Sonia Nouioua

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.

Autosomal recessive Charcot‐Marie‐Tooth disease: from genes to phenotypes

The prevalence of Charcot‐Marie‐Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) varies in different populations. While in some countries of Western Europe, the United States and Japan the dominant form of HMSN is the most frequent, in other countries such as those of the Mediterranean Basin, the autosomal recessive form (AR‐CMT) is more common. Autosomal recessive CMT cases are generally characterized by earlier onset, usually before the age of 2 or 3  years, and rapid clinical progression that results in severe polyneuropathy and more marked distal limb deformities such as pes equino‐varus, claw‐like hands, and often major spinal deformities. Recent clinical, morphological and molecular investigations of CMT families with autosomal recessive inheritance allowed the identification of many genes such as GDAP1, MTMR2, SBF2, NDRG1, EGR2, SH3TC2, PRX, FGD4, and FIG4, implicated in demyelinating forms (ARCMT1 or CMT4), and LMNA, MED25, HINT1, GDAP1, LRSAM1, NEFL, HSPB1 and MFN2 in axonal forms (ARCMT2). However, many patients remain without genetic diagnosis to date, prompting investigations into ARCMT families in order to help discover new genes and common pathways. This review summarizes recent advances regarding the genotypes and corresponding phenotypes of AR‐CMT.

Phenotypic variability in giant axonal neuropathy

Giant axonal neuropathy (GAN), a severe childhood disorder affecting both the peripheral nerves and the central nervous system, is due to mutations in the GAN gene encoding gigaxonin, a protein implicated in the cytoskeletal functions and dynamics. In the majority of the GAN series reported to date, patients had the classical clinical phenotype characterized by a severe axonal neuropathy with kinky hair and early onset CNS involvement including cerebellar and pyramidal signs. We present 12 patients (6 families) with GAN mutations and different clinical phenotypes. Four families were harbouring an identical homozygous nonsense mutation but with different severe clinical phenotypes, one patient had a novel missense homozygous mutation with a peculiar moderate phenotype and prominent skeletal deformations. The last family (4 patients) harbouring a homozygous missense mutation had the mildest form of the disease. In contrast with recent reported series of patients with typical GAN clinical features, the present series demonstrate obvious clinical heterogeneity.

Hereditary motor and sensory neuropathies or Charcot–Marie–Tooth diseases: An update

Hereditary motor and sensory neuropathies (HMSN) or Charcot-Marie-Tooth (CMT) diseases are the most common degenerative disorders of the peripheral nervous system. However, the frequency of the different subtypes varies within distinct populations. Although more than seventy clinical and genetic forms are known to date, more than 80% of CMT patients in Western countries have genetic abnormalities associated with PMP22, MPZ, MFN2 and GJB1. Given the considerable genetic heterogeneity of CMT, we emphasize the interest of both clinical and pathological specific features such that focused genetic testing could be performed. In this regard, peripheral nerve lesions in GDAP1 mutations (AR CMT1A), such as mitochondrial abnormalities, have been newly demonstrated. Otherwise, while demyelinating autosomal recessive CMT used to be classified as CMT4 (A, B, C …), we propose a simplified classification such as AR CMT1 (A, B, C …), and AR CMT2 for axonal forms. Also, we stress that next generation sequencing techniques, now considered to be the most efficient methods of genetic testing in CMT, will be helpful in molecular diagnosis and research of new genes involved. Finally, while no effective therapy is known to date, ongoing new therapeutic trials such as PXT3003 (a low dose combination of the three already approved drugs baclofen, naltrexone, and D-sorbitol) give hopes for potential curative treatment.

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.

Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide

BACKGROUND Arginine:glycine aminotransferase (AGAT) (GATM) deficiency is an autosomal recessive inborn error of creative synthesis. OBJECTIVE We performed an international survey among physicians known to treat patients with AGAT deficiency, to assess clinical characteristics and long-term outcomes of this ultra-rare condition. RESULTS 16 patients from 8 families of 8 different ethnic backgrounds were included. 1 patient was asymptomatic when diagnosed at age 3 weeks. 15 patients diagnosed between 16 months and 25 years of life had intellectual disability/developmental delay (IDD). 8 patients also had myopathy/proximal muscle weakness. Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels. 3 families had protein truncation/null mutations. The rest had missense and splice mutations. Treatment with creatine monohydrate (100-800 mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy. The 2 patients treated since age 4 and 16 months had normal cognitive and behavioral development at age 10 and 11 years. Late treated patients had limited improvement of cognitive functions. CONCLUSION AGAT deficiency is a treatable intellectual disability. Early diagnosis may prevent IDD and myopathy. Patients with unexplained IDD with and without myopathy should be assessed for AGAT deficiency by determination of urine/plasma GAA and cerebral creatine levels (via brain MRS), and by GATM gene sequencing.

Novel mutations in the PRX and the MTMR2 genes are responsible for unusual Charcot-Marie-Tooth disease phenotypes

Autosomal recessive Charcot-Marie-Tooth diseases, relatively common in Algeria due to high prevalence of consanguineous marriages, are clinically and genetically heterogeneous. We report on two consanguineous families with demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMT4) associated with novel homozygous mutations in the MTMR2 gene, c.331dupA (p.Arg111LysfsX24) and PRX gene, c.1090C>T (p.Arg364X) respectively, and peculiar clinical phenotypes. The three patients with MTMR2 mutations (CMT4B1 family) had a typical phenotype of severe early onset motor and sensory neuropathy with typical focally folded myelin on nerve biopsy. Associated clinical features included vocal cord paresis, prominent chest deformities and claw hands. Contrasting with the classical presentation of CMT4F (early-onset Dejerine-Sottas phenotype), the four patients with PRX mutations (CMT4F family) had essentially a late age of onset and a protracted and relatively benign evolution, although they presented marked spine deformities. These observations broaden the spectrum of clinical phenotypes associated with these two CMT4 forms.

G.P.18.01 Giant axonal neuropathy: Phenotype–genotype correlations in two cases with two novel mutations in the Gigaxonin gene

Background: Pompe disease is caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), resulting in glycogen accumulation in the lysosomes of muscle cells, and ultimately muscle weakness and cardiorespiratory failure. Previously we have shown that we can effectively treat a mouse model of Pompe disease with an AAV8 vector expressing GAA from a liver-restricted promoter, reducing glycogen to background levels and preventing loss of motor function. If aged Pompe mice with pre-existing muscle pathology were treated however, only partial function was recovered, and skeletal muscles retained residual glycogen. Objective: To enhance vector potency for treating more established disease, we evaluated a chimeric GAA construct (AAV8/SP-GAA) containing an alternative signal peptide derived from a highly secreted protein (alpha1-antitrypsin), designed to increase the efficiency of GAA secretion from the liver into circulation. Methods/Results: In the current study we compared AAV8/DC190-GAA (with the native secretion signal) to the chimeric vector to determine whether we could significantly increase circulating GAA levels from a given dose of virus and thereby clear glycogen more effectively. At equivalent doses AAV8/SP-GAA generated 2–3 fold higher serum levels of GAA than AAV8/DC190-GAA, but glycogen clearance from skeletal muscle was similar. Since uptake from serum into skeletal muscle is through the cation-independent mannose-6-phosphate receptor (CI-MPR), we evaluated the phosphorylation status of the GAA generated from the two vectors by analyzing serum samples on a CI-MPR affinity column. We found that the GAA generated from AAV8/DC190-GAA showed 6-fold higher binding to the CI-MPR column than that generated from AAV8/SP-GAA. Conclusion: The relatively lower phosphorylation of serum GAA produced from the AAV8/SP-GAA vector may explain the equivalent efficacies of the two vectors despite higher levels of circulating enzyme from AAV8/SP-GAA.