X-linked motor and sensory neuropathy with pyramidal signs and cerebral white matter lesions.

We report two brothers with hereditary motor and sensory neuropathies and pyramidal signs. Electrophysiological evaluation revealed polyneuropathy and involvement of the central motor, somatosensory, and auditory pathways. Brain magnetic resonance imaging studies showed diffuse white matter lesions, and sural nerve biopsy identified a reduction in the large myelinated nerve fibers. The patients' mother and sister exhibited similar, but milder neurologic findings suggesting that the genetic defect may be X-linked; however, a point mutation in the connexin 32 gene was negative.

Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients.

Three genes commonly causing Charcot-Marie-Tooth disease (CMT) encode myelin-related proteins: peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32). Demyelinating versus axonal phenotypes are major issues in CMT associated with mutations of these genes. We electrophysiologically, pathologically and genetically evaluated demyelinating and axonal features of 205 Japanese patients with PMP22 duplication, MPZ mutations or Cx32 mutations. PMP22 duplication caused mainly demyelinating phenotypes with slowed motor nerve conduction velocity (MCV) and demyelinating histopathology, while axonal features were variably present. Two distinctive phenotypic subgroups were present in patients with MPZ mutations: one showed preserved MCV and exclusively axonal pathological features, while the other was exclusively demyelinating. These axonal and demyelinating phenotypes were well concordant among siblings in individual families, and MPZ mutations did not overlap among these two subgroups, suggesting that the nature and position of the MPZ mutations mainly determine the axonal and demyelinating phenotypes. Patients with Cx32 mutations showed intermediate slowing of MCV, predominantly axonal features and relatively mild demyelinating pathology. These axonal and demyelinating features were present concomitantly in individual patients to a variable extent. The relative severity of axonal and demyelinating features was not associated with particular Cx32 mutations. Median nerve MCV and overall histopathological phenotype changed little with disease advancement. Axonal features of diminished amplitudes of compound muscle action potentials (CMAPs), axonal loss, axonal sprouting and neuropathic muscle wasting all changed as disease advanced, especially in PMP22 duplication and Cx32 mutations. Median nerve MCVs were well maintained independently of age, disease duration and the severity of clinical and pathological abnormalities, confirming that median nerve MCV is an excellent marker for the genetically determined neuropathic phenotypes. Amplitude of CMAPs was correlated significantly with distal muscle strength in PMP22 duplication, MPZ mutations and Cx32 mutations, while MCV slowing was not, indicating that clinical weakness results from reduced numbers of functional large axons, not from demyelination. Thus, the three major myelin-related protein mutations induced varied degrees of axonal and demyelinating phenotypic features according to the specific gene mutation as well as the stage of disease advancement, while clinically evident muscle wasting was attributable to loss of functioning large axons.

[Chronic and predominantly sensory polyneuropathy in Toroku Valley where a mining company produced arsenic].

We report 9 patients (5 males, 4 females, ages 63-77) with chronic polyneuropathy. They were exposed to arsenic for about 15-40 years in Toroku Valley, Takachiho-Town, Miyazaki Prefecture, Japan, where a mining company produced arsenic from 1920-1962. Predominantly sensory polyneuropathy was the most significant neurological finding. In 5 of them, superficial and deep sensation was equally affected over the entire body, including head, face, and mucous membranes of the mouth. The corneal reflexes were absent or sluggish. Pin-prick and light-touch perception was absent in their hands and legs. Another sensory disorder such as glove and stocking-type was seen in 4 of them. All 9 patients were comfortable with extremely hot water in their beverages, their baths, and their wash basins compared with controls. But these patients felt that their temperature sensation was normal. Motor involvement was minimal. Although motor-nerve conduction velocities were normal or reduced minimally, sensory-nerve conduction velocities were moderately reduced. Sural-nerve biopsy revealed reduction of both small myelinated and unmyelinated fibers, which occurs with axonal degeneration of peripheral nerves. Other main symptoms and signs were tension-type headaches, non-painful tonic spasms of limbs, and losses or significantly decreased sensations of taste and smell. Dantrolene-sodium was effective for the treatment of their non-painful tonic spasms of limbs. As for the general medical condition of these patients, all of them had suffered from chronic bronchitis and skin eruption during childhood or in their early life or in their young adulthood when the mine was producing arsenic. At the time of this study only four of them suffered from chronic bronchitis and none of them had skin eruptions or discoloration of the skin, 37 years after closure of the mine. These 9 patients were diagnosed as having chronic arsenic poisoning and arsenic polyneuropathy. The multiplicity of symptoms found in these patients--anosmia, ageusia, chronic bronchitis, tension-type headaches, and non-painful tonic spasms of limbs--differs from the symptoms previously reported cases with arsenic poisoning. This may be due to combined overexposure to environmentally hazardous arsenic by effluent gas, dust, and drinking water in Toroku Valley. As concerns the sensory disorders described above, it is necessary to investigate sensory conduction pathways, including cerebral sensory cortex, spinal cord, and skin sensory receptors such as Pacini corpuscles, and Meissner corpuscles. Unfortunately, no information has been obtained about this problem because there were no autopsy cases.