Charcot Marie Tooth disease (CMT4A) due to GDAP1 mutation: report of a colombian family.
Abstract
Background: Mutations of GDAP1 gene cause autosomal dominant and autosomal recessive Charcot-Marie-Tooth disease and more than 40 different mutations have been reported. The recessive Q163X mutation has been described in patients of Spanish ancestry, and a founder mutation in South American patients, originating in Spain has been demonstrated.
Objective: We describe physical and histological features, and the molecular impact of mutation Q163X in a Colombian family.
Methods: We report two female patients, daughters of consanguineous parents, with onset of symptoms within the first two years of life, developing severe functional impairment, without evidence of dysmorphic features, hoarseness or diaphragmatic paralysis. Electrophysiology tests showed a sensory and motor neuropathy with axonal pattern. Sequencing of GDAP1 gene was requested and the study identified a homozygous point mutation (c.487 C>T) in exon 4, resulting in a premature stop codon (p.Q163X). This result confirms the diagnosis of Charcot-Marie-Tooth disease, type 4A.
Results: The patients were referred to Physical Medicine and Rehabilitation service, in order to be evaluated for ambulation assistance. They have been followed by Pulmonology service, for pulmonary function assessment and diaphragmatic paralysis evaluation. Genetic counseling was offered. The study of the genealogy of the patient, phenotypic features, and electrophysiological findings must be included as valuable tools in the clinical approach of the patient with Charcot-Marie-Tooth disease, in order to define a causative mutation. In patients of South American origin, the presence of GDAP1 gene mutations should be considered, especially the Q163X mutation, as the cause of CMT4A disease.
Authors
Downloads
Keywords
- Founder effect
- hereditary sensory and motor neuropathy
- axonal neuropathy
- genetic counseling
- Charcot-Marie-Tooth Disease
References
Noack R, Frede S, Albrecht P, Henke N, Pfeiffer A, Knoll K, et al. Charcot-Marie-Tooth disease CMT4A: GDAP1 increases cellular glutathione and the mitochondrial membrane potential. Hum Mol Genet. 2012;21(1):150–162.
Banchs I, Casasnovas C, Albertí A , De Jorge L , Povedano M , Montero J , et al. Diagnosis of Charcot-Marie-Tooth disease. J Biomed Biotechnol. 2009;2009:985415–985415.
Shy ME, Patzkó A. Axonal Charcot-Marie-Tooth disease. Curr Opin Neurol. 2011;24(5):475–483.
Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009;8(7):654–667.
Claramunt R, Pedrola L, Sevilla T, López de Munain A, Berciano J, Cuesta A, et al. Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. J Med Genet. 2005;42(4):358–365.
Yiu EM, Ryan MM. Demyelinating prenatal and infantile developmental neuropathies. J Peripher Nerv Syst. 2012;17(1):32–52.
Bernard R, De Sandre-Giovannoli A, Delague V, Lévy N. Molecular genetics of autosomal-recessive axonal Charcot-Marie-Tooth neuropathies. Neuromolecular Med. 2006;8(1-2):87–106.
England JD, Gronseth GS, Franklin G, Carter GT, Kinsella LJ, Cohen JA, et al. Practice Parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology. 2009;72(2):185–192.
Szigeti K, Lupski JR. Charcot-Marie-Tooth disease. Eur J Hum Genet. 2009;17(6):703–710.
Niemann A, Ruegg M, La Padula V, Schenone A, Suter U. Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease. J Cell Biol. 2005;170(7):1067–1078.
Huber N, Guimaraes S, Schrader M, Suter U, Niemann A. Charcot-Marie-Tooth disease-associated mutants of GDAP1 dissociate its roles in peroxisomal and mitochondrial fission. EMBO Rep. 2013;14(6):545–552.
Cassereau J, Chevrollier A, Gueguen N, Desquiret V, Verny C, Nicolas G, et al. Mitochondrial dysfunction and pathophysiology of Charcot-Marie-Tooth disease involving GDAP1 mutations. Exp Neurol. 2011;227(1):31–41.
Zimon M, Baets J, Fabrizi GM, Jaakkola E. Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. Neurology. 2011;77(6):540–548.
Marco A, Cuesta A, Pedrola L, Palau F, Marín I. Evolutionary and structural analyses of GDAP1, involved in Charcot-Marie-Tooth disease, characterize a novel class of glutathione transferase-related genes. Mol Biol Evol. 2004;21(1):176–187.
Cuesta A, Pedrola L, Sevilla T, García-Planells J, Chumillas MJ, Mayordomo F, et al. The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat Genet. 2002;30(1):22–25.
Boerkoel CF, Takashima H, Nakagawa M, Izumo S, Armstrong D, Butler I, et al. CMT4A: identification of a Hispanic GDAP1 founder mutation. Ann Neurol. 2003;53(3):400–405.
Sevilla T, Cuesta A, Chumillas MJ, Mayordomo F, Pedrola L, Palau F, et al. Clinical, electrophysiological and morphological findings of Charcot-Marie-Tooth neuropathy with vocal cord palsy and mutations in the GDAP1 gene. Brain. 2003;126(Pt9):2023–2033.
Copyright (c) 2015 Universidad del Valle
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The copy rights of the articles published in Colombia Médica belong to the Universidad del Valle. The contents of the articles that appear in the Journal are exclusively the responsibility of the authors and do not necessarily reflect the opinions of the Editorial Committee of the Journal. It is allowed to reproduce the material published in Colombia Médica without prior authorization for non-commercial use
