Ataxia with oculomotor apraxia type 2: a clinical and genetic study of 19 patients.

Ataxia with oculo-motor apraxia type 2 (AOA2) is a recently described autosomal recessive cerebellar ataxia (ARCA) caused by mutations in the senataxin gene (SETX). We analysed the phenotypic spectrum of 19 AOA2 patients with mutations in SETX, which seems to be the third most frequent form of ARCA in Algeria after Freidreich ataxia and Ataxia with vitamin E deficiency. In AOA2 patients, the mean age at onset for all families was in the second decade. Cerebellar ataxia was progressive, slowly leading to disability which was aggravated by axonal polyneuropathy present in almost all the patients. Mean disease duration until wheelchair was around 20 years. Oculo-motor apraxia (OMA) was present in 32% of the patients while convergent strabismus was present in 37%. Strabismus is therefore also very suggestive of AOA2 when associated with ataxia and polyneuropathy even in the absence of OMA. Cerebellar atrophy was more severe in the eldest patients; however it may also be an early sign since it was present in the youngest and paucisymptomatic patients. The initial sign was gait ataxia in all but two patients who presented with head tremor and writer cramp, respectively. Serum alpha-fetoprotein, which was elevated in all tested patients, was a good marker to suggest molecular studies of the SETX gene.

Genetic heterogeneity in giant axonal neuropathy: an Algerian family not linked to chromosome 16q24.1.

Giant axonal neuropathy is a rare severe autosomal recessive childhood disorder affecting both the peripheral nerves and the central nervous system. Peripheral nerves characteristically show giant axonal swellings filled with neurofilaments. The giant axonal neuropathy gene was localised by homozygosity mapping to chromosome 16q24.1 and identified as encoding a novel, ubiquitously expressed cytoskeletal protein named gigaxonin.We describe a consanguineous Algerian family with three affected sibs aged 16, 14 and 12 years who present a mild demyelinating sensory motor neuropathy, hypoacousia and kyphoscoliosis which was moderate in the two elder patients, severe in the third one, with no sign of central nervous system involvement and normal cerebral magnetic resonance imaging. This clinical picture is different from the classical severe form, with kinky hairs and early onset of central nervous system involvement and from the less severe form, with protracted course and late involvement of central nervous system. Nerve biopsy showed a moderate loss of myelinated fibers and several giant axons with thin or absent myelin, filled with neurofilaments. This neuropathological aspect is similar to the previously described families linked to the gigaxonin gene. Genetic study in this family showed absence of linkage to chromosome 16q24.1, indicating for the first time, a genetic heterogeneity in giant axonal neuropathy. We propose to call this form of giant axonal neuropathy giant axonal neuropathy 2, and to use the name of giant axonal neuropathy 1 for the form linked to 16q24.1.

Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.

We report two sisters, aged 11 and 6years, with AGAT deficiency syndrome (OMIM 612718) which is the least common creatine deficiency syndrome. They were born full-term to consanguineous parents and had moderate developmental delay. Examination showed an important language delay, a progressive proximal muscular weakness in the lower limbs with Gowers sign and myopathic electromyography. Investigations revealed undetectable guanidinoacetate and low level of creatine in plasma and urine, characteristic findings of AGAT deficiency syndrome. Brain magnetic resonance spectroscopy showed a markedly reduced level of creatine. Guanidinoacetate methyltransferase (GATM) gene sequencing revealed a homozygous missense mutation in exon 4:c.608A>C, (p.Tyr203Ser). Thirteen months after beginning the treatment with oral creatine monohydrate 200mg/kg/day, then 400mg/kg/day, there was a dramatic improvement in muscle strength with Gowers sign disappearance in both patients, and a mild improvement in language and cognitive functions. AGAT deficiency syndrome should be considered in all patients with language retardation and cognitive impairment associated to a myopathy of unknown etiology such that early diagnosis must lead to creatine supplementation to cure the myopathy and improve language and cognitive function.

Founder effect and estimation of the age of the c.892C>T (p.Arg298Cys) mutation in LMNA associated to Charcot-Marie-Tooth subtype CMT2B1 in families from North Western Africa.

CMT2B1, an axonal subtype (MIM 605588) of the Charcot-Marie-Tooth disease, is an autosomal recessive motor and sensory neuropathy characterized by progressive muscular and sensory loss in the distal extremities with chronic distal weakness. The genetic defect associated with the disease is, to date, a unique homozygous missense mutation, p.Arg298Cys (c.892C>T), in the LMNA gene. So far, this mutation has only been found in affected individuals originating from a restricted region of North Western Africa (northwest of Algeria and east of Morocco), strongly suggesting a founder effect. In order to address this hypothesis, genotyping of both STRs and intragenic SNPs was performed at the LMNA locus, at chromosome 1q21.2-q21.3, in 42 individuals affected with CMT2B1 from 25 Algerian families. Our results indicate that the affected individuals share a common ancestral haplotype in a region of about 1.0 Mb (1 cM) and that the most recent common ancestor would have lived about 800-900 years ago (95% confidence interval: 550 to 1300 years).

The CHRNE 1293insG founder mutation is a frequent cause of congenital myasthenia in North Africa.

OBJECTIVE: Mutations in various genes of the neuromuscular junction cause congenital myasthenic syndrome (CMS). A single truncating mutation (epsilon1293insG) in the acetylcholine receptor epsilon subunit gene (CHRNE) was most often identified in CMS families originating from North Africa and was possibly a founder mutation. METHODS: Twenty-three families were studied with an early onset form of CMS and originating from Tunisia, Algeria, Morocco, and Libya. Screening for the mutation epsilon1293insG was performed by direct sequencing. Haplotype analysis was done with 9 (CA)n repeat microsatellite markers and 6 SNPs flanking epsilon1293insG on chromosome 17p13-p12. Dating was calculated using the ESTIAGE method for rare genetic diseases. RESULTS: The epsilon1293insG mutation was identified in 14 families (about 60% of the initial 23). The expression of the CMS in affected members of these families was relatively homogeneous, without fetal involvement or being life-threatening, with moderate hypotonia and oculobulbar involvement, mild and stable disease course, and good response to cholinesterase inhibitors. Haplotype analysis revealed a common conserved haplotype encompassing a distance of 63 kb. The estimated age of the founder event was at least 700 years. CONCLUSIONS: These results strongly support the hypothesis that epsilon1293insG derives from an ancient single founder event in the North African population. Identification of founder mutations in isolated or inbred populations may have important implications in the context of molecular diagnosis and genetic counseling of patients and families by detection of heterozygous carriers.

Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked, and autosomal recessive (AR) CMT. A locus responsible for the demyelinating form of ARCMT was assigned to the 5q23-q33 region (CMT4C) by homozygosity mapping. Recently, 11 mutations were identified in the SH3TC2 (KIAA1985) gene in 12 families with demyelinating ARCMT from Turkish, Iranian, Greek, Italian, or German origin. OBJECTIVE: To identify mutations in the SH3TC2 gene. METHODS: The authors searched for SH3TC2 gene mutations in 10 consanguineous CMT families putatively linked to the CMT4C locus on the basis of haplotype segregation and linkage analysis. RESULTS: Ten families had mutations, eight of which were new and one, R954X, recurrent. Six of the 10 mutations were in exon 11. Onset occurred between ages 2 and 10. Scoliosis or kyphoscoliosis and foot deformities were found in almost all patients and were often inaugural. The median motor nerve conduction velocity values (

Phenotypic variability in autosomal recessive axonal Charcot-Marie-Tooth disease due to the R298C mutation in lamin A/C.

Autosomal recessive forms of axonal Charcot-Marie-Tooth (ARCMT2) disease are frequent in some areas, such as North Africa and the Middle East, since consanguineous marriages are still common there. Recently, a unique homozygous mutation in LMNA, which encodes lamin A/C, a component of the nuclear envelope, was identified in members of three Algerian families with ARCMT2 linked to chromosome 1q21.2-q21.3. In the present study we describe a group of 21 ARCMT2 patients from seven unrelated Algerian families with the same R298C mutation in the lamin A/C gene and marked variability of the clinical phenotype. There is a wide range of age of onset, from 6 to 27 years, with a mean of 14.4 +/- 4.6 years. The course of the disease varies considerably from one patient to another. Twelve patients with a disease duration of 10-15 years had a severe CMT phenotype with distal wasting and weakness of all four limbs and areflexia associated with involvement of the proximal lower limb muscles. In contrast, nine patients had the classical CMT phenotype with mild functional disability without proximal lower limb involvement after a disease duration of 5-18 years. Electrophysiological studies showed a median motor nerve conduction velocity (MNCV) in the normal range in almost all the patients. MNCV and compound muscle action potential (CMAP) values were inversely correlated with the disease duration and the MNCV was strictly related to the CMAP, strongly supporting a pure axonal process without a demyelinating component. Six patients had a nerve biopsy, which revealed severe rarefaction of myelinated fibres in all cases and an increased density of unmyelinated fibres in the majority of cases. In conclusion, the ARCMT2 associated with the R298C mutation differs from other types of ARCMT2. The variability among patients in the age of onset and the course of the disease strongly suggests the action of modifying genes, which remain to be identified.