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Kiyoshi Hayasaka - One of the best experts on this subject based on the ideXlab platform.
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Compound heterozygous PMP22 deletion mutations causing severe Charcot–Marie–Tooth Disease type 1
Journal of Human Genetics, 2010Co-Authors: Kazuyuki Nakamura, Mitsuhiro Kato, Chikahiko Numakura, Tomomi Honma, Chizuru Seiwa, Emi Shirahata, Aiko Itoh, Yumiko Kishikawa, Kiyoshi HayasakaAbstract:We present a 31/3-year-old girl with severe Charcot–Marie–Tooth Disease type 1 (Dejerine–Sottas Disease), who was a compound heterozygote carrying a deletion of the whole peripheral myelin protein 22 ( PMP22 ) and a deletion of exon 5 in the other PMP22 allele. Haplotype analyses and sequence determination revealed a 11.2 kb deletion spanning from intron 4 to 3′-region of PMP22 , which was likely generated by nonhomologous end joining. Severely affected patients carrying a PMP22 deletion must be analyzed for the mutations of the other copy of PMP22.
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A novel mutation of the myelin P(o) gene segregating Charcot-Marie-ToothDisease type 1B manifesting as trigeminal nerve thickening.
Journal of Neurology Neurosurgery and Psychiatry, 1999Co-Authors: Masami Shizuka, Yoshio Ikeda, Mitsunori Watanabe, Koichi Okamoto, Mikio Shoji, Toru Ikegami, Kiyoshi HayasakaAbstract:Charcot-Marie-Tooth Disease (CMT) is the most common type of hereditary peripheral neuropathy. It is classified into two types based on pathological and electrophysiological findings: type 1 and type 2. CMT type 1 gene loci have been mapped to chromosome 17 (CMT1A), chromosome 1 (CMT1B),1 another unknown chromosome, (CMT1C) and the X chromosome (CMTX). CMT1B is a rare form of CMT1 associated with mutations of the myelin protein zero (P) gene. Mutations in the P gene have recently been recognised in DeJerine-Sottas Disease, peripheral neuropathy with an early onset in childhood, and a more severe phenotype than CMT1. CMT1 and DeJerine-Sottas Disease are characterised by thickening of peripheral nerves, and thickening of the cauda equina, nerve roots, and ganglia have often been found.2 3 Although cranial nerves are generally spared in CMT, thickening of the acoustic or optic nerve has been reported in some cases. We report here on a Japanese patient who exhibited severe polyneuropathy, bilateral trigeminal thickening on MRI, and an abnormality of the auditory brain stem response. Gene analysis disclosed a novel missense mutation (His81Arg) of P. The cranial nerve involvements in this patient may be associated with the novel missense mutation of P(His81Arg). A 15 year old Japanese girl presented with CMT Disease. She …
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Molecular basis of Charcot-Marie-Tooth neuropathy
Nihon rinsho. Japanese journal of clinical medicine, 1996Co-Authors: Kiyoshi HayasakaAbstract:: Charcot-Marie-Tooth neuropathy (CMT) is the most common inherited peripheral neuropathy. CMT is classified into type types on the basis of pathological and electrophysiological findings: type 1(CMT1), characterized by decreased nerve conduction velocities and by "onion bulb" formation: type 2(CMT2), in which nerve conduction velocities are normal and "onion bulb" formations are rarely seen. CMT1 loci map to chromosome 17 (CMT1A), chromosome 1(CMT1B), another unknown autosome (CMT1C) and the X chromosome (CMTX). Recent work has identified the gene products corresponding to CMT1A, CMT1B and CMTX as peripheral myelin protein-22(PMP22), Po and connexin 32, respectively. DeJerine-Sottas Disease has been identified as being caused by the mutation of PMP-22 or Po gene.
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A novel homozygous mutation of the myelin Po gene producing DeJerine-Sottas Disease (hereditary motor and sensory neuropathy type III)
Biochemical and Biophysical Research Communications, 1996Co-Authors: Tohru Ikegami, Hiroyuki Ikeda, Garth A. Nicholson, Robert A. Ouvrier, Akihiro Ishida, Heather M. Johnston, Grahame Wise, Kiyoshi HayasakaAbstract:Abstract We have previously reported that heterozygosity for myelin Po gene mutations were associated with Charcot–Marie–Tooth Disease type 1B (CMT1B) or Dejerine–Sottas Disease. We investigated the Po gene in a family with clinical Dejerine–Sottas Disease and found two children were homozygous for a deletion of Phe 64. The parents were heterozygous first cousins with subclinical CMT1B and slow nerve conduction velocities. These results suggest that the effect of homozygous Phe 64 deletion on impairment of myelination is dosage-dependent. Clinical phenotype and/or myelin impairment may be determined both by the type of mutation and by the dosage of mutated gene.
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Mutation of the myelin Po gene in hereditary motor and sensory neuropathy
Rinshō shinkeigaku Clinical neurology, 1995Co-Authors: Kiyoshi HayasakaAbstract:: Charcot-Marie-Tooth neuropathy type 1 (CMT1) or hereditary motor and sensory neuropathy (HMSN1) is the most common inherited peripheral neuropathy. Most cases show dominant inheritance. CMT1 loci map to chromosome 17 (CMT1A), chromosome 1 (CMT1B), another unknown autosome (CMT1C) and the X chromosome (CMTX). CMT1A has been demonstrated to be associated with a large DNA duplication of 17 p11.2 including the peripheral myelin protein-22 gene (PMP22) or a point mutation of PMP22. Myelin protein zero (Po), the major structural protein of peripheral myelin, is another integral myelin membrane protein like PMP22. We have mapped the locus of the Po gene to chromosome 1q22-q23 in the region of the CMT1B locus, investigated Po as a candidate gene in three families with CMT1B and identified that Po is a gene responsible for CMT1B. DeJerine-Sottas Disease (HMSN3) has been considered as another demyelinating Disease. However, we have demonstrated that a de novo mutation of Po gene is responsible for some sporadic cases with HMSN3. The term "DeJerine-Sottas Disease" may have represented the severely affected and sporadic cases with CMT. Identification of the primary defect in the Diseases enables us to classify the peripheral neuropathies based on their etiologies.
Nobutada Tachi - One of the best experts on this subject based on the ideXlab platform.
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A small direct tandem duplication of the myelin protein zero gene in a patient with DeJerine-Sottas Disease phenotype
Journal of the Neurological Sciences, 1998Co-Authors: Nobutada Tachi, Naoki Kozuka, Kazuhiro Ohya, Shunzo Chiba, Sumimasa YamashitaAbstract:We present a male patient with DeJerine-Sottas Disease phenotype, who had a small direct tandem duplication of the Po gene. The pathology of the sural nerve showed hypomyelinated fibers with absence of active demyelination and onion-bulb formations composed of two parallel layers of basement membrane, consistent with congenital hypomyelination neuropathy (CHN). However, his clinical features were more severe than those of previously reported CHN patients. A GGCA insertion was identified at the position of nucleotide 560 in the myelin protein zero (Po) gene. This insertional mutation was located in exon 4 coding for the transmembrane domain of the Po gene and caused a shift of reading frame, creating a stop codon. The mutation of the transmembrane domain probably has the largest impact on Po function. The mutation was not identified in both parents.
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MRI of peripheral nerves and pathology of sural nerves in hereditary motor and sensory neuropathy type III
Neuroradiology, 1995Co-Authors: Nobutada Tachi, Naoki Kozuka, Kazuhiro Ohya, S. Chiba, Mutsuo NaganumaAbstract:We investigated two patients with herediatary motor and sensory neuropathy type III, one with DeJerine-Sottas Disease and the other with congenital hypomyelination neuropathy based on nerve pathology and MRI of the sciatic nerve. On biopsy of the sural nerve of the patient with DeJerine-Sottas Disease, myelin debris, indicating demyelination, was observed in an onion-bulb pattern surrounding myelinated fibres. In the patient with congenital hypomyelination neuropathy, onion bulbs were formed of two parallel layers of basement membrane. There was no evidence of myelin breakdown. On axial T2-weighted MRI, a severely hypertropied sciatic nerve containing multiple rounded lesions, suggesting inflammation or demyelination, was observed in the patient with DeJerine-Sottas Disease. In contrast, the sciatic nerve of the patient with congenital hypomyelination neuropathy showed slight hypertrophy without demyelination. MRI of the sciatic nerve may represent a useful tool for characterisation of demyelinating Disease and its prognosis.
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De novo mutation of the myelin P_o gene in Dejerine–Sottas Disease (hereditary motor and sensory neuropathy type III)
Nature Genetics, 1993Co-Authors: Kiyoshi Hayasaka, Masato Himoro, Yukio Sawaishi, Kenji Nanao, Tsutomu Takahashi, Goro Takada, Garth A. Nicholson, Robert A. Ouvrier, Nobutada TachiAbstract:We have investigated the myelin P_o gene on chromosome 1 as a candidate gene in two sporadic cases with Dejerine–Sottas Disease or hereditary motor and sensory neuropathy (HMSN) type III. We found different mutations, a cysteine substitution for serine 63 in the extracellular domain and an arginine substitution for glycine 167 in the transmembrane domain. The patients were genetically heterozygous for the normal allele and the mutant allele, which was absent in their parents and in one hundred unrelated, healthy controls. The results strongly suggest that a de novo dominant mutation of the P_o gene is responsible for at least some sporadic cases of Dejerine–Sottas Disease.
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De novo mutation of the myelin P0 gene in DeJerine-Sottas Disease (hereditary motor and sensory neuropathy type III).
Nature Genetics, 1993Co-Authors: Kiyoshi Hayasaka, Masato Himoro, Yukio Sawaishi, Kenji Nanao, Tsutomu Takahashi, Goro Takada, Garth A. Nicholson, Robert A. Ouvrier, Nobutada TachiAbstract:We have investigated the myelin Po gene on chromosome 1 as a candidate gene in two sporadic cases with Dejerine–Sottas Disease or hereditary motor and sensory neuropathy (HMSN) type III. We found different mutations, a cysteine substitution for serine 63 in the extracellular domain and an arginine substitution for glycine 167 in the transmembrane domain. The patients were genetically heterozygous for the normal allele and the mutant allele, which was absent in their parents and in one hundred unrelated, healthy controls. The results strongly suggest that a de novo dominant mutation of the Po gene is responsible for at least some sporadic cases of Dejerine–Sottas Disease.
Robert A. Ouvrier - One of the best experts on this subject based on the ideXlab platform.
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Seeing big nerves in small children.
Neurology, 2015Co-Authors: Francis O. Walker, Robert A. OuvrierAbstract:Despite being a literally palpable clinical feature of some peripheral neuropathies, nerve enlargement is rarely studied systematically. Enlarged nerves can often be felt or seen, particularly in the neck, in the hereditary hypertrophic neuropathies, especially in DeJerine-Sottas Disease and Charcot-Marie-Tooth Disease type 1A (CMT1A). Even in affected children as young as 3 years, the authors have strongly suspected CMT1A when the child, and particularly a parent, has excessively large and easily palpable median nerves at the elbow, which approach or exceed the size of a standard pencil. Nerve hypertrophy is also encountered in Hansen Disease, chronic inflammatory demyelinating neuropathy, nerve tumors, and certain focal nerve lesions. For the first time, Yiu et al.1 have provided an analytical description of its distribution, evolution, and functional significance in children. Why has this taken so long? Unlike Disease in other organs, Disease in nerve and muscle has only been studied with the microscope—virtually never with the naked eye. Barring abscess or tumor, nerves and muscles are cut away at autopsy and most pathologists see nothing but tiny fragments from clinical donors. Even in the virtual world of MRI, most radiologists look past the nerves and muscles to seek out Disease in other organs. However, placing high-resolution ultrasound in the hands of enterprising investigators such as Yiu et al. has for the first time made it possible not just to recognize nerve enlargement, but to measure it.
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Effect of Oral Curcumin on Déjérine-Sottas Disease
Pediatric Neurology, 2009Co-Authors: Joshua Burns, Monique M. Ryan, Pathma D. Joseph, Kristy J. Rose, Robert A. OuvrierAbstract:Curcumin is the newest therapeutic agent for ameliorating the clinical and neuropathologic phenotype of a mouse model of DeJerine-Sottas Disease. We undertook a 12-month dose-escalation safety trial of oral curcumin in a 15-year-old Caucasian girl with DeJerine-Sottas Disease (point mutation, Ser72Leu) complicated by severe weakness, scoliosis, and respiratory impairment. The patient received 50mg/kg/day oral curcumin for the first 4 months and 75mg/kg/day thereafter, to complete a 12-month trial. Outcome measures included muscle strength, pulmonary function, upper/lower extremity disability, neurophysiologic studies, and health-related quality of life. After 12 months, the patient experienced no adverse events, and reported good compliance. There was little improvement in objective outcome measures. Knee flexion and foot strength increased slightly, but hand and elbow strength decreased. Pulmonary function, hand function, and measures of upper/lower extremity disability were stable or reduced. Her neurophysiologic findings were unchanged. Parent-reported quality of life improved for most domains, especially self-esteem, during the 12 months of treatment. Child-reported quality of life, assessed at the final visit, mirrored these results, with overall feelings of happiness and contentment. Further studies are required to explore the efficacy and safety of curcumin for severe demyelinating neuropathies of infancy and early childhood.
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A novel homozygous mutation of the myelin Po gene producing DeJerine-Sottas Disease (hereditary motor and sensory neuropathy type III)
Biochemical and Biophysical Research Communications, 1996Co-Authors: Tohru Ikegami, Hiroyuki Ikeda, Garth A. Nicholson, Robert A. Ouvrier, Akihiro Ishida, Heather M. Johnston, Grahame Wise, Kiyoshi HayasakaAbstract:Abstract We have previously reported that heterozygosity for myelin Po gene mutations were associated with Charcot–Marie–Tooth Disease type 1B (CMT1B) or Dejerine–Sottas Disease. We investigated the Po gene in a family with clinical Dejerine–Sottas Disease and found two children were homozygous for a deletion of Phe 64. The parents were heterozygous first cousins with subclinical CMT1B and slow nerve conduction velocities. These results suggest that the effect of homozygous Phe 64 deletion on impairment of myelination is dosage-dependent. Clinical phenotype and/or myelin impairment may be determined both by the type of mutation and by the dosage of mutated gene.
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Correlation between the histopathologic, genotypic, and phenotypic features of hereditary peripheral neuropathies in childhood.
Journal of Child Neurology, 1996Co-Authors: Robert A. OuvrierAbstract:: In recent years, there have been remarkable advances in the understanding of the molecular genetic basis of the hereditary polyneuropathies. Linkage of the genes for Charcot-Marie-Tooth Disease to chromosomes 1 and then 17 was followed by the discovery that the commonest form of Charcot-Marie-Tooth Disease (CMT1A) was due to a duplication of DNA at 17p11.2-12. This duplication was shown to contain the gene for peripheral myelin protein PMP22. The finding that mutations of the myelin protein PMP22 gene were present in some Charcot-Marie-Tooth Disease cases lacking the duplication confirmed the myelin protein PMP22 gene as the site of the defect in Charcot-Marie-Tooth Disease. Similarly, defects of the myelin protein P0 gene on chromosome 1 have been demonstrated in a rarer form of Charcot-Marie-Tooth Disease (CMT1B). A deletion of DNA at 17p11.2-12 results in the disorder hereditary neuropathy with liability to pressure palsies. Other mutations of the myelin protein PMP22 and myelin protein P0 genes have been associated with the clinical syndrome known as DeJerine-Sottas Disease. An X-linked form of Charcot-Marie-Tooth Disease (CMTX) has been characterized and shown to be due to mutations of the gap junction protein, connexin 32. Transgenic murine models with inactivated myelin protein PMP22 and myelin protein P0 genes have shown pathologic changes strinkingly similar to those seen in human patients with disturbances of those genes. In this paper, the clinical and histopathologic characteristics of these conditions are discussed in relation to the genotypic basis. It will be argued that there is still an important place for the clinician and nerve pathologist in a medical world immersed in the wonders of molecular genetics.
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De novo mutation of the myelin P_o gene in Dejerine–Sottas Disease (hereditary motor and sensory neuropathy type III)
Nature Genetics, 1993Co-Authors: Kiyoshi Hayasaka, Masato Himoro, Yukio Sawaishi, Kenji Nanao, Tsutomu Takahashi, Goro Takada, Garth A. Nicholson, Robert A. Ouvrier, Nobutada TachiAbstract:We have investigated the myelin P_o gene on chromosome 1 as a candidate gene in two sporadic cases with Dejerine–Sottas Disease or hereditary motor and sensory neuropathy (HMSN) type III. We found different mutations, a cysteine substitution for serine 63 in the extracellular domain and an arginine substitution for glycine 167 in the transmembrane domain. The patients were genetically heterozygous for the normal allele and the mutant allele, which was absent in their parents and in one hundred unrelated, healthy controls. The results strongly suggest that a de novo dominant mutation of the P_o gene is responsible for at least some sporadic cases of Dejerine–Sottas Disease.
Tohru Ikegami - One of the best experts on this subject based on the ideXlab platform.
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Novel mutations of the peripheral myelin protein22 gene in two pedigrees with DeJerine-Sottas Disease
Human Genetics, 1998Co-Authors: Tohru Ikegami, Hiroyuki Ikeda, Masahiro Aoyama, Takasumi Matsuki, Tsuyoshi Imota, Yasuo Fukuuchi, Takahiro Amano, Itaru Toyoshima, Yoshihito Ishihara, Hiroyuki EndohAbstract:Peripheral myelin protein22 (PMP22), a membrane glycoprotein, plays a significant role in the formation and/or maintenance of compact myelin in the peripheral nervous system. We studied two pedigrees with DeJerine-Sottas Disease and identified two novel mutations in the PMP22 gene: one a 2-bp deletional mutation at nucleotide positions426 and 427 of exon4 (this is predicted to alter the reading frame at leucine80 and thus to lead to frame-shifted translation), and the other a guanine to thymine substitution at nucleotide position636 leading to a cysteine substitution for glycine150. Both mutations were located in the putative transmembrane domains reported in many cases of Charcot-Marie-Tooth neuropathy, DeJerine-Sottas Disease, and hereditary neuropathy with liability to pressure palsies. The results suggest an important role for the putative transmembrane domains of PMP22 in its function.
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A novel homozygous mutation of the myelin Po gene producing DeJerine-Sottas Disease (hereditary motor and sensory neuropathy type III)
Biochemical and Biophysical Research Communications, 1996Co-Authors: Tohru Ikegami, Hiroyuki Ikeda, Garth A. Nicholson, Robert A. Ouvrier, Akihiro Ishida, Heather M. Johnston, Grahame Wise, Kiyoshi HayasakaAbstract:Abstract We have previously reported that heterozygosity for myelin Po gene mutations were associated with Charcot–Marie–Tooth Disease type 1B (CMT1B) or Dejerine–Sottas Disease. We investigated the Po gene in a family with clinical Dejerine–Sottas Disease and found two children were homozygous for a deletion of Phe 64. The parents were heterozygous first cousins with subclinical CMT1B and slow nerve conduction velocities. These results suggest that the effect of homozygous Phe 64 deletion on impairment of myelination is dosage-dependent. Clinical phenotype and/or myelin impairment may be determined both by the type of mutation and by the dosage of mutated gene.
Garth A. Nicholson - One of the best experts on this subject based on the ideXlab platform.
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A novel homozygous mutation of the myelin Po gene producing DeJerine-Sottas Disease (hereditary motor and sensory neuropathy type III)
Biochemical and Biophysical Research Communications, 1996Co-Authors: Tohru Ikegami, Hiroyuki Ikeda, Garth A. Nicholson, Robert A. Ouvrier, Akihiro Ishida, Heather M. Johnston, Grahame Wise, Kiyoshi HayasakaAbstract:Abstract We have previously reported that heterozygosity for myelin Po gene mutations were associated with Charcot–Marie–Tooth Disease type 1B (CMT1B) or Dejerine–Sottas Disease. We investigated the Po gene in a family with clinical Dejerine–Sottas Disease and found two children were homozygous for a deletion of Phe 64. The parents were heterozygous first cousins with subclinical CMT1B and slow nerve conduction velocities. These results suggest that the effect of homozygous Phe 64 deletion on impairment of myelination is dosage-dependent. Clinical phenotype and/or myelin impairment may be determined both by the type of mutation and by the dosage of mutated gene.
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De novo mutation of the myelin P_o gene in Dejerine–Sottas Disease (hereditary motor and sensory neuropathy type III)
Nature Genetics, 1993Co-Authors: Kiyoshi Hayasaka, Masato Himoro, Yukio Sawaishi, Kenji Nanao, Tsutomu Takahashi, Goro Takada, Garth A. Nicholson, Robert A. Ouvrier, Nobutada TachiAbstract:We have investigated the myelin P_o gene on chromosome 1 as a candidate gene in two sporadic cases with Dejerine–Sottas Disease or hereditary motor and sensory neuropathy (HMSN) type III. We found different mutations, a cysteine substitution for serine 63 in the extracellular domain and an arginine substitution for glycine 167 in the transmembrane domain. The patients were genetically heterozygous for the normal allele and the mutant allele, which was absent in their parents and in one hundred unrelated, healthy controls. The results strongly suggest that a de novo dominant mutation of the P_o gene is responsible for at least some sporadic cases of Dejerine–Sottas Disease.
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De novo mutation of the myelin P0 gene in DeJerine-Sottas Disease (hereditary motor and sensory neuropathy type III).
Nature Genetics, 1993Co-Authors: Kiyoshi Hayasaka, Masato Himoro, Yukio Sawaishi, Kenji Nanao, Tsutomu Takahashi, Goro Takada, Garth A. Nicholson, Robert A. Ouvrier, Nobutada TachiAbstract:We have investigated the myelin Po gene on chromosome 1 as a candidate gene in two sporadic cases with Dejerine–Sottas Disease or hereditary motor and sensory neuropathy (HMSN) type III. We found different mutations, a cysteine substitution for serine 63 in the extracellular domain and an arginine substitution for glycine 167 in the transmembrane domain. The patients were genetically heterozygous for the normal allele and the mutant allele, which was absent in their parents and in one hundred unrelated, healthy controls. The results strongly suggest that a de novo dominant mutation of the Po gene is responsible for at least some sporadic cases of Dejerine–Sottas Disease.