Phenotypic and genetic exploration of severe demyelinating and secondary axonal neuropathies resulting from GDAP1 nonsense and splicing mutations.

We identified two novel GDAP1 homozygous mutations in children affected with severe demyelinating peripheral neuropathies and born to consanguineous parents. A 9 year old Lebanese girl carried a nonsense mutation in exon 5 and two Algerian brothers aged 10 and 8 years carried a mutation at the intron 3 acceptor splicing site. The clinical, electrophysiological, and neuropathological explorations showed common features consistent with a severe demyelinating peripheral neuropathy associated with loss of major fibres. Our findings, supported by the first GDAP1 expression study in patients, show further evidence that mutations in this gene cause an autsomal recessive severe demyelinating peripheral phenotype (CMT4A) associated with axon loss. Charcot-Marie-Tooth disease (CMT) (also called hereditary motor and sensory neuropathy (HMSN)) is clinically, electrophysiologically, and genetically extremely heterogeneous with more than 40 loci and 16 genes identified to date. The most common inherited peripheral neuropathies are CMT type 1 and CMT type 2, which are characterised by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Myelination is mainly affected in CMT1, with neuropathological findings of demyelination and remyelination with onion bulb formation, clusters of regeneration, and Schwann cell proliferation. CMT2 is an axonal neuropathy characterised by the reduction of fibre density in the absence of clusters of myelin regeneration or proliferation of Schwann cells. Very often, neuropathological analysis of patients carrying demyelinating neuropathies shows concomitant axon fibre loss. A motor nerve conduction velocity (MNCV) threshold value of 38 ms at the median nerve is used to classify patients with CMT as being either CMT1 (MNCV<38 ms) or CMT2 (MNCV>38 ms). CMT4A defines a particularly severe polyneuropathy of the demyelinating type, associated with distal weakness and atrophy of the limbs, with early onset. The muscular atrophy rapidly progresses, extending proximally and leading to inability to walk by the end of the first decade. Skeletal deformities and scoliosis are frequent. Mutations in the ganglioside induced differentiation associated protein 1 gene (GDAP1) at chromosome 8q21.3 were originally reported in families carrying typical CMT4A and in families affected with autosomal recessive axonal CMT associated with vocal cord paresis. Other GDAP1 mutations in patients affected with demyelinating and axonal peripheral neuropathies have recently been reported. The 12 published GDAP1 mutations are listed in table 1. Here we report on two families, of Lebanese and Algerian origin, in which two new mutations in GDAP1 have been found. All affected persons had clinical, electrophysiological,