Abstract
Mutations in the GDAP1 gene can cause Charcot-Marie-Tooth disease. These mutations are quite rare in most Western countries but not so in certain regions of Spain or other Mediterranean countries. This cross-sectional retrospective multicenter study analyzed the clinical and genetic characteristics of patients with GDAP1 mutations across Spain. 99 patients were identified, which were distributed across most of Spain, but especially in the Northwest and Mediterranean regions. The most common genotypes were p.R120W (in 81% of patients with autosomal dominant inheritance) and p.Q163X (in 73% of autosomal recessive patients). Patients with recessively inherited mutations had a more severe phenotype, and certain clinical features, like dysphonia or respiratory dysfunction, were exclusively detected in this group. Dominantly inherited mutations had prominent clinical variability regarding severity, including 29% of patients who were asymptomatic. There were minor clinical differences between patients harboring specific mutations but not when grouped according to localization or type of mutation. This is the largest clinical series to date of patients with GDAP1 mutations, and it contributes to define the genetic distribution and genotype-phenotype correlation in this rare form of CMT.
Highlights
Phenotype, and certain clinical features, like dysphonia or respiratory dysfunction, were exclusively detected in this group
We identified 99 patients from 46 different families harboring causative ganglioside-induced differentiation-associated protein 1 (GDAP1) mutations
The only two patients with the homozygous p.R282C mutation seemed to have a milder clinical course, as did the only patient compound heterozygous for the p.Q163X and p.L344R mutations. This multicentric cross-sectional study provides information about 99 patients with Charcot–Marie–Tooth disease (CMT) caused by GDAP1 mutations
Summary
Phenotype, and certain clinical features, like dysphonia or respiratory dysfunction, were exclusively detected in this group. There were minor clinical differences between patients harboring specific mutations but not when grouped according to localization or type of mutation This is the largest clinical series to date of patients with GDAP1 mutations, and it contributes to define the genetic distribution and genotype-phenotype correlation in this rare form of CMT. Autosomal recessive mutations have been described in patients with axonal, intermediate and demyelinating forms of the disease, while dominantly inherited mutations cause axonal CMT1–4 These mutations are quite rare in Western countries, accounting for less than 1% of the genetically defined CMT patients in most clinical series[5, 6]. GDAP1 autosomal recessive (AR) inherited mutations cause a severe, early onset neuropathy often leading to wheelchair-dependency in the second or third decade Most of these patients develop unilateral or bilateral vocal cord paresis, and diaphragmatic weakness in the latter stages of the disease[13]. Like dysphonia or dysautonomia, have been described in isolated patients, but no clear genotype-phenotype correlation has been established in AD inherited mutations[9, 17]
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