In this study, we describe six familial cases of a novel malformation at the DMJ in three consanguineous Egyptian families. None of the three families are related to one another, according to our knowledge, but we cannot exclude a common shared ancestor or founder mutation. It is likely that these three families depict a novel developmental brain disorder not previously classified. Although we propose that the affected individuals in these families are likely to have the same unique condition, there are some differences in the degree of ventriculomegaly, with Family DMJD-1825 showing dramatic ventriculomegaly not observed in either of the other two families. Therefore, at this time, it remains a possibility that these represent genetically distinct diseases with a similar unique brainstem malformation.
Findings similar to these have appeared in the published literature previously, but not as a distinct entity or with clarified inheritance pattern. We previously reported two cases of midbrain enlargement with midline hyperintensity, pontocerebellar hypoplasia and a hyperintense (T2
-positive) midline stripe extending from the interpeduncular cistern to the aqueduct (Barkovich et al., 2007
). In these two cases, the midbrain showed some similarities in structure to those reported here, but were not identical. An additional case was identified in our subsequent report of the genetic classification for midbrain–hindbrain malformations (Barkovich et al., 2009
), which we attributed to a posterior-to-anterior transformation at the level of the DMJ. In these previous cases, we observed extension of the third ventricle and other diencephalic features into the upper part of a thickened midbrain, similar to what was observed in mouse upon overexpression of Pax6
or underexpression of En1/Pax2
in the anterior mesencephalon (Nakamura and Watanabe, 2005
). Whether these previously reported cases have the same genetic aetiology as the cases reported here will require identification of causative gene(s). Given the caudal shift of the DMJ and the interplay between the development of the DMJ and the midbrain–hindbrain junction, one might anticipate patterning defects of the midbrain–hindbrain boundary. It is therefore relevant that the affected individuals from Family DMJD-1825 showed cerebellar vermis hypoplasia.
DMJD joins a number of recessive brainstem developmental defects including pontocerebellar hypoplasia, Joubert’s syndrome, pontine tegmental cap dysplasia and horizontal gaze palsy with progressive scoliosis, among others (Rossi et al., 2004
; Barth et al., 2007
; Cassandrini et al., 2010
; Sattar and Gleeson, 2011
). In each of these conditions, unique MRI appearance of the brainstem and/or cerebellum is evident, which allows for a refined patient classification. For instance, pontocerebellar hypoplasia due to mutations in the TSEN54
gene shows a unique finding of flattening of the cerebellar hemisphere with relative sparing of the vermis producing a ‘dragonfly-like’ cerebellar pattern on coronal MRI (Namavar et al., 2011
). Joubert’s syndrome shows a ‘molar-tooth’ sign on axial images (Parisi, 2009
), PTCH shows a unique bulge of the posterior brainstem into the fourth ventricle, and horizontal gaze palsy with progressive scoliosis shows a ‘split pons’ sign on axial MRI (Barkovich et al., 2009
). The axial MRI in DMJD is highly unique, and appears to be clearly distinct from these other conditions, but additional work will be needed to substantiate these unique imaging findings.
Based upon these brainstem anatomical defects, we tested for fibre tract defects using diffusion tension imaging and found significant abnormalities in brain connectivity. Specifically, we noted abnormality in the continuity of the descending corticopontine/corticospinal tract. Given the limitation of diffusion tensor imaging, it was not possible to differentiate between a complete absence of this major tract from the cerebral cortex versus premature termination of the tract within the internal capsule. Additionally, it remains a formal possibility that the corticopontine/corticospinal tract originates normally but takes a sharp angle or projects in a different location, neither of which are possible to disprove using diffusion tensor imaging. Other developmental brain disorders display alterations in the corticopontine/corticospinal tract projections, specifically in Joubert’s syndrome and horizontal gaze palsy with progressive scoliosis the corticopontine/corticospinal tract fails to decussate at the cervicomedullary junction at least in some patients (Yachnis and Rorke, 1999
; Jen et al., 2004
). In the case of mutations in L1CAM
, humans have reduced corticospinal tract function (Dobson et al., 2001
), whereas L1cam
knockout mice show failed decussation and premature termination of the corticospinal tract at spinal levels (Cohen et al., 1998
), and spasticity is a key feature. The spasticity displayed by our patients would be consistent with failed descending corticospinal tract projection, as this tract is critical for setting peripheral neuromotor tone. The specific mechanisms underlying such tractography defects are not known and will require future work.
Although our patients shared many dysmorphic facial features, we could not specify a distinctive syndromic pattern that would aide in diagnosis. We found post-natal progressive microcephaly, autistic features, seizures and spasticity are consistent features among our patients suggesting penetrant clinical stigmata of this malformation. Vasomotor instability and unexplained fever might be related to diencephalic dysfunction. Moreover, variability among sibs was present in two of these families (Families DMJD-1592 and DMJD-1846), which might be due to the effect of the malformation or mere variable expressivity. We postulate that given our six familial cases of different sexes from three unrelated consanguineous families, DMJD appears to follow an autosomal recessive mode of inheritance. Genetic approaches should make it possible to identify the cause of this condition. Currently, despite exome sequencing in these affected individuals, no obvious candidate gene has emerged, but homozygosity mapping has revealed some potential chromosomal regions of interest in Family DMJD-1592 (). With further identification of such patients, the genetic basis and phenotypic presentation of DMJD should become clearer, and provide further insight to understanding this developmental brain disorder.
Figure 6 Homozygosity mapping results derived from comparison of exome sequencing of two affected individuals in Family DMJD-1592. The ~20000 variants from each patient were plotted as a function of heterozygosity/homozygosity at each allele for (more ...)