Late-onset Charcot–Marie–Tooth disease 4F caused by periaxin gene mutation

We identified the main features of Charcot–Marie–Tooth (CMT) disease, type 4F, caused by a periaxin gene (PRX) mutation in Japanese patients. Periaxin is known as one of the key myelination molecules, forming tight junction between myelin loop and axon. We collected 427 DNA samples from individuals with CMT or CMT-related neuropathy, negative for PMP22 duplication. We investigated PRX mutations using a purpose-built resequencing array screen during the period 2006–2012. We detected two types of PRX mutations in three patients; one patient showed a novel homozygous p.D651N mutation and the other two showed homozygous p.R1070X mutation. All PRX mutations reported so far have been of nonsense or frameshift type. In this study, we found homozygous missense mutation p.D651N. Aspartate 651 is located in a repeat domain; its position might indicate an important function. PRX mutations usually lead to early-onset, autosomal-recessive demyelinating CMT neuropathy 4F (CMT4F) or Dejerine–Sottas disease; their clinical phenotypes are severe. In our three patients, the onset of the disease was at the age of 27?years or later, and their clinical phenotypes were milder compared with those reported in previous studies. We showed a variation of clinical phenotypes for CMT4F caused by a novel, nonsense PRX mutation.     

Novel GJB1 mutation causing adult-onset Charcot–Marie–Tooth disease in a female patient

Charcot–Marie–Tooth disease (CMT), which is the eponym for hereditary motor and sensory neuropathy (HMSN), affects ～1 in 2500 individuals. The most common subtype of X-linked CMT, CMTX1, is caused by mutations in GJB1, the gene encoding connexin 32, a gap junction protein in myelinated Schwann cells. We report a woman, who presented at the age of 56 years with gait unsteadiness and tingling in her feet. Clinical investigation revealed impaired sensation to pinprick, light touch and vibration in her distal lower limbs. Ankle reflexes were bilaterally absent. Sequencing revealed a novel heterozygous c.712C>T (p.R238C) mutation in the GJB1 gene. This mutation is predicted to result in the loss of disulfide bonds and thus in abnormal protein structure. In this woman, the reported novel GJB1 mutation resulted in sensory abnormalities, slowly progressive loss of distal lower limb strength, and notable loss of balance, with onset of symptoms late in adult age.     

Vincristine exacerbates asymptomatic Charcot–Marie–Tooth disease with a novel EGR2 mutation

Neurotoxicity is a common side effect of vincristine (VCR) treatment. Severe exacerbations of neuropathy have been reported in patients with Charcot–Marie–Tooth disease (CMT) 1A with duplication of the peripheral myelin protein 22 (PMP22) gene. However, whether or not VCR exacerbates neuropathies through mutations in other CMT-associated genes besides PMP22 duplication has not been well studied. The purpose of this study was to identify mutations in any CMT-associated genes in a patient with hypersensitivity to VCR. We performed clinical, electrophysiological, and genetic examinations of a 23-year-old woman, who was hypersensitive to low-dose VCR, and her healthy mother. DNA analysis was performed using our specially designed resequencing array that simultaneously screens for 28 CMT-associated genes. Electrophysiological studies revealed that the patient and her healthy mother had demyelinating polyneuropathy. Furthermore, they showed the same novel mutation in the early growth response 2 (EGR2) gene. Recognizing pre-existing asymptomatic CMT by electrophysiological studies and genetic analysis before VCR treatment allowed us to prevent severe VCR-induced neuropathy.     

A novel AIFM1 mutation in a Chinese family with X-linked Charcot–Marie–Tooth disease type 4

X-linked Charcot–Marie–Tooth disease type 4 (CMTX4), caused by AIFM1 (Apoptosis-Inducing Factor, Mitochondrion associated 1) mutations and associated with deafness and cognitive impairment, is a rare subtype of Charcot–Marie–Tooth disease. Here, we report a novel missense variant of AIFM1 in a X-linked recessive Chinese family with childhood-onset, slowly progressive, isolated axonal motor and sensory neuropathy. Calf magnetic resonance imaging revealed fatty infiltration and atrophy severely involving the muscles of peroneal compartment. Pathologies exhibited abnormal mitochondrial morphology and accumulation in axoplasm of nerve fiber and subsarcolemmal area of muscle. A hemizygous variant (c.513G>A, p.Met171Ile) in the family was identified and was classified as likely pathogenic according to the standards and guidelines of the American College of Medical Genetics and Genomics. Our report expands the genetic spectrum of diseases related to AIFM1 mutations and indicates that fatty infiltration and atrophy of muscles in the peroneal compartment may be a feature of CMTX4 in early stage.     

A novel homozygous nonsense mutation in NEFL causes autosomal recessive Charcot–Marie–Tooth disease

The neurofilament light polypeptide (NEFL) gene mutations cause mainly autosomal dominant Charcot–Marie–Tooth disease (CMT) and rarely the recessive forms of CMT. We describe a 13-year-old girl born of consanguineous parents. She presented an early onset of gait disturbance with weakness in lower extremities during the first decade. Nerve conduction velocity of median nerve was 24 m/s and amplitude of compound muscle action potential was 2.2 mV. Sensory nerve action potential was not recordable. Sural nerve biopsy showed severe loss of the large myelinated fibers. Electron microscopy revealed absence of neurofilaments in both myelinated and unmyelinated axons. Genetic analysis identified a novel homozygous nonsense mutation in NEFL c.487G>T (p.Glu163*) as the potential causative mutation in this patient. Our study expands the mutation spectrum of NEFL-related neuropathy.     

Quality-of-life in Charcot–Marie–Tooth disease: The patient’s perspective

This study determines the impact of symptoms associated with Charcot–Marie–Tooth disease on quality-of-life. Charcot–Marie–Tooth patients in the Inherited Neuropathies Consortium Rare Diseases Clinical Research Network Contact Registry were surveyed. The survey inquired about 214 symptoms and 20 themes previously identified as important to Charcot–Marie–Tooth patients through patient interviews. Symptom population impact was calculated as the prevalence multiplied by the relative importance of each symptom identified. Prevalence and symptom impact were analyzed by age, symptom duration, gender, Charcot–Marie–Tooth type, and employment status. 407 participants returned the survey, identifying foot and ankle weakness (99.7%) and impaired balance (98.6%) as the most prevalent themes. Foot and ankle weakness and limitations with mobility were the themes with the highest impact. Both symptom prevalence and impact gradually increased with age and symptom duration. Several themes were more prevalent in women with Charcot–Marie–Tooth, including activity limitations, pain, fatigue, hip–thigh weakness, and gastrointestinal issues. All of the themes, except emotional or body image issues, were more prevalent among unemployed individuals. There were minimal differences in symptom prevalence between Charcot–Marie–Tooth types. There are multiple symptoms that impact Charcot–Marie–Tooth quality-of-life in adults. These symptoms have different levels of importance, are readily recognized by patients, and represent critical areas of Charcot–Marie–Tooth health.     

A novel mutation of the glycyl-tRNA synthetase (GARS) gene associated with Charcot–Marie–Tooth type 2D in a Chinese family

Abstract

Objective:

To explore the clinical features of a novel glycyl-tRNA synthetase (GARS) gene mutation in a family with Charcot–Marie–Tooth disease type 2D (CMT2D).

Methods:

Exome capture with the next-generation sequencing technique was used to detect gene mutations. The mutations were verified by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique combined with DNA sequencing.

Results:

In this pedigree, eight members were affected; seven males and one female. The affected members initially manifested with the onset of hand muscle weakness and atrophy in adolescence followed by gradual development of distal lower limb involvement and minor sensory involvement. Electrophysiological studies revealed that this disease mainly involves axonal damage. Genetic detection showed that all affected family members had a heterozygous missense mutation, c.999G>T (p.E333D), of the GARS gene.

Conclusions:

The c.999G>T mutation is a novel mutation of the GARS gene that has not been previously reported. The phenotype of this family is CMT2D, which is first reported in Chinese population.     

Charcot–Marie–Tooth disease: genetic subtypes in the Sardinian population

Charcot–Marie–Tooth disease (CMT) is characterised by great variability of genetic subtypes. This study aimed to assess the genetic subtypes of CMT disease in the Sardinian population. Genetic screening was performed for CMT cases (CMT1, CMT2, and hereditary neuropathy with susceptibility to pressure palsies [HNPP]). A total of 1,043 subjects (119 index cases) were evaluated. In CMT1 index cases (69/119; 58%), PMP22 duplication at 17p11.2 was the most frequent genetic diagnosis (60/69; 87%), followed by mutations in the GJB1 gene (5/69; 7.2%), in the SH3TC2 gene (3/69; 4.4%) and PMP22 Gly107Val point mutation (1/69; 1.4%). The CMT2 group (24/119; 20.1%) comprised 10/24 (41.6%) patients carrying MPZ gene Ser44Phe mutation, 6/24 (25%) with mutations in MFN2 and HSPB1, and 1/24 (4.2%) in GJB1 and LRSAM1. In the HNPP group (26/119; 21.9%), the majority of patients reported the PMP22 deletion (25/26; 96.2%). Further studies are needed to comprehend the overall picture of the disease in Mediterranean area.     

The first Japanese case of Charcot–Marie–Tooth disease type 4H with a novel FGD4 c.837-1G>A mutation

Charcot–Marie–Tooth disease type 4H (CMT4H) is an autosomal recessive demyelinating neuropathy. It presents as infancy or early childhood-onset neuropathy associated with FGD4 mutations. Clinically it causes predominantly distal muscle weakness. On nerve biopsy examination, myelin outfoldings are seen. The previous case reports have been from regions bordering the Mediterranean, as well as a family from Northern Ireland. This paper presents the detailed clinical course of the first reported case of CMT4H in a Japanese woman. The patient showed mild weakness without scoliosis and a severe sensory disturbance; her functional impairment was less severe than the previously published cases. In addition, a novel homozygous FGD4 c.837-1G>A mutation was identified in this patient.     

BAG3 p.Pro209Ser mutation identified in a Chinese family with Charcot–Marie–Tooth disease

Journal of Neurology - Bcl2-associated athanogene 3 (BAG3) gene mutations cause dilated cardiomyopathy and myofibrillar myopathy. Recently, a novel c.625C>T (p.Pro209Ser) mutation in BAG3...     

A novel Lys141Thr mutation in small heat shock protein 22 (HSPB8) gene in Charcot–Marie–Tooth disease type 2L

Charcot–Marie–Tooth disease (CMT) is a group of clinically and genetically heterogeneous peripheral neuropathies. HSPB8 gene encodes heat shock protein 22 (HSP22) which belongs to the superfamily of small stress induced proteins. Mutations in HSPB8 are implicated to CMT2L and distal hereditary motor neuropathy 2A (dHMN2A). All three reported HSPB8 mutations are interestingly located in the Lys141 residue. In the present study, we examined a Korean axonal CMT patient who presented distal limb atrophy, sensory loss, areflexia, and axonal loss of large myelinated fibers. Whole exome sequencing identified a novel missense mutation c.422A>C (p.Lys141Thr) in HSPB8 as the underlying cause of the CMT2 patient. The mutation was regarded as a de novo case because both unaffected parents have no such mutation. The patient with HSPB8 mutation is the first case in Koreans. Clinical heterogeneities have been revealed in patients with Lys141 mutation; the present patient revealed similar phenotype of CMT2L. In addition, the lower limb MRI revealed a similarity between our HSPB8 and HSPB1 patients. It seems that the Lys141 site in the alpha-crystallin domain of HSPB8 is regarded as a mutational hot spot for peripheral neuropathy development, and mutations even in the same codon can exhibit different CMT phenotypes.     

GJB1/Connexin 32 whole gene deletions in patients with X-linked Charcot–Marie–Tooth disease

The X-linked form of Charcot–Marie–Tooth disease (CMTX) is the second most common form of this genetically heterogeneous inherited peripheral neuropathy. CMT1X is caused by mutations in the GJB1 gene. Most of the mutations causative for CMT1X are missense mutations. In addition, a few disease causative nonsense mutations and frameshift deletions that lead to truncated forms of the protein have also been reported to be associated with CMT1X. Previously, there have been reports of patients with deletions of the coding sequence of GJB1; however, the size and breakpoints of these deletions were not assessed. Here, we report five patients with deletions that range in size from 12.2 to 48.3 kb and that completely eliminate the entire coding sequence of the GJB1 gene, resulting in a null allele for this locus. Analyses of the breakpoints of these deletions showed that they are nonrecurrent and that they can be generated by different mechanisms. In addition to PMP22, GJB1 is the second CMT gene for which both point mutations and genomic rearrangements can cause a neuropathy phenotype, stressing the importance of CMT as a genomic disorder.