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Charcot-Marie-Tooth Disease Type 2A From Typical to Rare Phenotypic and Genotypic Features

Francesco Bombelli, MD1; Tanya Stojkovic, MD1; Odile Dubourg, MD, PhD1; Andoni Echaniz-Laguna, MD, PhD2; Sandrine Tardieu, BS3; Kathy Larcher, BS3; Patrizia Amati-Bonneau, MD, PhD4; Philippe Latour, MD, PhD5; Odile Vignal, MD6; Cécile Cazeneuve, PharmD, PhD3,7; Alexis Brice, MD, PhD3,7,8; Eric Leguern, MD, PhD3,7,8
[+] Author Affiliations
1Groupe Hospitalier (GH) Pitié-Salpêtrière, Centre de Référence des Maladies Neuromusculaires Paris Est, Institut de Myologie, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France
2Département de Neurologie, Hôpitaux Universitaires, Centre Hospitalier Universitaire (CHU) de Strasbourg, Strasbourg, France
3Département de Génétique et de Cytogénétique, GH Pitié-Salpêtrière, AP-HP, Paris, France
4Département de Biochimie et Génétique, CHU Angers, Angers, France
5Département de Biochimie, Centre de Biologie Est, Hospices Civils de Lyon, Bron, France
6Service d’Ophtalmologie, Fondation Rothschild, Paris, France
7Institut National de la Santé et de la Recherche Médicale U 1127, Institut du Cerveau et de la Moelle Epiniere, Hôpital Pitié-Salpêtrière, Paris, France
8Université Pierre et Marie Curie-Paris-6, UMR S 1127, Cnrs UMR 7225 Paris, France
JAMA Neurol. 2014;71(8):1036-1042. doi:10.1001/jamaneurol.2014.629.
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Importance  Axonal Charcot-Marie-Tooth disease (CMT) is genetically heterogeneous, with 11 genes identified. Axonal CMT has most frequently been associated with mutations in the MFN2 gene (CMT2A).

Objectives  To describe the clinical and molecular features of CMT2A, to delineate prognostic factors, to understand connections between a certain phenotype and more serious clinical consequences, and to identify interactions among the associated genes.

Evidence Review  We describe the clinical, molecular, electrophysiological, and additional features of 43 patients with CMT2A. The degree of physical disability was determined by the CMT neuropathy score and adapted to the CMT neuropathy score gradient to evaluate the clinical course. We evaluated all data within the context of the most recent and important publications concerning this issue.

Findings  Twenty-five patients had early-onset CMT2A and severe functional disability, with 9 being wheelchair bound, and 18 had late-onset disease and a milder phenotype. Optic atrophy, vocal cord palsy, and auditory impairment were observed in 5, 6, and 2 patients, respectively. Among the 24 patients who underwent magnetic resonance imaging of the spinal cord, 6 had evidence of spinal atrophy with or without hydromyelia. In 1 patient, magnetic resonance imaging revealed hydrocephalus. Twenty different MFN2 mutations were identified, and 14 were considered new variants. Their transmission was predominantly autosomal dominant, with vertical transmission in 8 and de novo occurrence in 3. However, we also identified rare types of transmission, especially a germinal mosaicism and an autosomal recessive inheritance. One patient carried a rare variant in the GDAP1 gene and another in the OPA1 gene in association with MFN2 mutation.

Conclusions and Relevance  Charcot-Marie-Tooth disease type 2A associated with MFN2 mutations is clinically very heterogeneous. Ranging from a mild to a severe form, CMT2A exhibits various types of transmission. Optic atrophy and vocal cord palsy were observed in patients with severe disability and an early-onset form and also in patients with later onset. Hydromyelia and spinal cord atrophy support central nervous system involvement in CMT2A.

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Figure 1.
Magnetic Resonance Image (MRI) of the Brain of Patient 40 at Age 24 Years

Axial fluid-attenuated inversion recovery MRI reveals cortical atrophy and dilated ventricles. A indicates anterior; L, left.

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Figure 2.
Distribution of Disease-Associated Mutations in the MFN2 Protein

Schematic representation of the MFN2 protein and location of mutations. Cc1 and Cc2 indicate coil-coiled domains; GTPase, glutamyl transpeptidase; and TM, transmembrane domain. Numbers under the protein scaffold indicate the position of amino acids delimiting the different domains; 2× and 3× indicate the number of families with the mutation. Adapted from Knott and Bossy-Wetzel10 and Verhoeven et al.11aIndicates de novo mutation.

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Figure 3.
Pedigree of Family 2

Genotypes for the MFN2 and OPA1 genes are noted under the symbol of family members. Circle indicates female; square, male; solid symbols, affected; open symbols, healthy; and plus sign, wild type. The numbers in parentheses correspond to the patient numbers used in the text and the eTable in the Supplement.

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