Kazuhiro Ohya

MRI of peripheral nerves and pathology of sural nerves in hereditary motor and sensory neuropathy type III

We investigated two patients with herediatary motor and sensory neuropathy type III, one with Déjérine-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 Déjérine-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 Déjérine-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.

Tomaculous neuropathy in Charcot-Marie-Tooth disease with myelin protein zero gene mutation

Mutation of the myelin protein zero (MPZ) gene is associated with a small number of Charcot-Marie-Tooth (CMT) patients. We present a patient with Lys 130 Arg substitution in the extracellular domain who showed tomacula formation in biopsied sural nerve. CMT patients with mutations Ly 96 Glu, Lys 130 Arg and Ile 135 Leu showed tomaculous neuropathy. Present and previously reported investigations suggest that the pathological phenotypes of peripheral nerve are probably related to the mutations of the MPZ gene.

A new mutation of the Po gene in patients with Charcot-Marie-Tooth disease type 1B: screening of the Po gene by heteroduplex analysis

Most of Charcot-Marie-Tooth (CMT) 1 families are associated with a duplication in chromosome 17p11.2-p12, which includes the gene encoding peripheral myelin protein-22 (PMP-22). Point mutations of the Po gene have been identified in a few of the CMT 1 families in whom no duplication was found. We investigated a new mutation of the Po gene in one of those families. A to G substitution of nucleotide 389 in exon 3 resulted in Lys 131 Arg substitution. This structural change of extracellular domain of Po would alter the function of Po and result in an impairment of peripheral myelin compaction.

Muscle involvement in congenital insensitivity to pain with anhidrosis

A patient with congenital insensitivity to pain with anhidrosis, who had characteristic clinical features and biopsied sural nerve, is presented. Nerve pathology findings indicated a loss of the small myelinated and unmyelinated fibers. Biopsied muscle disclosed a marked variation in fiber size, some small fibers with central nuclei, and a small number of small angulated fibers, consistent with neurogenic and myogenic changes. Many patients with congenital insensitivity to pain with anhidrosis had muscle weakness and absent or decreased deep tendon reflexes with normal nerve conduction velocity. We confirmed that lack of small myelinated fibers in motor neurons resulted in a striking change of muscle in our patient.

Expression of myotonic dystrophy protein kinase in biopsied muscles

We present expression of myotonic dystrophy protein kinase (DM-PK) on biopsied muscles by immunocytochemistry using antibody against synthetic DM-PK peptide antigen. Immunolocalization of DM-PK was observed in neuromuscular junctions, muscle spindle, and sarcoplasm on both normal and DM muscles. DM-PK expression of sarcoplasm was present in adult normal and DM muscles. In Duchenne and Becker muscular dystrophies, DM-PK was intensively expressed in cytoplasm on immature regenerating fibers. DM-PK is initially produced in cytoplasm of regenerating fibers and migrates toward sarcoplasm with maturity of muscle cell.

CTG Repeat Size and Histologic Findings of Skeletal Muscle From Patients With Congenital Myotonic Dystrophy

An approximate correlation has been demonstrated between the degree of CTG repeat expansion and clinical severity among myotonic dystrophy patients. Congenital myotonic dystrophy, which is the most severe form of the disease, has the largest size of CTG repeat. Muscle immaturity is a characteristic finding in congenital myotonic dystrophy muscle. We compared the CTG repeat size and histologic findings of skeletal muscle from patients with congenital myotonic dystrophy. An 8.6 kb or 9.8 kb plus an expanding band ranging from 15 kb to 17.5 kb was observed in muscle from five patients with congenital myotonic dystrophy by Southern blot analysis using EcoRI-digested DNAs probed with p5B1.4. There was no correlation between immaturity of skeletal muscle and the degree of CTG repeat expansion on skeletal muscle. Undetermined maternal factors may have an important role in the cause of immaturity of muscle in congenital myotonic dystrophy patients. (J Child Neurol 1996; 11:430-432).

Rhabdomyolysis Associated With Human Parvovirus B19 Infection in a Patient With Fukuyama-Type Congenital Muscular Dystrophy

Patients with Fukuyama-type congenital muscular dystrophy sometimes experience transient exacerbations of muscle weakness. We took care of a 9-year-old boy with Fukuyama-type congenital muscular dystrophy who presented with acute respiratory failure and decreased exercise ability with marked elevation of serum creatine kinase indicating rhabdomyolysis. At that time, his younger sister suffered from erythema infectiosum. Although he had no particular symptoms, he was tested and proven to have acute human parvovirus B19 infection based on detection of anti-B19 IgM and parvovirus B19 DNA in his serum. His acute rhabdomyolysis was possibly triggered by human parvovirus B19 infection.

Expression of peripheral myelin protein zero in sural nerve of patients with Charcot-Marie-Tooth disease 1B.

A Charcot-Marie-Tooth disease 1B (CMT1B) family with a mutation of the Po gene is presented. A to G substitution of nucleotide 389 in exon 3 resulted in Lys 131 Arg substitution. Immunostaining for Po in biopsied sural nerve from one family member with CMT1B was expressed in a small number of myelinated fibers. Immunoblot analysis for Po revealed that it was of normal molecular weight (29 kDa) although significantly reduced in amount. This heterozygous mutation could lead to a reduction in the total amount of normal protein in peripheral nerves through a mechanism of loss of function.

Detection of the CTG repeat expansion in congenital myotonic dystrophy

SummaryMyotonic dystrophy (DM) is caused by an abnormal expansion of an unstable CTG trinucleotide repeat in the 3′ untranslated region of mRNA encoding a putative serine/threonine protein kinase. We analyzed 59 patients with DM (28 congenital DM families: 27 families with maternal transmission and 1 paternal transmission) and 27 normal control subjects to evaluate their CTG repeat size between DM patients and the normal controls, and to search for a correlation between the clinical characteristics of congenital DM (CDM) and CTG repeat expansions. Analysis was on the basis of the Southern blot and polymerase chain reaction (PCR) methods, and by direct sequencing of PCR amplified CTG repeats. Analysis of intergenerational differences in the CTG repeat size for mother-child pairs showed a positive correlation (y=1.0384x+1265.2, r2=0.311). In addition to the strong parental bias, this group showed genetic anticipation. There was a significant correlation of the CTG repeat expansion with disease severity. The largest CTG repeat expansion (2,293 CTG repeats) on average belonged to the severe CDM group, and the smallest (129 CTG repeats) to the subclinical DM group. The mutant allele of an asymptomatic father in the paternally transmitted pedigree revealed 75 CTG repeats, demonstrating that he was a DM protomutation carrier.

Molecular and pathological studies in Charcot-Marie-Tooth disease 1A

We analyzed a 1.5-Mb duplication of the p11.2-12 region of chromosome 17, including the PMP-22 gene (CMT1A duplication), seven families with Charcot-Marie-Tooth disease type I (CMT I) and six sporadic patients with suspected CMT I by Southern blot analysis. In order to detect the CMT 1A duplication, probe pVAW409R3a, probe PMP-22 cDNA and reference probe SF85 were used for Southern hybridization. In six out of seven families with CMT I, CMT1A duplication was identified. One of six sporadic CMT patients had CMT1A duplication. The probe pVAW4O9R3a was more informative than PMP-22 cDNA and SF85 for detecting CMT1A duplication. In pathological study of biopsied sural nerve, thickened myelin sheath was observed in some myelinated fibers in patients with CMT1A duplication.