A novel mutation of GDAP1 associated with Charcot-Marie-Tooth disease in three Italian families: evidence for a founder effect

BACKGROUND: Mutations in a gene encoding a novel protein of unknown function-the ganglioside-induced differentiation-associated protein 1 gene (GDAP1)-are associated with the autosomal recessive Charcot-Marie-Tooth disease type 4A (CMT4A). OBJECTIVE: To investigate the role of GDAP1 mutations in causing autosomal recessive neuropathies in an Italian population. METHODS AND RESULTS: 76 patients with severe early onset polyneuropathy and possible autosomal recessive inheritance were screened for mutations. A T>G transversion (c.347 T>G) at codon 116 (M116R) was detected in four affected subjects from three apparently unrelated families. All patients had early onset of disease with pronounced foot deformities and impaired walking. Neurophysiological studies showed an extremely variable expression. Sural nerve biopsies revealed signs of both de-remyelination and axonal impairment, the most prominent feature being a severe loss of larger fibres. Haplotype analysis of the GDAP1 locus demonstrated a common disease haplotype. CONCLUSIONS: The association of the mutation with a common haplotype suggested a common ancestor.     

L239F founder mutation in GDAP1 is associated with a mild Charcot–Marie–Tooth type 4C4 (CMT4C4) phenotype

Over 40 mutations in the GDAP1 gene have been shown to segregate with Charcot–Marie–Tooth disease (CMT). Among these, only two mutations, i.e., S194X and Q163X have been reported in a sufficient number of CMT families to allow for the construction of reliable phenotype–genotype correlations. Both the S194X and Q163X mutations have been shown to segregate with an early-onset and severe neuropathy resulting in loss of ambulance at the beginning of the second decade of life. In this study, we identified the L239F mutation in the GDAP1 gene in one Bulgarian and five Polish families. We hypothesized that the L239F mutation may result from a founder effect in the European population since this mutation has previously been reported in Belgian, Czech, and Polish patients. In fact, we detected a common disease-associated haplotype within the 8q13-q21 region in the Polish, German, Italian, Czech, and Bulgarian CMT families. Like the previously detected “regional” S194X and Q163X mutations, respectively present in Maghreb countries and in patients of Spanish descent, the L239F mutation seems to be the most common GDAP1 pathogenic variant in the Central and Eastern European population. Given the likely presence of a common ancestor harboring the L239F mutation, we decided to compare the phenotypes of the CMT (L239F) patients collected in this study with those of previously reported cases. In contrast to CMT4A caused by the S194X and Q163X mutations, the CMT phenotype resulting from the L239F substitution represents a milder clinical entity with a long-preserved period of ambulance at least until the end of the second decade of life.     

GDAP1 mutations in Czech families with early-onset CMT

Mutations in the ganglioside-induced differentiation associated protein-1 gene (GDAP1) cause autosomal recessive (AR) demyelinating or axonal Charcot-Marie-Tooth neuropathy (CMT). In order to establish the spectrum and frequency of GDAP1 mutations in Czech population, we sequenced GDAP1 in 74 Czech patients from 69 unrelated families with early-onset demyelinating or axonal CMT compatible with AR inheritance. We identified three isolated patients with GDAP1 mutations in both alleles. In one additional sporadic and one familial case, the second pathogenic mutation remained unknown. Overall, we detected two different mutations, a novel R191X nonsense and a L239F missense mutation. L239F previously described in a German-Italian family is a prevalent mutation in Czech population and we give evidence for its common ancestral origin. All Czech GDAP1 patients developed involvement of all four limbs evident by the end of second decade, except for one isolated patient showing very slow disease progression. All patients displayed axonal type of neuropathy.     

CMT4A: identification of a Hispanic GDAP1 founder mutation

Mutations of the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) cause autosomal recessive Charcot-Marie-Tooth disease type 4A. We report four additional families with recessive mutations (487C-->T, Q163X; 359G-->A, R120Q) of GDAP1; Q163X occurred in three unrelated Hispanic families that had the same haplotype suggesting a Spanish founder mutation. Both the Q163X and the R120Q mutation cause demyelination and axonal loss. The patients had symptoms within the first two years of life and involvement of cranial, sensory, and enteric nerves. Neuropathology showed loss of large myelinated fibers, onion bulb formations and focal folding of the outer myelin lamina.     

Two novel mutations in the GDAP1 and PRX genes in early onset Charcot-Marie-Tooth syndrome

Autosomal recessive Charcot-Marie-Tooth syndrome (AR-CMT) is often characterised by an infantile disease onset and a severe phenotype. Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene are thought to be a common cause of AR-CMT. Mutations in the periaxin (PRX) gene are rare. They are associated with severe demyelination of the peripheral nerves and sometimes lead to prominent sensory disturbances. To evaluate the frequency of GDAP1 and PRX mutations in early onset CMT, we examined seven AR-CMT families and 12 sporadic CMT patients, all presenting with progressive distal muscle weakness and wasting. In one family also prominent sensory abnormalities and sensory ataxia were apparent from early childhood. In three families we detected four GDAP1 mutations (L58LfsX4, R191X, L239F and P153L), one of which is novel and is predicted to cause a loss of protein function. In one additional family with prominent sensory abnormalities a novel homozygous PRX mutation was found (A700PfsX17). No mutations were identified in 12 sporadic cases. This study suggests that mutations in the GDAP1 gene are a common cause of early-onset AR-CMT. In patients with early-onset demyelinating AR-CMT and severe sensory loss PRX is one of the genes to be tested.     

Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene

BACKGROUND: The first locus for demyelinating autosomal recessive Charcot-Marie-Tooth (ARCMT) disease was identified in 8q13, where mutations in GDAP1 have been found. Mutations in the same gene have been detected in families with axonal ARCMT disease. OBJECTIVE: To determine the clinical, electrophysiologic, and morphologic characteristics of a consanguineous Moroccan family with ARCMT disease associated with the S194X mutation in the GDAP1 gene. METHODS: Four patients from a consanguineous Moroccan family were examined clinically and electrophysiologically. In one patient, a morphometric and ultrastructural study of a peroneal nerve biopsy sample was performed. Mutation in the coding region of the GDAP1 gene was identified by direct sequencing. RESULTS: Neuropathy was evident early in childhood, walking was delayed in one patient, and onset of symptoms occurred before 18 months in the others. The phenotype was severe: foot deformities and disabilities involving the hands and feet developed toward the end of the first decade, followed by involvement of proximal muscles in the lower limbs, leading to loss of autonomy. Electrophysiologic findings were consistent with an axonal form of CMT disease: motor nerve conduction velocities, recordable in one patient only, were greater than 40 m/sec. Sensory nerve action potentials were either abolished or substantially reduced in amplitude. The morphologic data supported the diagnosis of axonal neuropathy, showing a marked reduction in myelinated fibers and signs of axonal regeneration, including frequent pseudo-onion bulb formations. The 4 patients in this family were homozygous for the S194X mutation in the GDAP1 gene. CONCLUSION: Electrophysiologic and pathological findings support the hypothesis of an axonal disorder in this ARCMT family with the S194X mutation in the GDAP1 gene.     

A novel Met116Thr mutation in the GDAP1 gene in a Polish family with the axonal recessive Charcot-Marie-Tooth type 4 disease

Mutations in the gene coding for ganglioside-induced differentiation-associated protein-1 (GDAP1), which maps to chromosome 8q21, have been described in families with autosomal recessive Charcot-Marie-Tooth disease (CMT4A). Interestingly, some mutations in the GDAP1 gene have been reported in the demyelinating form of CMT1 disease, whereas others were found in patients with the axonal type of CMT disease. So far, 23 mutations in the GDAP1 gene have been reported in patients of different ethnic origins. In this study we report a novel mutation Met116Thr in the GDAP1 gene identified in a three generation Polish family with axonal CMT4.     

Variability of disease progression in a family with autosomal recessive CMT associated with a S194X and new R310Q mutation in the GDAP1 gene

Charcot-Marie-Tooth (CMT) with autosomal recessive (AR) inheritance is a heterogeneous group of inherited motor and sensory neuropathies. Six genes and five additional loci have been identified that are responsible for either demyelinating or axonal forms of the disease. The gene encoding the ganglioside-induced-differentiation-associated protein 1 (GDAP1) has been associated with both demyelinating and axonal phenotypes. We report a detailed clinical, electrophysiological, and genetic study of two siblings from a Moroccan ARCMT family who are compound heterozygotes for the already described S194X and a new R310Q mutation in the GDAP1 gene. The electrophysiological data are compatible with an axonal form of the disease. The phenotype included hoarse voice and paralysis of the diaphragm. This study shows the variability of the phenotype associated with mutations in GDAP1 gene in terms of associated signs and severity.     

A new missense <Emphasis Type="Italic">GDAP1</Emphasis> mutation disturbing targeting to the mitochondrial membrane causes a severe form of AR-CMT2C disease

Charcot–Marie–Tooth disease (CMT) caused by mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene is characterized by a spectrum of phenotypes. Recurrent nonsense mutations (Q163X and S194X) showing regional distribution segregate with an early onset, severe course of recessive CMT disease with early loss of ambulancy. Missense mutations in GDAP1 have been reported in sporadic CMT cases with variable course of disease, among them the recurrent L239F missense GDAP1 mutation occurring in the European population. Finally, some GDAP1 mutations are associated with a mild form of CMT inherited as an autosomal dominant trait. In this study, we characterize the CMT phenotype in one Polish family with recessive trait of inheritance at the clinical, electrophysiological, morphological, cellular, and genetic level associated with a new Gly327Asp mutation in the GDAP1 gene. In spite of the nature of Gly327Asp mutation (missense), the CMT phenotype associated with this variant may be characterized as an early onset, severe axonal neuropathy, with severe skeletal deformities. The mutation lies within the transmembrane domain of GDAP1 and interferes with the mitochondrial targeting of the protein, similar to the loss of the domain in the previously reported Q163X and S194X mutations. We conclude that the loss of mitochondrial targeting is associated with a severe course of disease. Our study shows that clinical outcome of CMT disease caused by mutations in the GDAP1 gene cannot be predicted solely on the basis of genetic results (missense/nonsense mutations).     

Two recessive intermediate Charcot-Marie-Tooth patients with GDAP1 mutations

Various phenotypes have been reported in Charcot-Marie-Tooth (CMT) disease carrying mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene. Here, we report two recessive intermediate Charcot-Marie-Tooth (RI-CMT) patients with GDAP1 missense mutations: a His256Arg homozygous mutation (c.767A>G + c.767A>G) and compound mutations of heterozygous Pro111His (c.332C>A) and Val219Gly (c.656T>G). The Pro111His and Val219Gly are unreported mutations, but the His256Arg was previously reported. In both patients, histopathological findings showed well-documented features of mixed demyelinating and axonal neuropathies, and nerve conduction velocities fall in the intermediate range. In addition, the patterns of fatty substitutions in leg magnetic resonance imaging (MRI) were different by the mutation sites within the same GDAP1 gene.     

Dominant GDAP1 founder mutation is a common cause of axonal Charcot-Marie-Tooth disease in Finland

We describe a founder mutation in the gene encoding ganglioside-induced differentiation associated-protein 1 (GDAP1), leading to amino acid change p.H123R, as a common cause of autosomal dominant axonal Charcot-Marie-Tooth (CMT2) neuropathy in Finland. The mutation explains up to 14 % of CMT2 in Finland, where most patients with axonal neuropathy have remained without molecular diagnosis. Only three families out of 28 were found to carry putative disease mutations in the MFN2 gene encoding mitofusin 2. In addition, the MFN2 variant p.V705I was commonly found in our patients, but we provide evidence that this previously described mutation is a common polymorphism and not pathogenic. GDAP1-associated polyneuropathy caused predominantly a mild and slowly progressive phenotype. Besides distal leg muscle weakness, most patients showed mild proximal weakness, often with asymmetry and pes cavus. Our findings broaden the understanding of GDAP1 mutations in CMT2 phenotypes and provide support for the use of whole-exome sequencing in CMT gene diagnostics.     

Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease

Mutations in the ganglioside-induced-differentiation-associated protein 1 gene (GDAP1) can cause Charcot-Marie-Tooth (CMT) disease with demyelinating (CMT4A) or axonal forms (CMT2K and ARCMT2K). Most of these mutations present a recessive inheritance, but few autosomal dominant GDAP1 mutations have also been reported. We performed a GDAP1 gene screening in a clinically well-characterized series of 81 index cases with axonal CMT neuropathy, identifying 17 patients belonging to 4 unrelated families in whom the heterozygous p.R120W was found to be the only disease-causing mutation. The main objective was to fully characterize the neuropathy caused by this mutation. The clinical picture included a mild-moderate phenotype with onset around adolescence, but great variability. Consistently, ankle dorsiflexion and plantar flexion were impaired to a similar degree. Nerve conduction studies revealed an axonal neuropathy. Muscle magnetic resonance imaging studies demonstrated selective involvement of intrinsic foot muscles in all patients and a uniform pattern of fatty infiltration in the calf, with distal and superficial posterior predominance. Pathological abnormalities included depletion of myelinated fibers, regenerative clusters and features of axonal degeneration with mitochondrial aggregates. Our findings highlight the relevance of dominantly transmitted p.R120W GDAP1 gene mutations which can cause an axonal CMT with a wide clinical profile.     

Charcot-Marie-Tooth disease type 1B: marked phenotypic variation of the Ser78Leu mutation in five Italian families

Objectives – To describe clinical, electrophysiological and genetic data of five unrelated Sicilian pedigrees harbouring a heterozygous Ser78Leu mutation in the myelin protein zero (MPZ) extracellular domain. Materials and methods – Clinical, electrophysiological and genetic findings of 16 patients were reported. Polymorphic markers flanking the coding sequence of MPZ gene were also analysed. Results – A wide range of age at onset was observed in families 1 and 3, with a clinical heterogeneity, in terms of severity of the disease, within the same family (families 1 and 3), and among families. A markedly unsteady gait was a distinctive feature of many members of family 1. All patients in family 2 complained of severe cramps and painful paresthesia. Molecular genetic analysis showed that all affected subjects shared a common haplotype at three microsatellite loci D1S2858, D1S2624 and D1S484. Conclusions – Our study provides further evidence that phenotypic features of MPZ mutations can vary within and among different families. High frequency of Ser78Leu mutation in Sicily as well as the results of haplotype analyses suggest that the mutation may have been inherited from a common ancestor.     

Clinical and Neuroimaging Features in Charcot-Marie-Tooth Patients with GDAP1 Mutations

Background and PurposeMutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) are known to cause Charcot-Marie-Tooth disease (CMT). These mutations are very rare in most countries, but not in certain Mediterranean countries. The purpose of this study was to identify the clinical and neuroimaging characteristics of Korean CMT patients with GDAP1 mutations.MethodsGene sequencing was applied to 1,143 families in whom CMT had been diagnosed from 2005 to 2020. PMP22 duplication was found in 344 families, and whole-exome sequencing was performed in 699 patients. Magnetic resonance imaging (MRI) were obtained using either a 1.5-T or 3.0-T MRI system.ResultsWe found ten patients from eight families with GDAP1 mutations: five with autosomal dominant (AD) CMT type 2K (three families with p.R120W and two families with p.Q218E) and three with autosomal recessive (AR) intermediate CMT type A (two families with homozygous p.H256R and one family with p.P111H and p.V219G mutations). The frequency was about 1.0% exclusive of the PMP22 duplication, which is similar to that in other Asian countries. There were clinical differences among AD GDAP1 patients according to mutation sites. Surprisingly, fat infiltrations evident in lower-limb MRI differed between AD and AR patients. The posterior-compartment muscles in the calf were affected early and predominantly in AD patients, whereas AR patients showed fat infiltration predominantly in the anterolateral-compartment muscles.ConclusionsThis is the first cohort report on Korean patients with GDAP1 mutations. The patients with AD and AR inheritance routes exhibited different clinical and neuroimaging features in the lower extremities. We believe that these results will help to expand the knowledge of the clinical, genetic, and neuroimaging features of CMT.     

Novel GDAP1 Mutation in a Turkish Family with CMT2K (CMT2K with Novel GDAP1 Mutation)

Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) cause Charcot–Marie–Tooth type 2 (CMT2), a severe autosomal recessive form of neuropathy associated with axonal phenotypes. It has been screened in this study for the presence of mutations in the coding region of GDAP1, which maps to chromosome 8q21, in a family with CMT2. To date, 29 mutations in the GDAP1 have been reported in patients of different ethnic origins. Here, we report a novel missense mutation (c.836A>G), and two polymorphisms: a silent variant (c.102G>C), and a 5′-splice site mutation (IVS5+24C>T) in GDPA1 gene identified in a five generation Turkish family with autosomal recessive CMT2.     

Autosomal recessive axonal form of Charcot-Marie-Tooth Disease caused by compound heterozygous 3'-splice site and Ser130Cys mutation in the GDAP1 gene

A recessive demyelinating subtype of Charcot-Marie-Tooth disease called CMT4 is a heterogeneous group of disorders. A relatively frequent form of recessive CMT (CMT4 A) has been mapped to the chromosome 8 q21 and shown to be caused by mutations in the ganglioside-induced differentiation protein 1 (GDAP1) gene. Twenty mutations in the GDAP1 gene have been reported in patients suffering from the axonal and demyelinating forms of CMT disease. In this study we report two novel mutations in the GDAP1 gene in a patient suffering from CMT2 disease and whose parents were asymptomatic carriers of a Ser130Cys and 3'-splice site (311-1G > A) mutation, respectively.     

Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy

BACKGROUND: Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were recently shown to be responsible for autosomal recessive (AR) demyelinating Charcot-Marie-Tooth disease (CMT) type 4A (CMT4A) as well as AR axonal CMT with vocal cord paralysis. METHODS: The coding region of GDAP1 was screened for the presence of mutations in seven families with AR CMT in which the patients were homozygous for markers of the CMT4A locus at chromosome 8q21.1. RESULTS: A nonsense mutation was detected in exon 5 (c.581C>G, S194X), a 1-bp deletion in exon 6 (c.786delG, G262fsX284), and a missense mutation in exon 6 (c.844C>T, R282C). CONCLUSIONS: Mutations in GDAP1 are a frequent cause of AR CMT. They result in an early-onset, severe clinical phenotype. The range of nerve conduction velocities (NCV) is variable. Some patients have normal or near normal NCV, suggesting an axonal neuropathy, whereas others have severely slowed NCV compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show features of demyelination and axonal degeneration.     

GDAP1 mutations are frequent among Brazilian patients with autosomal recessive axonal Charcot-Marie-Tooth disease

Mutations in ganglioside-induced differentiation-associated-protein 1 (GDAP1) are associated with several subtypes of Charcot-Marie-Tooth (CMT) disease, including autosomal recessive and demyelinating (CMT4A); autosomal recessive and axonal (AR-CMT2K); autosomal dominant and axonal (CMT2K); and an intermediate and recessive form (CMTRIA). To date, at least 103 mutations in this gene have been described, but the relative frequency of GDAP1 mutations in the Brazilian CMT population is unknown. In this study, we investigated the frequency of GDAP1 mutations in a cohort of 100 unrelated Brazilian CMT patients. We identified five variants in unrelated axonal CMT patients, among which two were novel and probably pathogenic (N64S, P119T) one was novel and was classified as VUS (K207L) and two were known pathogenic variants (R125* and Q163*). The prevalence rate of GDAP1 among the axonal CMT cases was 7,14% (5/70), all of them of recessive inheritance, thus suggesting that the prevalence was higher than what is observed in most countries. All patients exhibited severe early-onset CMT that was rapidly progressive. Additionally, this study widens the mutational spectrum of GDAP1-related CMT through identification of two novel likely pathogenic variants.     

A new disease allele for the p.C30071R mutation in titin causing hereditary myopathy with early respiratory failure

Hereditary myopathy with early respiratory failure is an autosomal dominant myopathy caused by mutations in the 119th fibronectin-3 domain of titin. To date all reported patients with the most common mutation in this domain (p.C30071R) appear to share ancestral disease alleles. We undertook this study of two families with the p.C30071R mutation to determine whether they share the same haplotype as previously reported British families or whether the mutation arose as a de novo event. We sequenced the 119th fibronectin-3 domain in these two probands and flanking polymorphisms associated with the British haplotype in hereditary myopathy with early respiratory failure. A family of Indian descent had a haplotype that was not compatible with the British shared haplotype. Cloning of the 119th fibronectin-3 domain in this patient demonstrated polymorphisms rs191484894 and novel noncoding variant c.90225C>T on the same allele as the mutation, which is distinct from previously reported British families. This proves that the p.C30071R mutation itself (rather than the haplotype containing this mutation) causes hereditary myopathy with early respiratory failure and suggests its independent origin in different ethnic groups.     

Novel mutations in the GDAP1 gene in patients affected with early-onset axonal Charcot-Marie-Tooth type 4A

We report a detailed study of eight patients from four Italian families presenting with autosomal recessive axonal Charcot-Marie-Tooth disease (AR-CMT2), characterized by early-onset and progressive severe weakness of all limbs. Vocal cord paresis was present in two cases. Sural nerve biopsy performed in three patients showed a severe neuropathy characterized by a predominant axonal involvement. Five novel mutations (p.Gln99stop, p.Gln122Lys, p.Arg125stop, p.Val219Asp, p.Asn297Lys) and one previously reported mutation (p.Leu239Phe) were identified in GDAP1 gene. GDAP1 mutations should be considered both in recessive and sporadic cases of early-onset axonal CMT.