Sun Wha Park

Different clinical and magnetic resonance imaging features between Charcot–Marie–Tooth disease type 1A and 2A

Charcot-Marie-Tooth disease type 1A (CMT1A) is the more frequent cause of demyelinating CMT, and CMT2A is the most common cause of axonal CMT. We conducted a magnetic resonance imaging (MRI) study on 39 CMT1A and 21 CMT2A patients to compare their neuroimaging patterns and correlate with clinical features. CMT1A patients showed selective fatty infiltration with a preference for anterior and lateral compartment muscles, whereas CMT2A patients showed a preference for superficial posterior compartment muscles. Early-onset CMT2A patients showed more severe leg fatty atrophy than late-onset CMT2A patients. In late-onset CMT2A, soleus muscle was the earliest, and most severely affected than the other leg muscles. Selective involvement of intrinsic foot muscles is a characteristic pattern of minimal CMT1A and CMT2A. Our MRI study demonstrates different patterns of fatty infiltration involving superficial posterior compartment muscles in CMT2A (partial T-type), and peroneal nerve innervated muscles in CMT1A (P-type).

Distal hereditary motor neuropathy in Korean patients with a small heat shock protein 27 mutation

Distal hereditary motor neuropathy (dHMN) is a heterogeneous disorder characterized by degeneration of motor nerves in the absence of sensory abnormalities. Recently, mutations in the small heat shock protein 27 (HSP27) gene were found to cause dHMN type II or Charcot-Marie-Tooth disease type 2F (CMT2F). The authors studied 151 Korean axonal CMT or dHMN families, and found a large Korean dHMN type II family with the Ser135Phe mutation in HSP27. This mutation was inherited in an autosomal dominant manner, and was well associated with familial members with the dHMN phenotype. This mutation site is located in the α-crystallin domain and is highly conserved between different species. The frequency of this HSP27 mutation in Koreans was 0.6%. Magnetic resonance imaging analysis revealed that fatty infiltrations tended to progressively extend distal to proximal muscles in lower extremities. In addition, fatty infiltrations in thigh muscles progressed to affect posterior and anterior compartments but to lesser extents in medial compartment, which differs from CMT1A patients presenting with severe involvements of posterior and medial compartments but less involvement of anterior compartment. The authors describe the clinical and neuroimaging findings of the first Korean dHMN patients with the HSP27 Ser135Phe mutation. To our knowledge, this is the first report of the neuroimaging findings of dHMN type II.

A complex phenotype of peripheral neuropathy, myopathy, hoarseness, and hearing loss is linked to an autosomal dominant mutation in MYH14

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. Hum Mutat 32:1–9, 2011.

Inheritance of Charcot–Marie–Tooth disease 1A with rare nonrecurrent genomic rearrangement

Rare copy number variations by the nonrecurrent rearrangements involving PMP22 have been recently suggested to be associated with CMT1A peripheral neuropathy. As a mechanism of the nonrecurrent rearrangement, replication-based fork stalling template switching (FoSTeS) by microhomology-mediated break-induced replication (MMBIR) has been proposed. We found three Korean CMT1A families with putative nonrecurrent duplication. The duplications were identified by microsatellite typing and applying a CGH microarray. The breakpoint sequences in two families suggested an Alu–Alu-mediated rearrangement with the FoSTeS by the MMBIR, and a two-step rearrangement of the replication-based FoSTeS/MMBIR and meiosis-based recombination. The two-step mechanism has still not been reported. Segregation analysis of 17p12 microsatellite markers and breakpoint junction analysis suggested that the nonrecurrent rearrangements are stably inherited without alteration of junction sequence; however, they may allow some alteration of the genomic contents in duplication across generations by recombination event. It might be the first study on the pedigree analysis of the large CMT1A families with nonrecurrent rearrangements. It seems that the exact mechanism of the nonrecurrent rearrangements in the CMT1A may have a far more complex process than has been expected.

Phylogenetic analysis of mitochondrial DNA control region in the swimming crab, portunus trituberculatus

Abstract The control region of mitochondrial DNA (13516–14619) is located between srRNA and tRNAlle gene in swimming crab, Portunus trituberculatus. The present study was investigated the genetic polymorphisms of the control region in samples of P. trituberculatus collected at coastal waters of the Yellow Sea in Korea. A total of 300 substitution and indel polymorphic sites were identified. In addition to SNPs and indel variation, a hypervariable microsatellite motif was also identified at position from 14358 to 14391, which exhibited 10 alleles including 53 different suballeles. When the hypervariable microsatellite motif was removed from the alignment, 95 haplotypes were identified (93 unique haplotypes). The nucleotide and haplotype diversities were ranged from 0.024 to 0.028 and from 0.952 to 1.000, respectively. The statistically significant evidence for geographical structure was not detected from the analyses of neighbor‐joining tree and minimum‐spanning network, neither. This result suggest that population of P. trituberculatus are capable of extensive gene flow among populations. We believed that the polymorphisms of the control region will be used for informative markers to study phylogenetic relationships of P. trituberculatus.

Development of a Y-STR 12-plex PCR system and haplotype analysis in a Korean population

A Y-chromosomal short tandem repeat (Y-STR) dodecaplex PCR system for 12 loci has been developed, and using this system allele frequencies and haplotypes were determined in a Korean male population. From a study of 320 unrelated Korean males, 254 different haplotypes were identified. The haplotype diversity and discrimination capacity were estimated to be 0.996 and 0.794, respectively. Gene diversities ranged from 0.196 to 0.764 (mean gene diversity 0.557). From four loci, five mutations were identified. All cases were single repeat mutations, and mean mutation rate was determined to be 2.64×10−3/locus/meiosis. The 12-plex Y-STR PCR system exhibited reliable typing results for the male–female mixed samples at ratios up to 1 : 100 and for several forensic materials from assaulted women. The system was highly sensitive even with minimal amounts of genomic DNA (0.1 ng). We believe that the newly developed 12-plex Y-STR PCR system will provide more discriminative power and will be suitable for practical forensic uses. Short tandem repeat (STR) loci have shown to be powerful markers for the identification of human individuals due to their hypervariability and wide distribution throughout the genome (Tautz 1989). Of these, Y-chromosomal STRs are effective in determination of paternal lineage as well as in forensic application of male/female cell admixture. It has been suggested that Y-STRs are useful in comparison

Compound mutations of PEO1 and TYMP in a progressive external ophthalmoplegia patient with incomplete mitochondrial neurogastrointestinal encephalomyopathy phenotype

The Mendelian inherited progressive external ophthalmoplegia (PEO) and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) are genetically heterogeneous mitochondrial diseases caused by nuclear-mitochondrial intergenomic defects. The PEO1 and TYMP nuclear genes are closely related in the machinery of the mitochondrial DNA (mtDNA) replication. Mutations in PEO1 and TYMP genes usually cause autosomal dominant PEO, and autosomal recessive MNGIE. We identified a PEO family of Korean origin with additional phenotype of incomplete MNGIE symptom (Family ID: MT16). The entire mitochondrial genome and all coding exons of PEO1, TYMP, ANT1, POLG1, POLG2, DGUOK, and TK2 nuclear genes were sequenced. Clinical information was obtained through history taking, physical examinations, clinical observations, and electrophysiological investigations. Muscle biopsy of left biceps brachii and shoulder magnetic resonance imaging (MRI) were undertaken. We found two heterozygous mutations, Arg374Gln in PEO1 and Glu106Gln in TYMP from the proband who showed complex phenotypes of a typical PEO and late-onset incomplete MNGIE. The PEO1 Arg374Gln has been reported in several PEO patients, but TYMP Glu106Gln has not been reported. Neither large deletion nor causative point mutations were observed in the mtDNA. We suggest that the heterozygous TYMP mutation might affect complex phenotypes as a secondary genetic cause in the co-presence of PEO1 mutation.

MPZ mutation in an early-onset Charcot-Marie-Tooth disease type 1B family by genome-wide linkage analysis

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.