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 novel GDAP1 mutation P78L responsible for CMT4A disease in three Moroccan families

BACKGROUND: The gene encoding the ganglioside-induced-differentiation-associated protein 1 (GDAP1) has been associated with both axonal and demyelinating neuropathy. Up to date, 25 mutations in the GDAP1 gene have been reported in patients from different origins. METHODS: Three Moroccan families with early onset ARCMT1 and autosomal recessive inheritance were genotyped to test linkage to 8q21.3 and their GDAP1 gene coding exons screened for mutations. RESULTS: A novel C233T transversion at codon 78 (P78L) was detected in 6 patients from 3 unrelated families. The mutation was found to be homozygous in two families and compound heterozygous in association with the already reported S194X mutation in one family. The P78L mutation was associated with a common haplotype suggesting a Moroccan founder mutation. The patients had symptoms within the two first years of life and developed common phenotype of CMT4A with evident hoarse-voice in two cases with the longer disease duration. CONCLUSION: P78L mutation was associated with a common haplotype suggesting a common ancestor.     

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.     

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).     

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.     

A novel GDAP1 mutation 439delA is associated with autosomal recessive CMT disease

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is the most common form of inherited motor and sensory neuropathy. Based on neurophysiological and neuropathological criteria CMT has been sub-classified into two main types: demyelinating and axonal. Furthermore, it is genetically heterogeneous with autosomal dominant, autosomal recessive (AR) and X-linked modes of inheritance. Thus far, seven genes have been identified in association with the demyelinating AR-CMT disease. We hereby report our clinical and molecular genetic findings in a consanguineous family with AR-CMT. METHODS: Two young sisters with AR-CMT and other non-affected family members were clinically and electrophysiologically evaluated and then molecular genetic investigation was carried out in order to identify the pathogenic mutation. RESULTS: Following an initial indication for linkage of the family to the CMT4A locus on chromosome 8, we sequenced the Ganglioside-induced differentiation-associated protein 1 (GDAP1) gene and identified a single nucleotide deletion in exon 3 that is associated with AR-CMT in the family. CONCLUSIONS: We identified a novel GDAP1 439delA mutation that is associated with AR-CMT in a consanguineous family of Iranian descent with two affected young girls and a history in other members of the family.     

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.     

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.     

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.     

A French family with Charcot-Marie-Tooth disease related to simultaneous heterozygous MFN2 and GDAP1 mutations

Either dominantly inherited mutations in MFN2 encoding mitofusin 2 or GDAP1 encoding ganglioside-induced differentiation associated protein 1 may be associated with mild neuropathy. The proband, a 41-year-old woman, and her daughter present a severe axonal form of Charcot-Marie-Tooth (CMT) disease. Both are heterozygous for the well-described mild variant p.R120W in GDAP1, which was transmitted by the pauci symptomatic proband's mother. Given that they had an early onset in the first decade and delayed walking acquisition, the other genes implicated in axonal forms of CMT disease were analyzed. A second mutation truncating MFN2 (p.Val160fsX26) was found in the proband and her daughter. This mutation was transmitted by the proband's father who has normal neurological examination. The proband underwent two nerve biopsies which showed an axonal degeneration, myelin modifications, and intra-axonal mitochondria with distorted cristae. Such abnormal mitochondria have been reported in cases with autosomal dominant MFN2 mutations and in one patient with an autosomal recessive GDAP1 mutation. Our two cases show that heterozygous truncation of MFN2, which is silent at least until the sixth decade, when combined with the mild p.R120W GDAP1 variant, leads to a severe neuropathy. This supports the emerging hypothesis of cumulative effects of MFN2 and GDAP1 mutation.     

A novel autosomal dominant GDAP1 mutation in an Italian CMT2 family

We report the clinical, electrophysiological, and skin biopsy findings of an Italian Charcot-Marie-Tooth disease type 2 (CMT2) family with a novel heterozygous GDAP1 mutation. We observed a marked intra-familial phenotypic variability, in age at onset and disease severity which ranged from a typical CMT phenotype to an asymptomatic status. Electrophysiological study, consistent with an axonal sensory-motor neuropathy, confirmed a different degree of severity and disclosed minimal electrophysiological abnormalities also in the asymptomatic subjects. Skin biopsy findings showed a variable loss of large and small somatic nerve fibers. Molecular analysis identified a novel heterozygous missense mutation (Arg120Gly) in the GDAP1 gene which co-segregated with the disease within the pedigree. In conclusion, our findings confirm that the GDAP1 autosomal dominant mutations underlie a pronounced phenotypic variability, mimicking the effects of reduced penetrance. Notably, electrophysiological study in this family allowed to reveal hidden positive family history and assess a dominant inheritance pattern, revealing subclinical neuropathy in asymptomatic mutation carriers.     

Clinical and electrophysiological characteristics of autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2B) that maps to chromosome 19q13.3

Charcot-Marie-Tooth disease (CMT) comprises a heterogeneous group of hereditary motor and sensory peripheral neuropathies. The autosomal recessive axonal form of CMT (ARCMT2) is rare. Eight patients of a large consanguineous family of Spanish ancestry in Costa Rica were diagnosed with ARCMT2B; previous genetic studies of this family revealed linkage to chromosome 19q13.3. The clinical and electrophysiological features of these patients are reported. All patients presented with a symmetric motor and sensory neuropathy, which was more pronounced in the lower limbs. Further, distal muscle wasting and impaired deep tendon reflexes were found. Age at onset was between 26 and 42 years, and the disease duration ranged from 2 to 19 years. Electrophysiological studies revealed a primary axonal degenerative process. The clinical characteristics of this family differed in several aspects from previously reported families with ARCMT2.     

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.     

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.     

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.     

WES homozygosity mapping in a recessive form of Charcot-Marie-Tooth neuropathy reveals intronic GDAP1 variant leading to a premature stop codon

Charcot-Marie-Tooth disease (CMT) refers to a group of clinically and genetically heterogeneous inherited neuropathies. Ganglioside-induced differentiation-associated protein 1 GDAP1-related CMT has been reported in an autosomal dominant or recessive form in patients presenting either axonal or demyelinating neuropathy. We report two Sri Lankan sisters born to consanguineous parents and presenting with a severe axonal sensorimotor neuropathy. The early onset of the disease, the distal and proximal weakness and atrophy leading to major disability, along with areflexia, and, most notably, vocal cord and diaphragm paralysis were highly evocative of a GDAP1-related CMT. However, sequencing of the coding regions of the gene was normal. Whole-exome sequencing (WES) was performed and revealed that the largest region of homozygosity was around GDAP1 with several variants, mostly in non-coding regions. In view of the high clinical suspicion of GDAP1 gene involvement, we examined the variants in this gene and this, along with functional studies, allowed us to identify an alternative splicing site revealing a cryptic in-frame stop codon in intron 4 responsible for a severe loss of wild-type GDAP1. This work is the first to describe a deleterious mutation in GDAP1 gene outside of coding sequences or intronic junctions and emphasizes the importance of interpreting molecular analysis, and in particular WES results, in light of the clinical and electrophysiological phenotype.     

Vocal cord and diaphragm paralysis, as clinical features of a French family with autosomal recessive Charcot-Marie-Tooth disease, associated with a new mutation in the GDAP1 gene

Axonal forms of Charot-Marie-Tooth disease, either dominantly or recessively inherited, are clinically and genetically heterogeneous. We describe the clinical and electrophysiological characteristics of an axonal autosomal recessive form of Charot-Marie-Tooth disease in a French family, associated with a new mutation of the ganglioside-induced differentiation-associated protein-1 gene (GDAP1). Two sisters, born to non-consanguineous parents, presented severe proximal and distal sensorimotor deficit, areflexia, pes cavus, scoliosis and vocal cord and diaphragm paralysis. They lost ambulation in the third decade and since then they have been wheelchair bound. Nerve conduction studies were consistent with an axonal neuropathy. Clinical and electrophysiological examination of their parents and their brother was normal. Genetic analysis revealed a homozygous thymidine deletion at nucleotide position 558 resulting in a frameshift at codon 186 and a stop codon at position 205. This axonal form of Charot-Marie-Tooth disease associated with a new GDAP1 mutation is recessively inherited and is characterized by a severe phenotype, since patients become wheelchair bound in the third decade, and present vocal cord and diaphram paralysis, which may be missed as they had no respiratory symptoms until the third decade.     

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.     

Giant axonal neuropathy: clinical and genetic study in six cases

BACKGROUND: Giant axonal neuropathy (GAN) is a severe recessive disorder characterised by variable combination of progressive sensory motor neuropathy, central nervous system (CNS) involvement, and "frizzly" hair. The disease is caused by GAN gene mutations on chromosome 16q24.1. AIMS: To search for GAN gene mutations in Turkish patients with GAN and characterise the phenotype associated with them. METHODS: Linkage and mutation analyses were performed in six affected patients from three consanguineous families. These patients were also investigated by cranial magnetic resonance imaging (MRI) and electroencephalography (EEG). Electromyography (EMG) was performed in heterozygous carriers from family 1 and family 3. RESULTS: Linkage to 16q24.1 was confirmed by haplotype analysis. GAN mutations were identified in all families. Family 1 had the R293X mutation, previously reported in another Turkish family. Families 2 and 3, originating from close geographical areas, shared a novel mutation, 1502+1G>T, at the donor splice site of exon 9. All patients displayed a common phenotype, including peripheral neuropathy, cerebellar ataxia, and frizzly hair. Cranial MRI showed diffuse white matter abnormalities in two patients from family 1 and the patient from family 3, and minimal white matter involvement in the patient from family 2. EMG of a heterozygous R293X mutation carrier showed signs of mild axonal neuropathy, whereas a 1502+1G>T mutation carrier had normal EMG. EEG abnormalities were found in three patients. CONCLUSION: These findings highlight the association of CNS involvement, in particular white matter abnormalities, with peripheral neuropathy in GAN. The phenotypical consequences of both mutations (when homozygous) were similar.