[show abstract][hide abstract] ABSTRACT: Charcot-Marie-Tooth disease type 2A (CMT2A) is one of the subdivisions of CMT2, an axonal defective form of peripheral neuropathy. Different mutations in the mitochondrial GTPase mitofusin 2 (MFN2) gene produce various degrees of severity of CMT2A phenotype or CMT2A related hereditary motor and sensory neuropathy VI (HMSN VI). The occurrence of de novo mutations in MFN2 is by far the most frequent as compared to other CMT genes. About 26% of the pathogenic MFN2 mutations reported in the Inherited Peripheral Neuropathies Mutations Database are de novo. This study identified two de novo mutations of MFN2, c.1048T>C (S350P) and c.310C>T (R104W), from two Korean CMT2A patients with early onset severe clinical symptoms. The comparative genotype-phenotype correlations of these mutations according to a previously reported case were also viewed. The R104W mutation has been reported recurrently, outspread over different ethnic backgrounds as de novo. The re-occurrence of the same pathogenic de novo variants within and amongst different ethnic groups clearly suggests a susceptible hot spot for mutation in the MFN2 gene. If the deleterious mutations discourage fitness and reproduction, this negative selection factor should ultimately reduce the prevalence of the disease. It appears that spontaneous de novo mutations in turn seem to be maintaining the disease phenotype’s prevalence.
[show abstract][hide abstract] ABSTRACT: Mutations in the Pleckstrin homology domain-containing, family G member 5 (PLEKHG5) gene has been reported in a family harboring an autosomal recessive lower motor neuron disease (LMND). However, the PLEKHG5 mutation has not been described to cause Charcot-Marie-Tooth disease (CMT).
To identify the causative mutation in an autosomal recessive intermediate CMT (RI-CMT) family with childhood onset, whole exome sequencing (WES), histopathology, and lower leg MRIs were performed. Expression and activity of each mutant protein were analyzed.
We identified novel compound heterozygous (p.Thr663Met and p.Gly820Arg) mutations in the PLEKHG5 gene in the present family. The patient revealed clinical manifestations of sensory neuropathy. Fatty replacements in the distal lower leg muscles were more severe than in the thigh muscles. Although the symptoms and signs of this patient harboring slow nerve conduction velocities suggested the possibility of demyelinating neuropathy, a distal sural nerve biopsy was compatible with axonal neuropathy. Immunohistochemical analysis revealed that the patient has a low level of PLEKHG5 in the distal sural nerve and an in vitro assay suggested that the mutant proteins have a defect in activating the NF-kappaB signaling pathway.
This study identifies compound heterozygous PLEKHG5 mutations as the cause of RI-CMT. We suggest that PLEKHG5 might play a role in the peripheral motor and sensory nervous system. This study expands the phenotypic spectrum of PLEKHG5 mutations.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: OBJECTIVE: To identify the genetic cause of an autosomal recessive demyelinating Charcot-Marie-Tooth disease type 4B (CMT4B) family. METHODS: We enrolled 14 members of a Korean family in which 3 individuals had demyelinating CMT4B phenotype and obtained distal sural nerve biopsies from all affected participants. We conducted exome sequencing on 6 samples (3 affected and 3 unaffected individuals). RESULTS: One pair of heterozygous missense mutations in the SET binding factor 1 (SBF1) gene (22q13.33), also called MTMR5, was identified as the underlying cause of the CMT4B family illness. Clinical phenotypes of affected study participants with CMT4B were similar, to some extent, to patients with CMT4B1 and CMT4B2. We found a similar loss of large myelinated fibers and focally folded myelin sheaths in our patients, but the actual number of myelinated fibers was different from CMT4B1 and CMT4B2. CONCLUSIONS: We suggest that the compound heterozygous mutations in SBF1 are the underlying causes of a novel CMT4B subtype, designated as CMT4B3. We believe that this study will lead to mechanistic studies to discover the function of SBF1 and to the development of molecular diagnostics for CMT disease.
[show abstract][hide abstract] ABSTRACT: Laing distal myopathy (LDM) is caused by mutations in the MYH7 gene, and known to have muscle weakness of distal limbs and neck flexors. Through whole exome sequencing, we identified a novel p.Ala1439Pro MYH7 mutation in a Korean LDM family. This missense mutation is located in more N-terminal than any reported rod domain LDM mutations. In the early stage of disease, the present patients showed similar clinical patterns to the previously described patients of LDM. However, in the later stage, fatty replacement and atrophy of paraspinal or proximal leg muscles was more severely marked than lower leg muscles, and asymmetric atrophies were observed in trapezius, subscapularis and adductor magnus muscles. Distal myopathy like LDM showed marked and predominant fatty infiltrations in paraspinal or proximal leg muscles with marked asymmetry. These observations expand the clinical spectrum of LDM with the MYH7 mutation.
[show abstract][hide abstract] ABSTRACT: IMPORTANCE Hereditary motor and sensory neuropathy with proximal dominance (HMSN-P) has been reported as a rare type of autosomal dominant adult-onset Charcot-Marie-Tooth disease. HMSN-P has been described only in Japanese descendants since 1997, and the causative gene has not been found. OBJECTIVES To identify the genetic cause of HMSN-P in a Korean family and determine the pathogenic mechanism. DESIGN Genetic and observational analysis. SETTING Translational research center for rare neurologic disease. PARTICIPANTS Twenty-eight individuals (12 men and 16 women) from a Korean family with HMSN-P. MAIN OUTCOME MEASURES Whole-exome sequencing, linkage analysis, and magnetic resonance imaging. RESULTS Through whole-exome sequencing, we revealed that HMSN-P is caused by a mutation in the TRK-fused gene (TFG). Clinical heterogeneities were revealed in HMSN-P between Korean and Japanese patients. The patients in the present report showed faster progression of the disease compared with the Japanese patients, and sensory nerve action potentials of the sural nerve were lost in the early stages of the disease. Moreover, tremor and hyperlipidemia were frequently found. Magnetic resonance imaging of the lower extremity revealed a distinct proximal dominant and sequential pattern of muscular involvement with a clearly different pattern than patients with Charcot-Marie-Tooth disease type 1A. Particularly, endoneural blood vessels revealed marked narrowing of the lumen with swollen vesicular endothelial cells. CONCLUSIONS AND RELEVANCE The underlying cause of HMSN-P proves to be a mutation in TFG that lies on chromosome 3q13.2. This disease is not limited to Japanese descendants, and marked narrowing of endoneural blood vessels was noted in the present study. We believe that TFG can affect the peripheral nerve tissue.
[show abstract][hide abstract] ABSTRACT: The objective of the study was to investigate the disease-causing mutation in an autosomal dominant Charcot-Marie-Tooth disease type 2 family and examine the clinical and histopathological evaluation. We enrolled a family of Korean origin with axonal Charcot-Marie-Tooth disease neuropathy (FC305; 13 males, six females) and applied genome-wide linkage analysis. Whole exome sequencing was performed for two patients. In addition, sural nerve biopsies were obtained from two patients. Through whole exome sequencing, we identified an average of 20,336 coding variants from two patients. We also found evidence of linkage mapped to chromosome 11p11-11q13.3 (LOD score of 3.6). Among these variants in the linkage region, we detected a novel p.S90W mutation in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene, after filtering 31 Korean control exomes. Our p.S90W patients had frequent sensory disturbances, pyramidal tract signs, and predominant right thenar muscle atrophy in comparison with reported p.S90L patients. The phenotypic spectra were wide and demonstrated intrafamilial variability. Two patients with different clinical features underwent sural nerve biopsies; the myelinated fiber densities were increased slightly in both patients, which differed from two previous case reports of BSCL2 mutations (p.S90L and p.N88S). This report expands the variability of the clinical spectrum associated with the BSCL2 gene and describes the first family with the p.S90W mutation.
[show abstract][hide abstract] ABSTRACT: Both peripheral neuropathy and distal myopathy are well-established inherited neuromuscular disorders characterized by progressive weakness and atrophy of the distal limb muscles. A complex phenotype of peripheral neuropathy, myopathy, hoarseness, and hearing loss was diagnosed in a large autosomal dominant Korean family. A high density single nucleotide polymorphism (SNP)-based linkage study mapped the underlying gene to a region on chromosome 19q13.3. The maximum multipoint LOD score was 3.794. Sequencing of 34 positional candidate genes in the segregating haplotype revealed a novel c.2822G>T (p.Arg941Leu) mutation in the gene MYH14, which encodes the nonmuscle myosin heavy chain 14. Clinically we observed a sequential pattern of the onset of muscle weakness starting from the anterior to the posterior leg muscle compartments followed by involvement of intrinsic hand and proximal muscles. The hearing loss and hoarseness followed the onset of distal muscle weakness. Histopathologic and electrodiagnostic studies revealed both chronic neuropathic and myopathic features in the affected patients. Although mutations in MYH14 have been shown to cause nonsyndromic autosomal dominant hearing loss (DFNA4), the peripheral neuropathy, myopathy, and hoarseness have not been associated with MYH14. Therefore, we suggest that the identified mutation in MYH14 significantly expands the phenotypic spectrum of this gene.
Human Mutation 06/2011; 32(6):669-77. · 5.21 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Journal of the Peripheral Nervous System 06/2011; 16(2):143-6. · 2.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous peripheral neuropathy. The objective of this study was to find the causative mutation(s) in a demyelinating autosomal dominant CMT family. A high density SNP-based genome-wide linkage scan was performed, and causative mutations were determined by sequencing of candidate genes in the linkage disequilibrium region. Linkage analysis mapped the underlying gene to a region on chromosome 1q22-q23 with a maximum two-point LOD score of 2.036. Sequencing analysis revealed a novel c.243C>G (His81Gln) mutation in the MPZ gene, which encodes the major integral membrane protein of the peripheral nerve system. MPZ is well known as a CMT-causative gene with wide phenotypic spectrum. The clinical symptoms were more similar to those of patients with the His81Arg than patients with the His81Tyr mutation. The novel mutation completely co-segregated with affected members, and was not found in controls. Therefore, we suggest that the identified mutation in MPZ is the underlying cause of CMT in the family. In addition, this study demonstrated that the clinical phenotypes may be variable with different mutations at the same site in the MPZ gene.
International Journal of Molecular Medicine 04/2011; 28(3):389-96. · 1.96 Impact Factor
[show abstract][hide abstract] ABSTRACT: Both the myotonic dystrophy type 1 (DM1) and the X-linked dominant Charcot-Marie-Tooth disease (CMTX1) are well-established inherited neuromuscular disorders characterized by progressive weakness and atrophy of the distal limb muscles. The underlying causes of the DM1 and CMTX1 are mutations in the DMPK and GJB1 gene, respectively. A patient with both DM1 and CMTX1 inherited these from his father and mother, respectively. Histopathological and electrodiagnostic studies revealed both chronic neuropathic and myopathic features. Physical disabilities were more severe than seen with either DM1 or CMTX1 alone. In addition, the present case reveals an asymmetric atrophy (22%) of the right calf muscle compared to the left side.
[show abstract][hide abstract] ABSTRACT: During mutational analysis of Charcot-Marie-Tooth (CMT) causative genes, we identified a CMT family with two missense mutations in different genes. A R359W mutation in EGR2 was shared by the affected daughter (proband) and her father. In addition, she had a V136A mutation in GJB1, which was determined to be a de novo mutation. The daughter with two different gene mutations showed more severe clinical, electrophysiological and histopathological phenotypes than her father who had only the EGR2 mutation. We suggest that these phenotypic differences between the proband and her father may have been caused by an altered effect of the genetic modifier in EGR2, or by the additive effect of the EGR2 and GJB1 mutations.