontocerebellar hypoplasia. Acta Neuropathol. 2007;114:401–2. [PubMed]
  • Hiesberger T, Trommsdorff M, Howell BW, Goffinet A, Mumby MC, Cooper JA, et al. Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron. 1999;24:481–9. [PubMed]
  • Hill AD, Chang BS, Hill RS, Garraway LA, Bodell A, Sellers WR, et al. A 2-Mb critical region implicated in the microcephaly associated with terminal 1q deletion syndrome. Am J Med Genet A. 2007;143A:1692–8. [PubMed]
  • Hirotsune S, Fleck MW, Gambello MJ, Bix GJ, Chen A, Clark GD, et al. Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality. Nat Genet. 1998;19:333–9. [PubMed]
  • Holve S, Friedman B, Hoyme HE, Tarby TJ, Johnstone SJ, Erickson RP, et al. Athabascan brainstem dysgenesis syndrome. Am J Med Genet A. 2003;120A:169–73. [PubMed]
  • Holzfeind PJ, Grewal PK, Reitsamer HA, Kechvar J, Lassmann H, Hoeger H, et al. Skeletal, cardiac and tongue muscle pathology, defective retinal transmission, and neuronal migration defects in the Large(myd) mouse defines a natural model for glycosylation-deficient muscle - eye - brain disorders. Hum Mol Genet. 2002;11:2673–87. [PubMed]
  • Hong SE, Shugart YY, Huang DT, Al Shahwan S, Grant PE, Hourihane JOB, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia (LCH) is associated with human reelin gene mutations. Nature Genet. 2000;26:93–6. [PubMed]
  • Hoshino M. Molecular machinery governing GABAergic neuron specification in the cerebellum. Cerebellum. 2006;5:193–8. [PubMed]
  • Hoshino M, Nakamura S, Mori K, Kawauchi T, Terao M, Nishimura YV, et al. Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum. Neuron. 2005;47:201–13. [PubMed]
  • Hoveyda N, Shield JP, Garrett C, Chong WK, Beardsall K, Bentsi-Enchill E, et al. Neonatal diabetes mellitus and cerebellar hypoplasia/agenesis: report of a new recessive syndrome. J Med Genet. 1999;36:700–4. [PMC free article] [PubMed]
  • Illarioshkin SN, Tanaka H, Markova ED, Nikolskaya NN, Ivanova-Smolenskaya IA, Tsuji S. X-linked nonprogressive congenital cerebellar hypoplasia: clinical description and mapping to chromosome Xq. Ann Neurol. 1996;40:75–83. [PubMed]
  • Illarioshkin SN, Allen KM, Gleeson JG, Tsuji S, Ikeuchi T, Markova ED, et al. Studies of the candidate genes in X-linked congenital cerebellar hypoplasia. J Neurol. 1999;246:1177–80. [PubMed]
  • Jalali A, Aldinger K, Chary A, McLone D, Bowman R, Le L, et al. Linkage to chromosome 2q36.1 in autosomal dominant Dandy-Walker malformation with occipital cephalocele and evidence for genetic heterogeneity. Hum Genet. 2008;123:237–45. [PMC free article] [PubMed]
  • Jen JC, Chan W-M, Bosley TM, Wan J, Carr JR, Rub U, et al. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science. 2004;304:1509–13. [PMC free article] [PubMed]
  • Jissendi-Tchofo P, Doherty D, McGillivray G, Hevner R, Shaw D, Ishak G, et al. Pontine tegmental cap dysplasia: MR imaging and diffusion tensor imaging features of impaired axonal navigation. AJNR Am J Neuroradiol. 2009;30:113–9. [PMC free article] [PubMed]
  • Joubert M, Eisenring JJ, Robb JP, Andermann F. Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology. 1969;19:813–25. [PubMed]
  • Kadonaga D, Barkovich A, Edwards M, Frieden I. Neurocutaneous melanosis in association with the Dandy-Walker malformation. Pediatr Dermatol. 1992;9:37–43. [PubMed]
  • Kaindl A, Asimiadou S, Manthey D, Hagen M, Turski L, Ikonomidou C. Antiepileptic drugs and the developing brain. Cell Mol Life Sci. 2006;63:399–413. [PubMed]
  • Kanagawa M, Toda T. The genetic and molecular basis of muscular dystrophy: roles of cell-matrix linkage in the pathogenesis. J Hum Genet. 2006;51:915–26. [PubMed]
  • Kawauchi D, Taniguchi H, Watanabe H, Saito T, Murakami F. Direct visualization of nucleogenesis by precerebellar neurons: involvement of ventricle-directed, radial fibre-associated migration. Development. 2006;133:1113–23. [PubMed]
  • Ke N, Ma H, Diedrich G, Chionis J, Liu G, Yu D-H, et al. Biochemical characterization of genetic mutations of GPR56 in patients with bilateral frontoparietal polymicrogyria (BFPP) Biochem Biophys Res Commun. 2008;366:314–20. [PubMed]
  • Keays DA, Tian G, Poirier K, Huang GJ, Siebold C, Cleak J, et al. Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. Cell. 2007;128:45–57. [PMC free article] [PubMed]
  • Keeler LC, Marsh SE, Leeflang EP, Woods CG, Sztriha L, Al-Gazali L, et al. Linkage analysis in families with Joubert syndrome plus oculo-renal involvement identifies the CORS2 locus on chromosome 11p12-q13.3. Am J Hum Genet. 2003;73:656–62. [PubMed]
  • Kelley RI, Robinson D, Puffenberger EG, Strauss KA, Morton DH. Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria. Am J Med Genet. 2002;112:318–26. [PubMed]
  • Kenney AM, Cole MD, Rowitch DH. Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development. 2003;130:15–28. [PubMed]
  • Kier G, Winchester BG, Clayton P. Carbohydrate deficient glycoprotein syndromes: inborn errors of protein glycosylation. Ann Clin Biochem. 1999;36:20–36. [PubMed]
  • Kilickesmez O, Yavuz N, Hoca E. Unilateral absence of cerebellar hemispheres: incidental diagnosis with magnetic resonance imaging. Acta Radiol. 2004;45:876–7. [PubMed]
  • Kobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura Y, et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature. 1998;394:388–92. [PubMed]
  • Kohlhase J, Chitayat D, Kotzot D, Ceylaner S, Froster UG, Fuchs S, et al. SALL4 mutations in Okihiro syndrome (Duane-radial ray syndrome), acro-renal-ocular syndrome, and related disorders. Hum Mutat. 2005;26:176–83. [PubMed]
  • Kohlhase J, Heinrich M, Schubert L, Liebers M, Kispert A, Laccone F, et al. Okihiro syndrome is caused by SALL4 mutations. Hum Mol Genet. 2002;11:2979–87. [PubMed]
  • Koirala S, Jin Z, Piao X, Corfas G. GPR56-Regulated Granule Cell Adhesion Is Essential for Rostral Cerebellar Development. J Neurosci. 2009;29:7439–49. [PMC free article] [PubMed]
  • Kornak U, Reynders E, Dimopoulou A, van Reeuwijk J, Fischer B, Rajab A, et al. Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2. Nat Genet. 2008;40:32–4. [PubMed]
  • Landsberg RL, Awatramani RB, Hunter NL, Farago AF, DiPietrantonio HJ, Rodriguez CI, et al. Hindbrain rhombic lip is comprised of discrete progenitor cell populations allocated by Pax6. Neuron. 2005;48:933–47. [PubMed]
  • Leroy J, Lyon G, Fallet C, Amiel J, De Praeter C, Van Den Broecke C, et al. Congenital pontocerebellar atrophy and telencephalic defects in three siblings: a new subtype. Acta Neuropathol. 2007;114:387–99. [PubMed]
  • Leto K, Carletti B M. WI, Magrassi L, Rossi F. Different types of cerebellar GABAergic interneurons originate from a common pool of multipotent progenitor cells. |J Neurosci. 2006;26:11682–94. [PubMed]
  • Li S, Jin Z, Koirala S, Bu L, Xu L, Hynes RO, et al. GPR56 Regulates Pial Basement Membrane Integrity and Cortical Lamination. J Neurosci. 2008;28:5817–26. [PMC free article] [PubMed]
  • Lim Y, Golden JA. Patterning the developing diencephalon. Brain Res Rev. 2007;53:17–26. [PubMed]
  • Longman C, Brockington M, Torelli S, Jimenez-Mallebrera C, Kennedy C, Khalil N, et al. Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. Hum Mol Genet. 2003;12:2853–61. [PubMed]
  • Louie CM, Gleeson JG. Genetic basis of Joubert syndrome and related disorders of cerebellar development. Hum Mol Genet. 2005;14(Suppl 2):R235–42. [PubMed]
  • Lumsden A. Segmentation and compartition in the early avian hindbrain. Mech Dev. 2004;121:1081–8. [PubMed]
  • Lumsden A, Krumlauf R. Patterning the vertebrate neuraxis. Science. 1996;274:1009–115.
  • Mamourian A, Miller G. Neonatal pontomedullary disconnection with aplasia or destruction of the lower brain stem: a case of pontoneocerebellar hypoplasia? AJNR Am J Neuroradiol. 1994;15:1483–5. [PubMed]
  • Manzini MC, Gleason D, Chang B, Sean Hill R, Barry B, Partlow J, et al. Ethnically diverse causes of Walker-Warburg syndrome (WWS): FCMD mutations are a more common cause of WWS outside of the Middle East. Hum Mutat. 2008;29:E231–41. [PMC free article] [PubMed]
  • Mark M, Lufkin T, Vonesch JL, Ruberte E, Olivo JC, Dolle P, et al. Two rhombomeres are altered in Hoxa-1 mutant mice. Development. 1993;119:319–38. [PubMed]
  • Marquardt T, Denecke J. Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr. 2003;162:359–79. [PubMed]
  • Marsh DJ, Kum JB, Lunetta KL, Bennett MJ, Gorlin RJ, Ahmed SF, et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan- Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet. 1999;8:1461–72. [PubMed]
  • Martin PT. Congenital muscular dystrophies involving the O-mannose pathway. Curr Molec Med. 2007;7:417–525. [PMC free article] [PubMed]
  • McCann E, Pilling D, Hesseling M, Roberts D, Subhedar N, Sweeney E. Pontomedullary disconnection: fetal and neonatal considerations. Pediatr Radiol. 2005;V35:812. [PubMed]
  • McCormack WM, Jr, Shen JJ, Curry SM, Berend SA, Kashork C, Pinar H, et al. Partial deletions of the long arm of chromosome 13 associated with holoprosencephaly and the Dandy-Walker malformation. Am J Med Genet. 2002;112:384–9. [PubMed]
  • McCormack WM, Shen JJ, Jr, Curry SM, Berend SA, Kashork C, Pinar H, et al. Partial deletions of the long arm of chromosome 13 associated with holoprosencephaly and the Dandy-Walker malformation. Am J Med Genet A. 2003;118A:384–9. [PubMed]
  • Melaragno MI, Brunoni D, Patricio FR, Corbani M, Mustacchi Z, dos Santos Rde C, et al. A patient with tetrasomy 9p, Dandy-Walker cyst and Hirschsprung disease. Ann Genet. 1992;35:79–84. [PubMed]
  • Metry DW, Dowd CF, Barkovich AJ, Frieden IJ. The many faces of PHACE syndrome. J Pediatr. 2001;139:117–23. [PubMed]
  • Michaud J, Mizrahi EM, Urich H. Agenesis of the vermis with fusion of the cerebellar hemispheres, septo-optic dysplasia and associated anomalies. Report of a case. Acta Neuropathol. 1982;56:161–6. [PubMed]
  • Michielse CB, Bhat M, Brady A, Jafrid H, van den Hurk JA, Raashid Y, et al. Refinement of the locus for hereditary congenital facial palsy on chromosome 3q21 in two unrelated families and screening of positional candidate genes. Eur J Hum Genet. 2006;14:1306–12. [PubMed]
  • Millet S, Campbell K, Epstein DJ, Losos K, Harris E, Joyner AL. A role for Gbx2 in repression of Otx2 and positioning the mid/hindbrain organizer. Nature. 1999;401:161–4. [PubMed]
  • Millonig JH, Millen KJ, Hatten ME. The mouse Dreher gene Lmx1a controls formation of the roof plate in the vertebrate CNS. Nature. 2000;403:764–9. [PubMed]
  • Miossec-Chauvet E, Mikaeloff Y, Heron D, Merzoug V, Cormier-Daire V, de Lonlay P, et al. Neurological presentation in pediatric patients with congenital disorders of glycosylation type Ia. Neuropediatrics. 2003;34:1–6. [PubMed]
  • Miyake N, Chilton J, Psatha M, Cheng L, Andrews C, Chan WM, et al. Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome. Science. 2008;321:839–43. [PMC free article] [PubMed]
  • Miyata T, Nakajima K, Mikoshiba K, Ogawa M. Regulation of Purkinje cell alignment by reelin as revealed with CR-50 antibody. J Neurosci. 1997;17:3599–609. [PubMed]
  • Moog U, Jones MC, Bird LM, Dobyns WB. Oculocerebrocutaneous syndrome: the brain malformation defines a core phenotype. J Med Genet. 2005;42:913–21. [PMC free article] [PubMed]
  • Moore SA, Saito F, Chen J, Michele DE, Henry MD, Messing A, et al. Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature. 2002;418:422–5. [PubMed]
  • Morava E, Wopereis S, Coucke P, Gillessen-Kaesbach G, Voit T, Smeitink J, et al. Defective protein glycosylation in patients with cutis laxa syndrome. Eur J Hum Genet. 2005;13:414–21. [PubMed]
  • Moro F, Carrozzo R, Veggiotti P, Tortorella G, Toniolo D, Volzone A, et al. Familial periventricular heterotopia: missense and distal truncating mutations of the FLN1 gene. Neurology. 2002;58:916–21. [PubMed]
  • Morris-Rosendahl DJ, Najm J, Lachmeijer AM, Sztriha L, Martins M, Kuechler A, et al. Refining the phenotype of alpha-1a Tubulin (TUBA1A) mutation in patients with classical lissencephaly. Clin Genet. 2008;74:425–33. [PubMed]
  • Muntoni F, Goodwin F, Sewry C, Cox P, Cowan F, Airaksinen E, et al. Clinical spectrum and diagnostic difficulties of infantile ponto-cerebellar hypoplasia type 1. Neuropediatrics. 1999;30:243–8. [PubMed]
  • Najm J, Horn D, Wimplinger I, Golden JA, Chizhikov VV, Sudi J, et al. Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat Genet. 2008;40:1065–7. [PubMed]
  • Nakamura H, Watanabe Y. Isthmus organizer and regionalization of the mesencephalon and metencephalon. Int J Dev Biol. 2005;49:231–5. [PubMed]
  • Nakamura H, Katahira T, Matsunaga E, Sato K. Isthmus organizer for midbrain and hindbrain development. Brain Res Brain Res Rev. 2005;49:120–6. [PubMed]
  • Nakano M, Yamada K, Fain J, Sener EC, Selleck CJ, Awad AH, et al. Homozygous mutations in ARIX (PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet. 2001;29:315–20. [PubMed]
  • Narayanan HS, Gandhi DH, Girimaji SR. Neurocutaneous melanosis associated with Dandy-Walker syndrome. Clin Neurol Neurosurg. 1987;89:197–200. [PubMed]
  • Nelen M, Padberg G, Peeters E, Lin A, van den Helm B, Frants R, et al. Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Nat Genet. 1996;13:114–6. [PubMed]
  • Nishikawa S, Goto S, Yamada K, Hamasaki T, Ushio Y. Lack of Reelin causes malpositioning of nigral dopinergic neurons: evidence from comparison of normal and Reln-/- mutant mice. J Comp Neurol. 2003;461:166–73. [PubMed]
  • Norman MG, McGillivray BC, Kalousek DK, Hill A, Poskitt KJ. Congenital malformations of the brain: pathologic, embryologic, clinical, radiologic and genetic aspects. Oxford: Oxford University Press; 1995.
  • Parisi MA, Dobyns WB. Human malformations of the midbrain and hindbrain: review and proposed classification scheme. Mol Genet Metab. 2003;80:36–53. [PubMed]
  • Parisi MA, Bennett CL, Eckert ML, Dobyns WB, Gleeson JG, Shaw DW, et al. The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am J Hum Genet. 2004;75:82–91. [PubMed]
  • Parrini E, Ramazzotti A, Dobyns WB, Mei D, Moro F, Veggiotti P, et al. Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations. Brain. 2006;129:1892–906. [PubMed]
  • Pascual-Castroviejo I, Pascual-Pascual SI, Velazquez-Fragua R, Lapunzina P. Oculocerebrocutaneous (Delleman) syndrome: report of two cases. Neuropediatrics. 2005;36:50–4. [PubMed]
  • Pascual-Castroviejo I, Pascual-Pascual SI, Quijano-Roy S, Gutierrez-Molina M, Morales MC, Velazquez-Fragua R, et al. Cerebellar ataxia of Normal-Jaeken. Presentation of seven Spanish patients. Rev Neurol. 2006;42:723–8. [PubMed]
  • Patel MS, Becker LE, Toi A, Armstrong DL, Chitayat D. Severe, fetal-onset form of olivopontocerebellar hypoplasia in three sibs: PCH type 5? American Journal of Medical Genetics Part A. 2006;140A:594–603. [PubMed]
  • Patel S, Barkovich A. Analysis and classification of cerebellar malformations. AJNR Am J Neuroradiol. 2002;23:1074–87. [PubMed]
  • Pattyn A, Goridis C, Brunet JF. Specification of the central noradrenergic phenotype by the homeobox gene Phox2b. Mol Cell Neurosci. 2000;15:235–43. [PubMed]
  • Pattyn A, Hirsch M, Goridis C, Brunet JF. Control of hindbrain motor neuron differentiation by the homeobox gene Phox2b. Development. 2000;127:1349–58. [PubMed]
  • Pavone L, Curatolo P, Rizzo R, Micali G, Incorpora G, Garg B, et al. Epidermal nevus syndrome: a neurologic variant with hemimegalencephaly, gyral malformation,mental retardation, seizures, and facial hemihypertrophy. Neurology. 1991;41:266–71. [PubMed]
  • Pelayo R, Barasch E, Kang H, Marion R, Moshé LS. Progressively intractable seizures, focal alopecia, and hemimegalencephaly. Neurology. 1994;44:969–71. [PubMed]
  • Peserico A, Battistella PA, Bertoli P, Drigo P. Unilateral hypomelanosis of Ito with hemimegalencephaly. Acta Paediatr Scand. 1988;77:446–7. [PubMed]
  • Peters V, Penzien JM, Reiter G, Korner C, Hackler R, Assmann B, et al. Congenital disorder of glycosylation IId (CDG-IId) – a new entity: clinical presentation with Dandy-Walker malformation and myopathy. Neuropediatrics. 2002;33:27–32. [PubMed]
  • Philip N, Chabrol B, Lossi AM, Cardoso C, Guerrini R, Dobyns WB, et al. Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia. J Med Genet. 2003;40:441–6. [PMC free article] [PubMed]
  • Piao X, Chang BS, Bodell A, Woods K, BenZeev B, Topcu M, et al. Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes. Ann Neurol. 2005;58:680–7. [PubMed]
  • Piao X, Hill RS, Bodell A, Chang BS, Basel-Vanagaite L, Straussberg R, et al. G protein-coupled receptor-dependent development of human frontal cortex. Science. 2004;303:2033–6. [PubMed]
  • Poirier K, Keays DA, Francis F, Saillour Y, Bahi N, Manouvrier S, et al. Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A) Human Mutation. 2007;28:1055–64. [PubMed]
  • Poot M, Kroes HY, SE VDW, Eleveld MJ, Rooms L, Nievelstein RA, et al. Dandy-Walker complex in a boy with a 5 Mb deletion of region 1q44 due to a paternal t(1; 20)(q44; q13.33) Am J Med Genet A. 2007;143A:1038–44. [PubMed]
  • Porcionatto MA. The extracellular matrix provides directional cues for neuronal migration during cerebellar development. Braz J Med Biol Res. 2006;39:313–20. [PubMed]
  • Poretti A, Boltshauser E, Plecko B. Brainstem disconnection: case report and review of the literature. Neuropediatrics. 2007;38:210–2. [PubMed]
  • Poretti A, Prayer D, Boltshauser E. Morphological spectrum of prenatal cerebellar disruptions. Eur J Paediatr Neurol. 2009;13:397–407. [PubMed]
  • Poretti A, Boltshauser E, Loenneker T, Valente E, Brancati F, Il'yasov K, et al. Diffusion tensor imaging in Joubert syndrome. AJNR Am J Neuroradiol. 2007;28:1929–33. [PubMed]
  • Poretti A, Leventer R, Cowan F, Rutherford M, Steinlin M, Klein A, et al. Cerebellar cleft: a form of prenatal cerebellar disruption. Neuropediatrics. 2008;39:106–12. [PubMed]
  • Qu Q, Crandall JE, Luo T, McCaffery PJ, Smith FI. Defects in tangential neuronal migration of pontine nuclei neurons in the Largemyd mouse are associated with stalled migration in the ventrolateral hindbrain. Eur J Neurosci. 2006;23:2877–86. [PubMed]
  • Quisling R, Barkovich A, Maria B. Magnetic resonance imaging features and classification of central nervous system malformations in Joubert syndrome. J Child Neurol. 1999;14:628–35. [PubMed]
  • Rajab A, Manzini MC, Mochida GH, Walsh CA, Ross ME. A novel form of lethal microcephaly with simplified gyral pattern and brain stem hypoplasia. Am J Med Genet A. 2007;143A:2761–7. [PubMed]
  • Rajab A, Mochida GH, Hill A, Ganesh V, Bodell A, Riaz A, et al. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11–21. Neurology. 2003;60:1664–7. [PubMed]
  • Rakic P, Sidman RL. Histogenesis of cortical layers in human cerebellum, particularly the lamina dessicans. J Comp Neurol. 1970;139:473–500. [PubMed]
  • Richards LJ, Plachez C, Ren T. Mechanisms regulating the development of the corpus callosum and its agenesis in mouse and human. Clin Genet. 2004;66:276–89. [PubMed]
  • Robain O, Gelot A. Neuropathology of hemimegalencephaly. In: Guerrini R, Andermann F, Canapicchi R, Roger J, Zifkin B, Pfanner P, editors. Dysplasias of cerebral cortex and epilepsy. Philadelphia: Lippencott-Raven; 1996. pp. 89–92.
  • Romanengo M, Tortori-Donati P, Di Rocco M. Rhombencephalosynapsis with facial anomalies and probably autosomal recessive inheritance: a case report. Clin Genet. 1997;52:184–6. [PubMed]
  • Rorke LB, Fogelson M, Riggs HE. Cerebellar heterotopia in infancy. Dev Med Child Neurol. 1968;10:644–50. [PubMed]
  • Ross ME, Swanson K, Dobyns WB. Lissencephaly with cerebellar hypoplasia (LCH): a heterogeneous group of cortical malformations. Neuropediatrics. 2001;32:256–63. [PubMed]
  • Rossi A, Catala M, Biancheri R, Di Comite R, Tortori-Donati P. MR Imaging of Brain-Stem Hypoplasia in Horizontal Gaze Palsy with Progressive Scoliosis. AJNR Am J Neuroradiol. 2004;25:1046–8. [PubMed]
  • Round J, Stein E. Netrin signaling leading to directed growth conse steering. Curr Opin Neurobiol. 2007;17:15–21. [PubMed]
  • Rudnik-Schoneborn S, Wirth B, Rohrig D, Saule H, Zerres K. Exclusion of the gene locus for spinal muscular atrophy on chromosome 5q in a family with infantile olivopontocerebellar atrophy (OPCA) and anterior horn cell degeneration. Neuromuscul Disord. 1995;5:19–23. [PubMed]
  • Rudnik-Schoneborn S, Goebel HH, Schlote W, Molaian S, Omran H, Ketelsen U, et al. Classical infantile spinal muscular atrophy with SMN deficiency causes sensory neuronopathy. Neurology. 2003;60:983–7. [PubMed]
  • Ryan MM, Cooke-Yarborough CM, Procopis PG, Ouvrier RA. Anterior horn cell disease and olivopontocerebellar hypoplasia. Pediatr Neurol. 2000;23:180–4. [PubMed]
  • Saar K, Al-Gazali L, Sztriha L, et al. Homozygosity mapping in families with Joubert syndrome identifies a locus on chromosome 9q34.3 and evidence for genetic heterogeneity. Am J Hum Genet. 1999;65:1666–71. [PubMed]
  • Saito Y, Yamamoto T, Mizuguchi M, Kobayashi M, Saito K, Ohno K, et al. Altered glycosylation of [alpha]-dystroglycan in neurons of Fukuyama congenital muscular dystrophy brains. Brain Res. 2006;1075:223–8. [PubMed]
  • Sakaki-Yumoto M, Kobayashi C, Sato A, Fujimura S, Matsumoto Y, Takasato M, et al. The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in anorectal, heart, brain and kidney development. Development. 2006;133:3005–13. [PubMed]
  • Sapir T, Sapoznik S, Levy T, Finkelshtein D, Shmueli A, Timm T, et al. Accurate balance of the polarity kinase MARK2/Par-1 is required for proper cortical neuronal migration. J Neurosci. 2008;28:5710–20. [PubMed]
  • Sarkisian MR, Bartley CM, Chi H, Nakamura F, Hashimoto-Torii K, Torii M, et al. MEKK4 signaling regulates filamin expression and neuronal migration. Neuron. 2006;52:789–801. [PMC free article] [PubMed]
  • Sarnat HB. Molecular Genetic Classification of Central Nervous System Malformations. J Child Neurol. 2000;15:675–87. [PubMed]
  • Sarnat HB, Benjamin DR, Siebert JR, Kletter GB, Cheyette SR. Agenesis of the mesencephalon and metencephalon with cerebellar hypoplasia: putative mutation in the EN2 gene – report of 2 cases in early infancy. Pediatr Dev Pathol. 2002;5:54–68. [PubMed]
  • Sayer JA, Otto EA, O’Toole JF, Nurnberg G, Kennedy MA, Becker C, et al. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet. 2006;38:674–81. [PubMed]
  • Schachenmayr W, Friede RL. Rhombencephalosynapsis: a Viennese malformation? Dev Med Child Neurol. 1982;24:178–82. [PubMed]
  • Schell-Apacik CC, Cohen M, Vojta S, Ertl-Wagner B, Klopocki E, Heinrich U, et al. Gomez-Lopez-Hernandez syndrome (cerebello-trigeminal-dermal dysplasia): description of an additional case and review of the literature. Eur J Pediatr. 2008;167:123–6. [PubMed]
  • Schmid T, Kruger M, Braun T. NSCL-1 and -2 control the formation of precerebellar nuclei by orchestrating the migration of neuronal precursor cells. J Neurochem. 2007 ; Sep; 102: 2061–72. [PubMed]
  • Schneider-Maunoury S, Seitanidou T, Charnay P, Lumsden A. Segmental and neuronal architecture of the hindbrain of Krox-20 mouse mutants. Development. 1997;124:1215–26. [PubMed]
  • Schneider-Maunoury S, Topilko P, Seitandou T, Levi G, Cohen-Tannoudji M, Pournin S, et al. Disruption of Krox-20 results in alteration of rhombomeres 3 and 5 in the developing hindbrain. Cell. 1993;75:1199–214. [PubMed]
  • Sellick GS, Barker KT, Stolte-Dijkstra I, Fleishmann C, Coleman RJ, Garrett C, et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet. 2004;36:1301–5. [PubMed]
  • Sener R. MR demonstration of cerebral hemimegalencephaly associated with cerebellar involvement (total hemimegalencephaly) Comput Med Imaging Graph. 1997;21:201–4. [PubMed]
  • Sgaier SK, Millet S, Villanueva MP, Bereshteyn F, Song C, Joyner AL. Morphogenetic and cellular movements that shape the mouse cerebellum: insights from genetic fate mapping. Neuron. 2005;45:27–40. [PubMed]
  • Sheen VL, Ganesh VS, Topcu M, Sebire G, Bodell A, Hill RS, et al. Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat Genet. 2004;36:69–76. [PubMed]
  • Sicotte NL, Salamon G, Shattuck DW, Hageman N, Rub U, Salamon N, et al. Diffusion tensor MRI shows abnormal brainstem crossing fibers associated with ROBO3 mutations. Neurology. 2006;67:519–21. [PubMed]
  • Sieber MA, Storm R, Martinez-de-la-Torre M, Muller T, Wende H, Reuter K, et al. Lbx1 Acts as a selector gene in the fate determination of somatosensory and viscerosensory relay neurons in the hindbrain. J Neurosci. 2007;27:4902–9. [PubMed]
  • Siebert JR. A pathological approach to anomalies of the posterior fossa. Birth Defects Res A Clin Mol Teratol. 2006;76:674–84. [PubMed]
  • Slee JJ, Smart RD, Viljoen DL. Deletion of chromosome 13 in Moebius syndrome. J Med Genet. 1991;28:413–4. [PMC free article] [PubMed]
  • Sotelo C. Cellular and genetic regulation of the development of the cerebellar system. Prog Neurobiol. 2004;72:295–339. [PubMed]
  • Soto-Ares GY, Joyes B, Lemaitre M, Vallee L, Pruvo J. MRI in children with mental retardation. Pediatr Radiol. 2003;33:334–45. [PubMed]
  • Soto-Ares G, Devisme L, Jorriot S, Deries B, Pruvo JP, Ruchoux MM. Neuropathologic and MR imaging correlation in a neonatal case of cerebellar cortical dysplasia. AJNR Am J Neuroradiol. 2002;23:1101–4. [PubMed]
  • Soto-Ares G, Deries B, Delmaire C, Devisme L, Ruchoux MM, Pruvo J. Dysplasie du cortex cérébelleux: aspects en IRM et signification. J Radiol. 2004;85:729–40. [PubMed]
  • Sprecher E, Ishida-Yamamoto A, Mizrahi-Koren M, Rapaport D, Goldsher D, Indelman M, et al. A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma. Am J Hum Genet. 2005;77:242–51. [PubMed]
  • Studer M, Gavalas A, Marshall H, Ariza-McNaughton L, Rijli FM, Chambon P, et al. Genetic interactions between Hoxa1 and Hoxb1 reveal new roles in regulation of early hindbrain patterning. Development. 1998;125:1025–36. [PubMed]
  • Sztriha L, Johansen JG. Spectrum of malformations of the hindbrain (cerebellum, pons, and medulla) in a cohort of children with high rate of parental consanguinity. Am J Med Genet Part A. 2005;135A:134–41. [PubMed]
  • Sztriha L, Johansen JG, Al-Gazali LI. Extreme microcephaly with agyria-pachygyria, partial agenesis of the corpus callosum, and pontocerebellar dysplasia. J Child Neurol. 2005;20:170–2. [PubMed]
  • Sztriha L, Al-Gazali L, Varady E, Nork M, Varughese M. Microlissencephaly. Pediatr Neurol. 1998;18:362–5. [PubMed]
  • Takanashi J, Sugita K, Barkovich AJ, Takano H, Kohno Y. Partial midline fusion of the cerebellar hemispheres with vertical folia: a new cerebellar malformation? AJNR Am J Neuroradiol. 1999;20:1151–3. [PubMed]
  • Takano T, Akahori S, Takeuchi Y, Ohno M. Neuronal apoptosis and gray matter heterotopia in microcephaly produced by cytosine arabinoside in mice. Brain Res. 2006;1089:55–66. [PubMed]
  • Tan TY, McGillivray G, Goergen SK, White SM. Prenatal magnetic resoance imaging in Gomez-Lopez-Hernandez syndrome and review of the literature. Am J Med Genet. 2005;138A:369–73. [PubMed]
  • Tanabe Y, Jessell TM. Diversity and pattern in the developing spinal cord. Science. 1996;274:1115–23. [PubMed]
  • ten Donkelaar HJ, Lammens M, Cruysberg JRM, Cremers CWJR. Development and developmental disorders of the brain stem. In: ten Donkelaar HJ, Lammens M, Hori A, editors. Clinical Neuroembryol. Berlin: Springer; 2006. pp. 269–308.
  • Tessier-Lavigne M, Goodman CS. The molecular biology of axon guidance. Science. 1996;274:1123–33. [PubMed]
  • Thomsen M, Steffen H, Sabo D, Niethard FU. Juvenile progressive scoliosis and congenital horizontal gaze palsy. J Pediatr Orthop B. 1996;5:185–9. [PubMed]
  • Tischfield MA, Bosley TM, Salih MA, Alorainy IA, Sener EC, Nester MJ, et al. Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nat Genet. 2005;37:1035–7. [PubMed]
  • Toelle S, Yalcinkaya C, Kocer N, Deonna T, Overweg-Plandsoen W, Bast T, et al. Rhombencephalosynapsis: clinical findings and neuroimaging in 9 children. Neuropediatrics. 2002;33:209–214. [PubMed]
  • Toyo-oka K, Shionoya A, Gambello M, Cardoso C, Leventer R, Ward HL, et al. 14–3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome. Nat Genet. 2003;34:274–85. [PubMed]
  • Trabousli EI. Congenital abnormalities of cranial nerve development: overview, molecular mechanisms and further evidence of heterogeneity and complexity of syndromes with congenital limitation of eye movements. Trans Am Ophthalomol Soc. 2004;102:373–90. [PMC free article] [PubMed]
  • Triki C, Louhichi N, Méziou M, choyakh F, Kéchaou MS, Jlidi R, et al. Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts, unlinked to the LAMA2, FCMD, MEB, and CMD1B loci in three Tunisian patients. Neuromuscul Disord. 2003;13:4–12. [PubMed]
  • Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J, et al. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell. 1999;97:689–701. [PubMed]
  • Tsao JW, Neal J, Apse K, Stephan MJ, Dobyns WB, Hill RS, et al. Cerebellar ataxia with progressive improvement. Arch Neurol. 2006;63:594–7. [PubMed]
  • Valente EM, Salpietro DC, Brancati F, Bertini E, Galluccio T, Tortorella G, et al. Description, nomenclature, and mapping of a novel cerebello-renal syndrome with the molar tooth malformation. Am J Hum Genet. 2003;73:663–70. [PubMed]
  • Valente EM, Marsh SE, Castori M, Dixon-Salazar T, Bertini E, Al-Gazali L, et al. Distinguishing the four genetic causes of Jouberts syndrome-related disorders. Ann Neurol. 2005;57:513–9. [PubMed]
  • Valente EM, Silhavy JL, Brancati F, Barrano G, Krishnaswami SR, Castori M, et al. Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat Genet. 2006;38:623–5. [PubMed]
  • Valente EM, Brancati F, Silhavy JL, Castori M, Marsh SE, Barrano G, et al. AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders. Ann Neurol. 2006;59:527–34. [PubMed]
  • van Amelsvoort T, Daly E, Henry J, Robertson D, Ng V, Owen M, et al. Brain anatomy in adults with velocardiofacial syndrome with and without schizophrenia: preliminary results of a structural magnetic resonance imaging study. Arch Gen Psychiatry. 2004;61:1085–96. [PubMed]
  • van Bon BW, Koolen DA, Borgatti R, Magee A, Garcia-Minaur S, Rooms L, et al. Clinical and molecular characteristics of 1qter microdeletion syndrome: delineating a critical region for corpus callosum agenesis/hypogenesis. J Med Genet. 2008;45:346–54. [PubMed]
  • Van Maldergem L, Yuksel-Apak M, Kayserili H, Seemanova E, Giurgea S, Basel-Vanagaite L, et al. Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debre type. Neurology. 2008;71:1602–8. [PubMed]
  • van Reeuwijk J, Maugenre S, van den Elzen C, Verrips A, Bertini E, Muntoni F, et al. The expanding phenotype of POMT1 mutations: from Walker-Warburg syndrome to congenital muscular dystrophy, microcephaly, and mental retardation. Human Mutation. 2006;27:453–9. [PubMed]
  • van Reeuwijk J, Janssen M, van den Elzen C, Beltran-Valero de Bernabe D, Sabatelli P, Merlini L, et al. POMT2 mutations cause {alpha}-dystroglycan hypoglycosylation and Walker-Warburg syndrome. J Med Genet. 2005;42:907–12. [PMC free article] [PubMed]
  • Ventura P, Presicci A, Perniola T, Campa MG, Margari L. Mental retardation and epilepsy in patients with isolated cerebellar hypoplasia. J Child Neurol. 2006;21:776–81. [PubMed]
  • Vogel MW, Caston J, Yuzaki M, Mariani J. The Lurcher mouse: fresh insights from an old mutant. Brain Res. 2007;1140:4–18. [PubMed]
  • Wallace VA. Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol. 1999;9:445–8. [PubMed]
  • Wang VY, Zoghbi HY. Genetic regulation of cerebellar development. Nat Rev Neurosci. 2001;2:484–91. [PubMed]
  • Wang VY, Rose MF, Zoghbi HY. Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron. 2005;48:31. [PubMed]
  • Warren M, Wang W, Spiden S, Chen-Murchie D, Tannahill D, Steel KP, et al. A Sall4 mutant mouse model useful for studying the role of Sall4 in early embryonic development and organogenesis. Genesis. 2007;45:51–8. [PMC free article] [PubMed]
  • Waters ST, Lewandoski M. A threshold requirement for Gbx2 levels in hindbrain development. Development. 2006;133:1991–2000. [PubMed]
  • Webb SJ, Sparks BF, Friedman SD, Shaw DW, Giedd J, Dawson G, et al. Cerebellar vermal volumes and behavioral correlates in children with autism spectrum disorder. Psychiatry Res. 2009;172:61–7. [PMC free article] [PubMed]
  • Wechsler-Reya RJ, Scott MP. Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron. 1999;22:103–14. [PubMed]
  • Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, Silvestri JM, Curran ME, et al. Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b. Am J Med Genet A. 2003;123A:267–78. [PubMed]
  • Weisheit G, Gliem M, Endl E, Pfeffer PL, Busslinger M, Schilling K. Postnatal development of the murine cerebellar cortex: formation and early dispersal of basket, stellate and Golgi neurons. Eur J Neurosci. 2006;24:466–78. [PubMed]
  • Wetts R, Herrup K. Interaction of granule, Purkinje and inferior olivary neurons in lurcher chimeric mice. II. Granule cell death. Brain Res. 1982;250:358–63. [PubMed]
  • Widjaja E, Blaser S, Raybaud C. Diffusion tensor imaging of midline posterior fossa malformations. Pediatr Radiol. 2006;36:510–7. [PubMed]
  • Wieck G, Leventer RJ, Squier WM, Jansen A, Andermann E, Dubeau F, et al. Periventricular nodular heterotopia with overlying polymicrogyria. Brain. 2005;128:2811–21. [PubMed]
  • Wingate RJ, Hatten ME. The role of the rhombic lip in avian cerebellum development. Development. 1999;126:4395–404. [PubMed]
  • Wurst W, Bally-Cuif L. Neural plate patterning: upstream and downstream of the isthmic organizer. Nat Rev Neurosci. 2001;2:99–108. [PubMed]
  • Yachnis AT, Rorke LB. Neuropathology of Joubert syndrome. J Child Neurol. 1999;14:655–9. [PubMed]
  • Yachnis AT, Trojanowski JQ, Memmo M, Schlaepfer WW. Expression of neurofilament proteins in the hypertrophic granule cells of Lhermitte-Duclos disease: an explanation for the mass effect and the myelination of parallel fibers in the disease state. J Neuropathol Exp Neurol. 1988;47:206–16. [PubMed]
  • Yamada M, Terao M, Terashima T, Fujiyama T, Kawaguchi Y, Nabeshima Y-I, et al. Origin of Climbing Fiber Neurons and Their Developmental Dependence on Ptf1a. J Neurosci. 2007;27:10924–34. [PubMed]
  • Ye W, Shimamura K, Rubenstein JLR, Hynes MA, Rosenthal A. FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell. 1998;93:755–66. [PubMed]
  • Yoshida A, Kobayashi K, Manya H, Taniguchi K, Kano H, Mizuno M, et al. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell. 2001;1:717–24. [PubMed]
  • Zaki M, Shehab M, El-Aleem AA, Abdel-Salam G, Koeller HB, Ilkin Y, et al. Identification of a novel recessive RELN mutation using a homozygous balanced reciprocal translocation. Am J Med Genet Part A. 2007;143A:939–44. [PubMed]
  • Zaki MS, Abdel-Aleem A, Abdel-Salam GMH, Marsh SE, Silhavy JL, Barkovich AJ, et al. The molar tooth sign: a new Joubert syndrome and related cerebellar disorders classification system tested in Egyptian families. Neurology. 2008;70:556–65. [PubMed]
  • Zanni G, Saillour Y, Nagara M, Billuart P, Castelnau L, Moraine C, et al. Oligophrenin 1 mutations frequently cause X-linked mental retardation with cerebellar hypoplasia. Neurology. 2005;65:1364–9. [PubMed]
  • Zinkstok J, van Amelsvoort T. Neuropsychological profile and neuroimaging in patients with 22q11.2 Deletion Syndrome: a review. Child Neuropsychol. 2005;11:21–37. [PubMed]
  • Ziter FA, Wiser WC, Robinson A. Three-generation pedigree of a Mobius syndrome variant with chromosome translocation. Arch Neurol. 1977;34:437–42. [PubMed]

Articles from Brain are provided here courtesy of Oxford University Press