Autosomal-recessive Charcot-Marie-Tooth diseases.

In certain countries around the Mediterranean basin such as Algeria, which have a high prevalence of consanguineous marriages, autosomal-recessive (AR) inheritance may account for more than 50% of all forms of Charcot-Marie-Tooth (CMT) disease. Like with the dominant forms, it is usual to differentiate the demyelinating forms (CMT 4 corresponding to autosomal-recessive CMT 1 [AR-CMT 1] from the axonal forms [AR-CMT 2]). Genetic analysis of large families with recessive transmission has uncovered novel CMT genotypes (genes: GDAP 1, MTMR 2, MTMR 13, KIAA1985, NDGR1, periaxi, lamin). The clinical and especially the histologic phenotypes often indicate that a specific gene is implicated. We present and discuss microscopic lesions seen on nerve biopsies from patients in a number of consanguineous Algerian families, and we outline the characteristic lesions that would prompt a search for mutations in genes such as MTMR 2, MTMR 13, KIAA1985, periaxin for CMT 4, and lamin for AR-CMT 2. Like with the dominant forms, there are undoubtedly many more mutations of other genes to be discovered.

[Autosomal recessive forms of Charcot-Marie-Tooth disease]. / Formes autosomales récessives de la maladie de Charcot-Marie-Tooth.

In some countries with a high prevalence of consanguineous mariage, autosomal recessive inheritance probably accounts for the vast majority of all forms of CMT. Like dominant forms, autosomal recessive forms are generally subdivided into demyelinating forms (autosomal recessive CMT1: AR-CMT1 or CMT4) and axonal forms (AR-CMT2). Genetic analysis of large families with recessive transmission has identified several novel CMT-related genes (GDAP1, MTMR2, MTMR13, KIAA1985, NDGR1, periaxin and lamin). Given the clinical, electrophysiological and histological heterogeneity of this disease, numerous culprit genes probably remain to be discovered, leading to an even more complex classification. Clinical and histological features often point to the involvement of a particular gene. Nerve biopsy and molecular studies can contribute to the diagnosis, but this approach is highly time-consuming and can only be performed in specialized laboratories.

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.

Diagnostic value of ultrastructural nerve examination in Charcot-Marie-Tooth disease: two CMT 1B cases with pseudo-recessive inheritance.

We report two sporadic patients of CMT disease in different consanguineous families. The electrophysiological examination led to the diagnosis of a severe demyelinating neuropathy. The nerve biopsies exhibited numerous outfoldings of the myelin sheaths and onion-bulb proliferations. The consanguinity and the histological findings pointed to a diagnosis of CMT 4B. However, the detection of abnormal and regular widenings between the major dense lines of the myelin lamellae by electron microscopy led us to search for a P0 gene mutation. Two heterozygous mutations of this gene were identified: S63F and N131Y. Different aspects of uncompacted myelin lamellae have been described in some cases of P0 mutations and a few now appear to be quite specific to it. More than 30 genes are implicated in CMT and as mutation search is time- and money-consuming, we believe that in some selected patients ultrastructural examination of nerves, among other criteria, helps orientate the molecular diagnosis of CMT.

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.

Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse.

The Charcot-Marie-Tooth (CMT) disorders comprise a group of clinically and genetically heterogeneous hereditary motor and sensory neuropathies, which are mainly characterized by muscle weakness and wasting, foot deformities, and electrophysiological, as well as histological, changes. A subtype, CMT2, is defined by a slight or absent reduction of nerve-conduction velocities together with the loss of large myelinated fibers and axonal degeneration. CMT2 phenotypes are also characterized by a large genetic heterogeneity, although only two genes---NF-L and KIF1Bbeta---have been identified to date. Homozygosity mapping in inbred Algerian families with autosomal recessive CMT2 (AR-CMT2) provided evidence of linkage to chromosome 1q21.2-q21.3 in two families (Zmax=4.14). All patients shared a common homozygous ancestral haplotype that was suggestive of a founder mutation as the cause of the phenotype. A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family. Ultrastructural exploration of sciatic nerves of LMNA null (i.e., -/-) mice was performed and revealed a strong reduction of axon density, axonal enlargement, and the presence of nonmyelinated axons, all of which were highly similar to the phenotypes of human peripheral axonopathies. The finding of site-specific amino acid substitutions in limb-girdle muscular dystrophy type 1B, autosomal dominant Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy type 1A, autosomal dominant partial lipodystrophy, and, now, AR-CMT2 suggests the existence of distinct functional domains in lamin A/C that are essential for the maintenance and integrity of different cell lineages. To our knowledge, this report constitutes the first evidence of the recessive inheritance of a mutation that causes CMT2; additionally, we suggest that mutations in LMNA may also be the cause of the genetically overlapping disorder CMT2B1.