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Phenotypic and genetic exploration of severe demyelinating and secondary axonal neuropathies resulting from GDAP1 nonsense and splicing mutations
  1. A De Sandre-Giovannoli1,
  2. M Chaouch2,
  3. I Boccaccio1,
  4. R Bernard4,
  5. V Delague3,
  6. D Grid5,
  7. J M Vallat6,
  8. N Lévy1,4,
  9. A Mégarbané3
  1. 1Inserm U491, Génétique Médicale et Développement, Faculté de Médecine la Timone, 13385 Marseille, France
  2. 2Service de Neurologie, Centre Hospitalier Univérsitaire Ben Aknoun, Algiers, Algeria
  3. 3Unité de Génétique Médicale, Université Saint-Joseph, Faculté de Médecine, BP 11–5076, Beyrouth, Lebanon
  4. 4Département de Génétique Médicale, Hôpital d’Enfants de la Timone, 13385 Marseille, France
  5. 5Généthon III, Evry, France
  6. 6Service et Laboratoire de Neurologie, Centre Hospitalier Universitaire Dupuytren, Limoges, France
  1. Correspondence to:
 Dr N Lévy, Inserm U491, Génétique Médicale et Développement, Faculté de Médecine la Timone, 13385 Marseille Cedex 05, France; 

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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.1 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.2 A motor nerve conduction velocity (MNCV) threshold value of 38 ms−1 at the median nerve is used to classify patients with CMT as being either CMT1 (MNCV<38 ms−1) or CMT2 (MNCV>38 ms−1). 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 …

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