Dysequilibrium syndrome (DES) is a genetically heterogeneous condition that combines autosomal recessive, non-progressive cerebellar ataxia with mental retardation. Here we report the first patient heterozygous for two novel mutations in VLDLR. An 18-month old girl presented with significant hypotonia, global developmental delay, and truncal and peripheral ataxia. MR imaging of the brain demonstrated hypoplasia of the inferior cerebellar vermis and hemispheres, small pons, and a simplified cortical sulcation pattern. Sequence analysis of the VLDLR gene identified a nonsense and missense mutation. Six mutations in VLDLR have now been identified in five families with a phenotype characterized by moderate-to-profound mental retardation, delayed ambulation, truncal and peripheral ataxia and occasional seizures. Neuroanatomically, the loss-of-function effect of the different mutations is indistinguishable. VLDLR-associated cerebellar hypoplasia is emerging as a panethnic, clinically and molecularly well-defined genetic syndrome.
VLDLR; Cerebellar hypoplasia; Dysequilibrium syndrome
Congenital hereditary non‐progressive hypoplasia of the cerebellum is a rare condition, frequently associated with other neuropathology such as lissencephaly. Clinically, the condition is associated with variable degrees of mental retardation, microcephaly, seizures, and movement disorders due to ataxia. In severe cases, patients are unable to ambulate independently, but nevertheless do use bipedal locomotion.
Methods and Results
Here we present a family with seven affected members, five of whom never learned to walk on two legs but have fully adapted to quadrupedal palmigrade locomotion. These subjects show signs of cerebellar ataxia and are mentally retarded. MRI analysis demonstrated hypoplasia of the cerebellum and the cerebellar vermis as well as a small nucleus dentatus and a thin corpus callosum but no other malformations. We show, by a genome‐wide linkage scan, that quadrupedal locomotion is a recessive trait linked to chromosome 17p.
Our findings have implications for understanding the neural mechanism mediating bipedalism, and, perhaps, the evolution of this unique hominid trait.
bipedality; cerebellar hypoplasia; linkage; quadrupedal locomotion
CAMOS (Cerebellar Ataxia with Mental retardation, Optic atrophy and Skin abnormalities) is a rare autosomal recessive syndrome characterized by a nonprogressive congenital cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities. Using homozygosity mapping in a large inbred Lebanese Druze family, we previously reported the mapping of the disease gene at chromosome 15q24–q26 to a 3.6-cM interval between markers D15S206 and D15S199. Screening of candidate genes lying in this region led to the identification of a homozygous p.Gly1046Arg missense mutation in ZNF592, in all five affected individuals of the family. ZNF592 encodes a 1267-amino-acid zinc-finger (ZnF) protein, and the mutation, located within the eleventh ZnF, is predicted to affect the DNA-binding properties of ZNF592. Although the precise role of ZNF592 remains to be determined, our results suggest that ZNF592 is implicated in a complex developmental pathway, and that the mutation is likely to disturb the highly orchestrated regulation of genes during cerebellar development, by either disrupting interactions with target DNA or with a partner protein.
CAMOS; missense mutation; ZNF592; C2H2 zinc-finger domain; cerebellar ataxia; nonprogressive
We describe a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. Genome-wide linkage analysis identified a 5.8 Mb interval on chromosome 8q with shared homozygosity among the affected persons. Sequencing of genes contained in the interval revealed a homozygous mutation, S100P, in carbonic anhydrase related protein 8 (CA8), which is highly expressed in cerebellar Purkinje cells and influences inositol triphosphate (ITP) binding to its receptor ITPR1 on the endoplasmatic reticulum and thereby modulates calcium signaling. We demonstrate that the mutation S100P is associated with proteasome-mediated degradation, and thus presumably represents a null mutation comparable to the Ca8 mutation underlying the previously described waddles mouse, which exhibits ataxia and appendicular dystonia. CA8 thus represents the third locus that has been associated with quadrupedal gait in humans, in addition to the VLDLR locus and a locus at chromosome 17p. Our findings underline the importance of ITP-mediated signaling in cerebellar function and provide suggestive evidence that congenital ataxia paired with cerebral dysfunction may, together with unknown contextual factors during development, predispose to quadrupedal gait in humans.
We identified a homozygous missense mutation (S100P) in the gene encoding carbonic anhydrase VIII in a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. The affected persons walk on their hands and feet with their legs held straight with a “bear-like” gait. Our results show that the mutation S100P induces proteasome-mediated degradation with a severe reduction of the level of CA8 protein. The waddles (wdl) mouse, a spontaneous animal model with ataxia, was previously shown to harbor a 19-bp deletion in Ca8 that leads to an almost complete lack of detectable Ca8 protein, resulting in abnormalities in cerebellar synaptic transmission. Therefore, we speculate that the reduction in CA8 protein concentration associated with the S100P mutation could result in similar pathophysiological effects. With the current report, alterations at three gene loci (CA8, VLDLR, and a yet-to-be discovered gene on chromosome 17p) have been reported to be associated with quadrupedal gait. It is unknown whether quadrupedal gait is related to specific molecular abnormalities or is an adaptive response to ataxia in some circumstances. However, we note that ataxia associated with mutations at all three loci is congenital and also associated with mental retardation, which is not generally a feature of other hereditary ataxias.
Joubert syndrome (JS) is an autosomal recessive disorder characterised by hypotonia, ataxia, mental retardation, altered respiratory pattern, abnormal eye movements, and a brain malformation known as the molar tooth sign (MTS) on cranial MRI. Four genetic loci have been mapped, with two genes identified (AHI1 and NPHP1).
We screened a cohort of 117 JS subjects for AHI1 mutations by a combination of haplotype analysis and sequencing of the gene, and for the homozygous NPHP1 deletion by sequencing and marker analysis.
We identified a total of 15 novel AHI1 mutations in 13 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Eight families were consanguineous, but no single founder mutation was apparent. In addition to the MTS, retinal dystrophy was present in 11 of 12 informative families; however, no subjects exhibited variable features of JS such as polydactyly, encephalocele, colobomas, or liver fibrosis. In contrast to previous reports, we identified two families with affected siblings who developed renal disease consistent with nephronophthisis (NPH) in their 20s. In addition, two individuals with classic NPH were found to have homozygous NPHP1 deletions.
Overall, 11% of subjects had AHI1 mutations, while ∼2% had the NPHP1 deletion, representing a total of less than 15% in a large JS cohort. Some preliminary genotype‐phenotype correlations are possible, notably the association of renal impairment, specifically NPH, in those with NPHP1 deletions. Subjects with AHI1 mutations may be at risk of developing both retinal dystrophy and progressive kidney disease.
; cerebellar vermis hypoplasia; Joubert syndrome; nephronophthisis;
To identify genetic causes of COACH syndrome
COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD).
In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced.
19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%).
Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L.
Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.
CASK gene; XLMR; intellectual disability; congenital nystagmus
Congenital nonprogressive spinocerebellar ataxia is characterized by early gross motor delay, hypotonia, gait ataxia, mild dysarthria and dysmetria. The clinical presentation remains fairly stable and may be associated with cerebellar atrophy. To date, only a few families with autosomal dominant congenital nonprogressive spinocerebellar ataxia have been reported. Linkage to 3pter was demonstrated in one large Australian family and this locus was designated spinocerebellar ataxia type 29. The objective of this study is to describe an unreported Canadian family with autosomal dominant congenital nonprogressive spinocerebellar ataxia and to identify the underlying genetic causes in this family and the original Australian family.
Methods and Results
Exome sequencing was performed for the Australian family, resulting in the identification of a heterozygous mutation in the ITPR1 gene. For the Canadian family, genotyping with microsatellite markers and Sanger sequencing of ITPR1 gene were performed; a heterozygous missense mutation in ITPR1 was identified.
ITPR1 encodes inositol 1,4,5-trisphosphate receptor, type 1, a ligand-gated ion channel that mediates calcium release from the endoplasmic reticulum. Deletions of ITPR1 are known to cause spinocerebellar ataxia type 15, a distinct and very slowly progressive form of cerebellar ataxia with onset in adulthood. Our study demonstrates for the first time that, in addition to spinocerebellar ataxia type 15, alteration of ITPR1 function can cause a distinct congenital nonprogressive ataxia; highlighting important clinical heterogeneity associated with the ITPR1 gene and a significant role of the ITPR1-related pathway in the development and maintenance of the normal functions of the cerebellum.
Congenital nonprogressive spinocerebellar ataxia; Spinocerebellar ataxia type 29; Cerebellar atrophy; ITPR1; Gene identification
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that constitutes the most common genetic cause of renal failure in the first three decades of life. Using positional cloning, six genes (NPHP1‐6) have been identified as mutated in NPHP. In Joubert syndrome (JBTS), NPHP may be associated with cerebellar vermis aplasia/hypoplasia, retinal degeneration and mental retardation. In Senior–Løken syndrome (SLSN), NPHP is associated with retinal degeneration. Recently, mutations in NPHP6/CEP290 were identified as a new cause of JBTS.
Mutational analysis was performed on a worldwide cohort of 75 families with SLSN, 99 families with JBTS and 21 families with isolated nephronophthisis.
Six novel and six known truncating mutations, one known missense mutation and one novel 3 bp pair in‐frame deletion were identified in a total of seven families with JBTS, two families with SLSN and one family with isolated NPHP.
; Joubert syndrome; Senior–Løken syndrome; nephronophthisis; mutational analysis
Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder. It is characterized by early-onset, progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, conjunctival telangiectasias, immunodeficiency, and an increased risk of malignancy. Although A-T is known to be the most common cause of progressive cerebellar ataxia in childhood, there have been no confirmed cases in Korea. We report the clinical and genetic findings of Korean siblings who presented with limb and truncal ataxia, oculomotor apraxia, choreoathetosis, and telangiectasias of the eyes. Sequence analysis of the ataxia-telangiectasia mutated (ATM) gene revealed a known missense mutation (c.8546G>C; p.Arg2849Pro) and a novel intronic variant of intron 17 (c.2639-19_2639-7del13). Reverse-transcription PCR and sequencing analysis revealed that the c.2639-19_2639-7del13 variant causes a splicing aberration that potentiates skipping exon 18. Because A-T is quite rare in Korea, the diagnosis of A-T in Korean patients can be delayed. We recommend that a diagnosis of A-T should be suspected in Korean patients exhibiting the clinical features
Ataxia; Ataxia telangiectasia; Ataxia telangiectasia mutated protein; Korea
Joubert syndrome (JS) is a developmental brain disorder characterized by cerebellar vermis hypoplasia, abnormal eye movement, ataxia and mental retardation. Mutations in CEP290 mutations are responsible for the cerebello–oculo–renal subtype of JS that includes kidney cysts and retinal degeneration, two phenotypes commonly linked to ciliopathies. CEP290 mutations are also associated with Meckel–Gruber syndrome and Bardet–Biedl syndrome (BBS). Here we demonstrate that CEP290 interacts with a centriolar satellite protein PCM-1, which is implicated in BBS4 function. CEP290 binds to PCM-1 and localizes to centriolar satellites in a PCM-1- and microtubule-dependent manner. The depletion of CEP290 disrupts subcellular distribution and protein complex formation of PCM-1. In accord with PCM-1’s role in microtubule organization, CEP290 knockdown causes the disorganization of the cytoplasmic microtubule network. Moreover, we show that both CEP290 and PCM-1 are required for ciliogenesis and are involved in the ciliary targeting of Rab8, a small GTPase shown to collaborate with BBS protein complex to promote ciliogenesis. Our results suggest that PCM-1 is a potential mediator that may link CEP290 with BBS proteins in common molecular pathways.
Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis. At least 30 patients with MVA and 180 patients with HIDS have been reported worldwide. MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. The febrile episodes are commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes. Life expectancy is often compromised. In HIDS, only febrile attacks are present, but a subgroup of patients may also develop neurological abnormalities of varying degree such as mental retardation, ataxia, ocular symptoms and epilepsy. A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders. In MVA, the diagnosis is established by detection of highly elevated levels of mevalonic acid excreted in urine. Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA), in combination with enhanced excretion of mevalonic acid provide strong evidence for HIDS. The diagnosis is confirmed by low activity of mevalonate kinase or by demonstration of disease-causing mutations. Genetic counseling should be offered to families at risk. There is no established successful treatment for MVA. Simvastatin, an inhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial effect in HIDS.
We identified a two-branch consanguineous family in which four affected members (three females and one male) presenting with constitutive growth delay, severe psychomotor retardation, microcephaly, cerebellar hypoplasia, and second degree heart block. They also shared distinct facial features and similar appearance of their hands and feet. Childhood-onset insulin-dependent diabetes mellitus developed in one affected child around the age of 9 years. Molecular analysis excluded mutations in potentially related genes such as PTF1A, EIF2AK3, EOMES and WDR62. This condition appears to be unique of other known conditions, suggesting a unique clinical entity of autosomal recessive mode of inheritance.
Microcephaly; insulin-dependent diabetes; cerebellar hypoplasia; mental retardation; heart block
We identified a two-branch consanguineous family in which four affected members (three females and one male) presented with constitutive growth delay, severe psychomotor retardation, microcephaly, cerebellar hypoplasia, and second-degree heart block. They also shared distinct facial features and similar appearance of their hands and feet. Childhood-onset insulin-dependent diabetes mellitus developed in one affected child around the age of 9 years. Molecular analysis excluded mutations in potentially related genes such as PTF1A, EIF2AK3, EOMES, and WDR62. This condition appears to be unique of other known conditions, suggesting a unique clinical entity of autosomal recessive mode of inheritance. © 2011 Wiley Periodicals, Inc.
microcephaly; insulin-dependent diabetes; cerebellar hypoplasia; mental retardation; heart block
Bilateral frontoparietal polymicrogyria is an autosomal recessively inherited human brain malformation with abnormal cortical lamination. The affected cortex appears to consist of numerous small gyri, with scalloping of the cortical-white matter junction. There are associated white matter, brainstem and cerebellar changes. Affected individuals present with mental retardation, language impairment, motor developmental delay and seizure disorder. GPR56 is the causative gene. Here we report a novel missense mutation of GPR56, E496K, identified in a consanguineous pedigree with bilateral frontoparietal polymicrogyria. GPR56 is cleaved at the G protein-coupled receptor proteolytic site into an N- and a C-terminal fragment, named GPR56N and GPR56C respectively. E496K is located in GPR56C. Further biochemical studies show that this mutation affects GPR56C cell surface expression similar to the effect of a previously reported mutation, R565W. These results provide further insights into how GPR56 mutation causes neurological disease.
To date over 150 X linked mental retardation (XLMR) conditions have been documented. We describe a five generation South African family with XLMR, comprising 16 affected males and 10 carrier females. The clinical features common to the 16 males included profound mental retardation (100%), mutism despite apparently normal hearing (100%), grand mal epilepsy (87.5%), and limited life expectancy (68.8%). Of the four affected males examined, all had mild craniofacial dysmorphology and three were noted to have bilateral ophthalmoplegia and truncal ataxia. Three of 10 obligate female carriers had mild mental retardation. Cerebellar and brain stem atrophy was shown by cranial imaging and postmortem examination. Linkage analysis shows the gene to be located between markers DXS424 (Xq24) and DXS548 (Xq27.3), with a maximum two point lod score of 3.10.
Keywords: X linked mental retardation; epilepsy; cerebellar atrophy; ophthalmoplegia
X-linked disorders with cerebellar dysgenesis (XLCD) are a genetically heterogeneous and clinically variable group of disorders in which the hallmark is a cerebellar defect (hypoplasia, atrophy or dysplasia) visible on brain imaging, caused by gene mutations or genomic imbalances on the X-chromosome. The neurological features of XLCD include hypotonia, developmental delay, intellectual disability, ataxia and/or other cerebellar signs. Normal cognitive development has also been reported. Cerebellar dysgenesis may be isolated or associated with other brain malformations or multiorgan involvement. There are at least 15 genes on the X-chromosome that have been constantly or occasionally associated with a pathological cerebellar phenotype. 8 XLCD loci have been mapped and several families with X-linked inheritance have been reported. Recently, two recurrent duplication syndromes in Xq28 have been associated with cerebellar hypoplasia. Given the report of several forms of XLCD and the excess of males with ataxia, this group of conditions is probably underestimated and families of patients with neuroradiological and clinical evidence of a cerebellar disorder should be counseled for high risk of X-linked inheritance.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive degenerative movement disorder characterized by kinetic tremor, cerebellar gait ataxia, parkinsonism, and cognitive decline. This disorder occurs in both males and females, frequently in families with children who have fragile X syndrome. The clinical features of this disorder, both classic and newly described, are summarized in this paper. In screening studies, fragile X mental retardation 1 (FMR1) gene premutation (55–200 CGG) expansions are most frequently seen in men with ataxia who have tested negative for spinocerebellar ataxias. Since the original description, the classic FXTAS phenotype has now been reported in females and in carriers of smaller (45–54 CGG) and larger (>200 CGG) expansions in FMR1. Premutation carriers may present with a Parkinson disease phenotype or hypotension, rather than with tremor and/or ataxia. Parkinsonism and gait ataxia may also be seen in individuals with gray zone (41–54 CGG) expansions. Studies regarding medication to treat the symptoms in FXTAS are few in number and suggest that medications targeted to specific symptoms, such as kinetic tremor or gait ataxia, may be most beneficial. Great progress has been made in regards to FXTAS research, likely given the readily available gene test and the screening of multiple family members, including parents and grandparents, of fragile X syndrome children. Expansion of genotypes and phenotypes in the disorder may suggest that a broader disease definition might be necessary in the future.
FMR1; FXTAS; genetics; ataxia; gray zone; premutation
A novel autosomal recessive condition, dilated cardiomyopathy with ataxia (DCMA) syndrome, has been identified in the Canadian Dariusleut Hutterite population, characterised by early onset dilated cardiomyopathy with conduction defects, non‐progressive cerebellar ataxia, testicular dysgenesis, growth failure, and 3‐methylglutaconic aciduria.
To map DCMA syndrome and identify the mutation underlying this condition.
A genome wide scan was undertaken on consanguineous Hutterite families using a homozygosity mapping approach in order to identify the DCMA associated chromosomal region. Mutation analysis was carried out on positional candidate genes in this region by sequencing. Reverse transcriptase polymerase chain reaction and bioinformatics analyses were then used to characterise the mutation and determine its effect on the protein product.
The association of DCMA syndrome with a 2.2 Mb region of chromosome 3q26.33 was found. A disease associated mutation was identified: IVS3‐1 G→C in the DNAJC19 gene, encoding a DNAJ domain containing protein of previously unknown function (Entrez Gene ID 131118).
The DNAJC19 protein was previously localised to the mitochondria in cardiac myocytes, and shares sequence and organisational similarity with proteins from several species including two yeast mitochondrial inner membrane proteins, Mdj2p and Tim14. Tim14 is a component of the yeast inner mitochondrial membrane presequence translocase, suggesting that the unique phenotype of DCMA may be the result of defective mitochondrial protein import. It is only the second human disorder caused by defects in this pathway that has been identified.
mitochondrial protein import; dilated cardiomyopathy; 3‐methylglutaconic aciduria
Rett syndrome (RTT), a common cause of mental retardation in girls, is associated with mutations in the MECP2 gene. Most human cases of MECP2 mutation in girls result in classical or variant forms of RTT. When these same mutations occur in males, they often present as severe neonatal encephalopathy. However, some MECP2 mutations can also lead to diseases characterized as mental retardation syndromes, particularly in boys. One of these mutations, A140V, is a common, recurring missense mutation accounting for about 0.6% of all MeCP2 mutations and ranking 21st by frequency. It has been described in familial X-linked mental retardation (XLMR), PPM- X syndrome (Parkinsonism, Pyramidal signs, Macroorchidism, X-linked mental retardation) and in other neuropsychiatric syndromes. Interestingly, this mutation has been reported to preserve the methyl-CpG binding function of the MeCP2 protein while compromising its ability to bind to the mental retardation associated protein ATRX.
We report the construction and initial characterization of a mouse model expressing the A140V MeCP2 mutation. These initial descriptive studies in male hemizygous mice have revealed brain abnormalities seen in both RTT and mental retardation. The abnormalities found include increases in cell packing density in the brain and a significant reduction in the complexity of neuronal dendritic branching. In contrast to some MeCP2 mutation mouse models, the A140V mouse has an apparently normal lifespan and normal weight gain patterns with no obvious seizures, tremors, breathing difficulties or kyphosis.
We have identified various neurological abnormalities in this mouse model of Rett syndrome/X-linked mental retardation which may help to elucidate the manner in which MECP2 mutations cause neuronal changes resulting in mental retardation without the confounding effects of seizures, chronic hypoventilation, or other Rett syndrome associated symptoms.
We report an early onset spastic ataxia-neuropathy syndrome in two brothers of a consanguineous family characterized clinically by lower extremity spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. Whole-exome sequencing identified a homozygous missense mutation (c.1847G>A; p.Y616C) in AFG3L2, encoding a subunit of an m-AAA protease. m-AAA proteases reside in the mitochondrial inner membrane and are responsible for removal of damaged or misfolded proteins and proteolytic activation of essential mitochondrial proteins. AFG3L2 forms either a homo-oligomeric isoenzyme or a hetero-oligomeric complex with paraplegin, a homologous protein mutated in hereditary spastic paraplegia type 7 (SPG7). Heterozygous loss-of-function mutations in AFG3L2 cause autosomal-dominant spinocerebellar ataxia type 28 (SCA28), a disorder whose phenotype is strikingly different from that of our patients. As defined in yeast complementation assays, the AFG3L2Y616C gene product is a hypomorphic variant that exhibited oligomerization defects in yeast as well as in patient fibroblasts. Specifically, the formation of AFG3L2Y616C complexes was impaired, both with itself and to a greater extent with paraplegin. This produced an early-onset clinical syndrome that combines the severe phenotypes of SPG7 and SCA28, in additional to other “mitochondrial” features such as oculomotor apraxia, extrapyramidal dysfunction, and myoclonic epilepsy. These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias.
Mitochondria are cellular organelles important for converting sugar or fats into energy that cells can use for their functions and survival. Many neurological diseases are the result of mitochondrial dysfunction as affected cells are unable to cope with lowered energy supplies and increased oxidative stress. These deficiencies cause accumulation of cellular damage and eventually cell death. Spastic ataxias are neurological disorders involving cells with large energy requirements, the cerebellar Purkinje cells and the cerebral upper motor neurons. When these cells function improperly or die, individuals develop symptoms of incoordination (ataxia) and abnormal muscle tone in their legs (spastic paraplegia). Using emerging techniques of whole-exome sequencing we discovered that homozygous mutations in the AFG3L2 gene caused spastic ataxia in two brothers of a consanguineous family. AFG3L2 encodes a subunit of mitochondrial matrix proteases (m-AAA proteases) that regulate the functional integrity of mitochondria. Heterozygous mutations in AFG3L2 were previously found to cause a disorder involving the Purkinje cells of the cerebellum resulting in ataxia. Interestingly, another isoform of m-AAA proteases consists of AFG3L2 complexing with paraplegin, a similar protein associated with a hereditary spastic paraplegia. Our analysis provides insight into why different mutations in m-AAA protease subunits cause different neurological disorders.
Background: Joubert syndrome (JS) is a recessively inherited disorder characterised by hypotonia at birth and developmental delay, followed by truncal ataxia and cognitive impairment, characteristic neuroimaging findings (cerebellar vermis hypoplasia, "molar tooth sign") and suggestive facial features. JS is clinically heterogeneous with some patients presenting with breathing abnormalities in the neonatal period, oculomotor apraxia, retinal dystrophy, retinal coloboma, ptosis, hexadactyly, and nephronophtisis or cystic dysplastic kidneys. JS is also genetically heterogeneous, with two known loci, on 9q34 (JBTS1) and 11p11-q12 (CORS2), representing only a fraction of cases.
Methods: A large consanguineous Joubert family (five affected) was analysed for linkage with a marker set covering the entire genome and 16 smaller families were subsequently tested for candidate loci.
Results: We report here the identification of a third locus in 6q23 (JBTS3) from the study of two consanguineous families. LOD score calculation, including the consanguinity loops, gave a maximum value of 4.1 and 2.3 at q = 0 for the two families, respectively.
Conclusions: Linkage between the disease and the D6S1620–D6S1699 haplotype spanning a 13.1 cM interval is demonstrated. Genotype-phenotype studies indicate that, unlike CORS2, JBTS3 appears not to be associated with renal dysfunction.
A novel missense mutation in the mediator of RNA polymerase II transcription subunit 12 (MED12) gene has been found in the original family with Lujan syndrome and in a second family (K9359) that was initially considered to have Opitz–Kaveggia (FG) syndrome. A different missense mutation in the MED12 gene has been reported previously in the original family with FG syndrome and in five other families with compatible clinical findings. Neither sequence alteration has been found in over 1400 control X chromosomes. Lujan (Lujan–Fryns) syndrome is characterised by tall stature with asthenic habitus, macrocephaly, a tall narrow face, maxillary hypoplasia, a high narrow palate with dental crowding, a small or receding chin, long hands with hyperextensible digits, hypernasal speech, hypotonia, mild‐to‐moderate mental retardation, behavioural aberrations and dysgenesis of the corpus callosum. Although Lujan syndrome has not been previously considered to be in the differential diagnosis of FG syndrome, there are some overlapping clinical manifestations. Specifically, these are dysgenesis of the corpus callosum, macrocephaly/relative macrocephaly, a tall forehead, hypotonia, mental retardation and behavioural disturbances. Thus, it seems that these two X‐linked mental retardation syndromes are allelic, with mutations in the MED12 gene.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG repeat expansion in the premutation range (55-200) in the fragile X mental retardation 1 gene. Onset is typically in the early seventh decade and men are principally affected. The major signs are cerebellar gait ataxia, intention tremor, frontal executive dysfunction, and global brain atrophy. Other frequent findings are parkinsonism (mild), peripheral neuropathy, psychiatric symptoms (depression, anxiety, agitation), and autonomic dysfunction. The clinical presentation is heterogeneous, with individuals presenting with varied dominating signs, such as tremor, dementia or neuropathy. MR imaging shows atrophy and patchy white matter lesions in the cerebral hemispheres and middle cerebellar peduncles. The latter has been designated the ‘MCP sign’, occurs in about 60% of affected men, and is relatively specific for FXTAS. Affected females generally have less severe disease, less cognitive decline, and some symptoms different from that of men, e.g., muscle pain. Management of FXTAS is complex and includes assessment of the patient's neurological and medical deficits, treatment of symptoms, and provision of relevant referrals, especially genetic counseling. Treatment is empiric, based on anecdotal experience and on knowledge of what works for symptoms of other disorders that also exist in FXTAS. Presently the disorder is under-recognized, since the first published report was in 2001, and since the presentation is variable and mainly consists of a combination of signs common in the elderly. However, accurate diagnosis is critical, for the patient and for the family, as they need education regarding their genetic and health risks.
fragile X tremor/ataxia syndrome; FXTAS; fragile X mental retardation 1 gene; treatment
A new group of recessively inherited metabolic disorders affecting glycoprotein metabolism has been identified--the carbohydrate-deficient-glycoprotein (CDG) syndromes. Here the course and clinical expression of CDG syndrome type I in 13 patients who have passed the age of 15 years are described. All presented with early onset psychomotor retardation, in most cases combined with slight facial dysmorphic features, some degree of hepatic dysfunction, and in one case, pericardial effusion. About half of the patients had subcutaneous lipodystrophy and comatose or stroke-like episodes during childhood. After the age of 15 the disease was mainly characterised by neurological symptoms consisting of non-progressive ataxia associated with cerebellar hypoplasia, stable mental retardation, variable peripheral neuropathy, and strabismus. One third of the patients had generalised seizures, usually sporadic, and all had retinal pigmentary degeneration. In all cases there was more or less pronounced thoracic deformity and no female had passed puberty. Also, the oldest female showed premature aging. Severe internal organ symptoms, which are common in pediatric patients, were absent. All patients had highly raised serum concentrations of the biochemical marker carbohydrate-deficient transferrin, which can be used to verify the diagnosis. It is concluded that after childhood, CDG syndrome type I is a largely non-progressive disease compatible with a socially functioning but dependent lifestyle.