Tarik Hamadouche

Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H.

Charcot-Marie-Tooth (CMT) disorders are a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies characterized by muscle weakness and wasting, foot and hand deformities, and electrophysiological changes. The CMT4H subtype is an autosomal recessive demyelinating form of CMT that was recently mapped to a 15.8-Mb region at chromosome 12p11.21-q13.11, in two consanguineous families of Mediterranean origin, by homozygosity mapping. We report here the identification of mutations in FGD4, encoding FGD4 or FRABIN (FGD1-related F-actin binding protein), in both families. FRABIN is a GDP/GTP nucleotide exchange factor (GEF), specific to Cdc42, a member of the Rho family of small guanosine triphosphate (GTP)-binding proteins (Rho GTPases). Rho GTPases play a key role in regulating signal-transduction pathways in eukaryotes. In particular, they have a pivotal role in mediating actin cytoskeleton changes during cell migration, morphogenesis, polarization, and division. Consistent with these reported functions, expression of truncated FRABIN mutants in rat primary motoneurons and rat Schwann cells induced significantly fewer microspikes than expression of wild-type FRABIN. To our knowledge, this is the first report of mutations in a Rho GEF protein being involved in CMT.

LRRK2 G2019S mutation in Parkinson’s disease: A neuropsychological and neuropsychiatric study in a large Algerian cohort ☆

A series of 106 patients with isolated or familial Parkinsonism underwent clinical evaluation and genetic testing for the LRRK2 G2019S mutation which was identified in 34/106 patients (32%). Seventy one of them accepted to be evaluated for neuropsychological and neuropsychiatric studies with the aim to compare mutation carriers with non-carriers. For neuropsychological testing, comparisons between LRRK2 G2019S carriers and non-carriers were made after stratification according to the level of education: median and high school versus low level. Memory was investigated with the five words test, 2 novel tests with verbalized visual material dedicated to illiterate patients, the TNI-93 (nine pictures test), The TMA-93 (associative memory test), and digit spans (forward/backward). Cognitive analyse did not show major differences between the two groups of patients. Nevertheless, behavioral abnormalities, mostly depression and hallucinations, were more frequent in the LRRK2 G2019S carriers, suggesting the presence of a greater involvement of the limbic system in these patients. Sleep disorders which were also more common amongst mutation carriers than non-carriers might be related to depression.

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.

Charcot-Marie-Tooth 2-like presentation of an Algerian family with giant axonal neuropathy

Giant axonal neuropathy is a rare autosomal recessive childhood disorder characterized by a peripheral neuropathy and features of central nervous system involvement. We describe four patients belonging to a consanguineous Algerian family with late onset (6-10 years) slowly progressive autosomal recessive giant axonal neuropathy. The propositus presented with a Charcot-Marie-Tooth 2-like phenotype with foot deformity, distal amyotrophy of lower limbs, areflexia and distal lower limb hypoesthesia. Central nervous system involvement occurred 10 years later with mild cerebellar dysarthria and nystagmus in the propositus and 16 years after onset, a spastic paraplegia in the oldest patient. The two youngest patients (13 and 8 years old) do not present any signs of central nervous involvement. Magnetic resonance imaging showed cerebellar atrophy in the two older. Nerve biopsy showed moderate axonal loss with several giant axons filled with neurofilaments. Genetic study established a linkage to chromosome 16q locus. This clinical presentation differs from the classical form of giant axonal neuropathy.

Autosomal recessive hereditary neuropathy with focally folded myelin sheaths and linked to chromosome 11q23: a distinct and homogeneous entity

We describe a six generation Saudi kindred, with a recessive hereditary motor and sensory neuropathy (HMSN). Four individuals were affected including two children (a boy and a girl) and a 23-year-old man. The fourth (a female) died at the age of 14 years. Onset of the disease was early (< 2 years) and the clinical and neurophysiological features were, generally, quite similar to those of an Italian family linked to chromosome 11q23. The peculiar pathologic pattern was irregular and redundant loops associated with folding of the myelin sheaths. The genetic study confirmed linkage to chromosome 11q23 and refined the location of the gene between D11S1311 and D11S917, a 3.3 cM region. These findings support the existence of a homogeneous and distinct entity within the form of HMSN associated with focally folded myelin sheaths.

Molecular and clinical study of a cohort of 110 Algerian patients with autosomal recessive ataxia

BackgroundAutosomal recessive cerebellar ataxias (ARCA) are a complex group of neurodegenerative disorders with great genetic and phenotypic heterogeneity, over 30 genes/loci have been associated with more than 20 different clinical forms of ARCA. Genetic heterogeneity combined with highly variable clinical expression of the cerebellar symptoms and overlapping features complicate furthermore the etiological diagnosis of ARCA. The determination of the most frequent mutations and corresponding ataxias, as well as particular features specific to a population, are mandatory to facilitate and speed up the diagnosis process, especially when an appropriate treatment is available.MethodsWe explored 166 patients (115 families) refered to the neurology units of Algiers central hospitals (Algeria) with a cerebellar ataxia phenotype segregating as an autosomal recessive pattern of inheritance. Genomic DNA was extracted from peripheral blood samples and mutational screening was performed by PCR and direct sequencing or by targeted genomic capture and massive parallel sequencing of 57 genes associated with inherited cerebellar ataxia phenotypes.ResultsIn this work we report the clinical and molecular results obtained on a large cohort of Algerian patients (110 patients/76 families) with genetically determined autosomal recessive ataxia, representing 9 different types of ARCA and 23 different mutations, including 6 novel ones. The five most common ARCA in this cohort were Friedreich ataxia, ataxia with isolated vitamin E deficiency, ataxia with oculomotor apraxia type 2, autosomal recessive spastic ataxia of Charlevoix-Saguenay and ataxia with oculomotor apraxia type 1.ConclusionWe report here a large cohort of patients with genetically determined autosomal recessive ataxia and the first study of the genetic context of ARCA in Algeria. This study showed that in Algerian patients, the two most common types of ataxia (Friedreich ataxia and ataxia with isolated vitamin E deficiency) coexist with forms that may be less common or underdiagnosed. To refine the genotype/phenotype correlation in rare and heteregeneous diseases as autosomal recessive ataxias, more extensive epidemiological investigations and reports are necessary as well as more accurate and detailed clinical characterizations. The use of standardized clinical and molecular protocols would thus enable a better knowledge of the different forms of ARCA.

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.

Two novel missense mutations in FGD4/FRABIN cause Charcot‐Marie‐Tooth type 4H (CMT4H)

By sequencing of the FGD4 coding sequence in a cohort of 101 patients affected by autosomal recessive demyelinating Charcot‐Marie‐Tooth disease (CMT), we have identified two novel missense mutations in FGD4 in two patients from consanguineous descent: p.Arg442His in an Algerian patient and p.Met566Ile in a Lebanese girl. The patients present early onset, slowly progressive CMT, with drastic reduction of nerve conduction velocities. These mutations are the second and third missense mutations characterized in FGD4. They are likely to lead to conformational changes in the PH1 and FYVE domains.

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.