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Published on: January 7, 2019
Expanding the Clinical Spectrum of DRP2-Associated Charcot-Marie-Tooth Disease
Rafael Sivera1, Ana L Pelayo-Negro1, Ivonne Jericó1
1From the Servicio de Neurología (R.S., J.I.T., T.S.) and Servicio de Neurofisiología (E.M.), Unidad de Enfermedades Neuromusculares, Hospital Universitari i Politècnic La Fe, Grupo de Investigación en enfermedades neuromusculares y ataxias, Instituto de Investigación Sanitaria La Fe, Valencia; CIBER de enfermedades raras (CIBERER) (R.S., C.D.-G., I.A., J.J.V., C.E., T.S.) and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (A.L.P.-N., E.G.), Instituto de Salud Carlos III, Madrid; Servicio de Neurología (A.L.P.-N.), Hospital Universitario Marqués de Valdecilla (IDIVAL), Santander; Departamento de Neurología (I.J., M.I.P.L.), Hospital Universitario de Navarra, Instituto de Investigación Sanitaria de Navarra-IdiSNA, Pamplona; Servicio de Neurología (C.D.-G., L.B.-G.), Unidad de Enfermedades Neuromusculares, Hospital Universitario 12 de Octubre, Grupo de Investigación en Enfermedades mitocondriales y neuromusculares, Instituto de Investigación imas12; Servicio de Neurología (A.H.) and Unidad de Genética Clínica (M.M.F.-C.), Servicio de Análisis Clínicos, Instituto de Medicina de Laboratorio, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos de Madrid-IdISSC; Servicio de Neurología (F.J.R.D.R.), Instituto de Investigación Sanitaria del Hospital Universitario La Paz - IDIPAZ, Hospital Universitario La Paz, Universidad Autónoma de Madrid; Servicio de Radiodiagnóstico (E.G.), Hospital Universitario Marqués de Valdecilla, Santander; Grupo de Investigación en enfermedades neuromusculares y ataxias (I.A., J.J.V.), Instituto de Investigación Sanitaria La Fe, Valencia; Área de Neurología (M.C.), Health in code; Unidad de Genética Clínica (M.M.F.-C.), Servicio de Análisis Clínicos, Instituto de Medicina de Laboratorio, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos de Madrid-IdISSC; Lab of Rare Neurodegenerative Diseases (C.E.), Centro de Investigación Príncipe Felipe (CIPF), Valencia; Unidad de Medicina Genómica (M.A.-R.), Instituto de Investigación Sanitaria de Navarra-IdiSNA, Universidad Pública de Navarra (UPNA), Navarrabiomed, Hospital Universitario de Navarra (HUN), Pamplona; and Departamento de Medicina (T.S.), Universitat de Valencia, Spain.
Background And Objectives:
Germline truncating variants in the DRP2 gene (encoding dystrophin-related protein 2) cause the disruption of the periaxin-DRP2-dystroglycan complex and have been linked to Charcot-Marie-Tooth disease. However, the causality and the underlying phenotype of the genetic alterations are not clearly defined.
Methods:
This cross-sectional retrospective observational study includes 9 patients with Charcot-Marie-Tooth disease (CMT) with DRP2 germline variants evaluated at 6 centers throughout Spain.
Results:
We identified 7 Spanish families with 4 different DRP2 likely pathogenic germline variants. In agreement with an X-linked inheritance, men harboring hemizygous DRP2 variants presented with an intermediate form of CMT, whereas heterozygous women were asymptomatic. Symptom onset was variable (36.6 ± 16 years), with lower limb weakness and multimodal sensory loss producing a mild-to-moderate functional impairment. Nerve echography revealed an increase in the cross-sectional area of nerve roots and proximal nerves. Lower limb muscle magnetic resonance imaging confirmed the presence of a length-dependent fatty infiltration. Immunostaining in intradermal nerve fibers demonstrated the absence of DRP2 and electron microscopy revealed abnormal myelin thickness that was also detectable in the sural nerve sections.
Discussion:
Our findings support the causality of DRP2 pathogenic germline variants in CMT and further define the phenotype as a late-onset sensory and motor length-dependent neuropathy, with intermediate velocities and thickening of proximal nerve segments.
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