A novel MPZ gene mutation in dominantly inherited neuropathy with focally folded myelin sheaths.

We found the association of a heterozygous novel MPZ gene point mutation, Ile62Phe in exon 2, with autosomal dominant motor and sensory neuropathy with focally folded myelin sheaths. Family study revealed that de novo Ile62Phe mutation on the MPZ gene occurred in the proband and was inherited by her children with early onset slowly progressive neuropathy. Our study suggests that the characteristic pathologic findings of the sural nerve in these patients are closely related to the site and nature of amino acid substitutions of the MPZ gene.

Choroideremia with leukoencephalopathy and arylsulfatase A pseudodeficiency.

A 33-year-old male patient was admitted to our hospital because of progressive gait disturbance and involuntary movement of the neck. He showed choroideremia, distal motor neuropathy, and leukoencephalopathy on T2-weighted brain magnetic resonance imaging (MRI). Choroideremia is a rare X-linked, progressive, degenerative disease of retina and choroid. There have been some reports of choroideremia patients with neurological complications. Recent studies have assigned its genetic locus to a small segment of Xq21.3 and it encodes a protein that resembles component A of rat Rab geranyl-geranyl transferase, a protein essential for cell function. This patient did not have the reported genetic abnormalities for choroideremia. Known disorders causing leukoencephalopathy were not detected except for a partial deficiency of arylsulfatase A (17.3% of normal controls in lymphocytes and 13.7% in fibroblasts). Deficiency of arylsulfatase A activity occurs in the late infantile, juvenile, and adult forms of metachromatic leukodystrophy (MLD) which is also an inherited disorder of myelin metabolism, but because of its unstability, it occurs in normal individuals and in patients with other neurological diseases. Consequently, we suspect that this patient had partial deficiency of arylsulfatase A and choroideremia as predisposing factors for white matter degeneration.

Morphologic findings in biopsied skeletal muscle and cultured fibroblasts from a female patient with Danon's disease (lysosomal glycogen storage disease without acid maltase deficiency).

A family is reported in which three members were affected by cardiomyopathy. Two members died unexpectedly in their second decade. Only a 23-year-old male suffered from the triad of clinical manifestations (cardiomyopathy, mental retardation and vacuolar myopathy). Morphologic findings and biochemical studies of his biopsied skeletal muscle and cultured fibroblasts confirmed lysosomal glycogen storage disease with normal acid maltase that was first described by Danon et al. In this study we demonstrated early morphologic changes, storage of glycogen and abnormal membranous structures in disorganized myofibers in biopsied skeletal muscle from the elder sister, who only showed cardiomyopathy clinically. The aggregation of autophagosomes was prominent in cultured fibroblasts, with an increased glycogen content. The activity of acid alpha-glucosidase was higher than normal. This is a systemic storage disease with different expression in males and females.

Manganese intoxication during total parenteral nutrition: report of two cases and review of the literature.

We report two cases of manganese (Mn) intoxication during total parenteral nutrition including manganese (Mn). Both patients showed parkinsonism with psychiatric symptoms and elevated serum Mn levels. T1-weighted magnetic resonance images (MRI) revealed symmetrical high intensity lesions in the globus pallidus. Discontinuation of Mn supplementation and levodopa treatment improved the symptoms and MRI abnormalities in the both patients. Thus, careful attention should be paid to the long-term intravenous administration of Mn.

Cerebrotendinous xanthomatosis: clinical and biochemical evaluation of eight patients and review of the literature.

We present the clinical and laboratory findings of 8 patients with cerebrotendinous xanthomatosis. The clinical features consisted of a combination of bilateral Achilles tendon xanthomas, cataracts, low intelligence, pyramidal signs, cerebellar signs, convulsions, peripheral neuropathy, foot deformity, cardiovascular disease or atherosclerosis, EEG abnormality, and increased CSF protein. Increased cholesterol was present in the serum, CSF and red cell membrane of all 8 patients. The bile of one patient with late age onset of the disease showed an attenuated production of bile acids and bile alcohols. Three of the 7 had obstruction and/or marked narrowing of the coronary arteries. Data on 136 patients reported throughout the world are reviewed.

Atherogenic risk factors in cerebrotendinous xanthomatosis.

In a study of coronary artery disease in patients with cerebrotendinous xanthomatosis (CTX), we documented the presence or absence of atherogenic risk factors and performed detailed analyses of serum lipid and lipoprotein profiles. Four of the seven patients examined had coronary arterial narrowing and/or obstruction, but multiple atherogenic risk factors were not found in any of these patients. Total cholesterol (T.ch) levels and low density lipoprotein-cholesterol (LDL-ch) levels were lower, and high density lipoprotein2-cholesterol (HDL2-ch) levels were higher in CTX patients than in controls. Triglyceride and very low density lipoprotein (VLDL) levels were significantly lower in the former. Indices correlating with the risk of atherosclerosis, such as the atherogenic index, and the ratios of apolipoprotein B/apolipoprotein AI, HDL2-ch/LDL-ch, HDL2-ch/HDL3-ch, indicated that CTX serum was, in fact, 'anti-atherogenic'. However, coronary artery disease is frequently seen in patients with CTX. This discrepancy suggests the existence of a unique mechanism by which atherosclerosis is induced in patients with CTX. We discuss a mechanism of disturbed lipoprotein metabolism which might be responsible for the deposition of sterols in the tissues of patients with CTX.

The effects of tobacco smoking on the short, middle, and long latency responses of the blink reflex in humans.

The three responses (R1, R2, and R3) of the electrically elicited blink reflex (BR) obtained in four normal human subjects were investigated before and after smoking both a filtered and an unfiltered cigarette. The changes observed in the BR were stronger and statistically more significant for the unfiltered than for the filtered cigarette, (p < 0.0001) and were more dramatic in R3 than R1 or R2. The action of nicotine on central pathways located at the interneuronal network of the brainstem, basal ganglia, and C fiber structures involved with this reflex seems to be the most likely mechanism for these findings.

Idiopathic hypoparathyroidism with fungal seminal vesiculitis.

A 23-year-old man was suffering from high fever and general fatigue 6 months before admission. The levels of serum Ca and intact-parathyroid hormone (PTH) were low. His brain computed tomography (CT) revealed marked calcifications of the basal ganglia, and pelvis magnetic resonance imaging (MRI) showed inflammation of his seminal vesicle. His candida antigen titer was high and antibiotic therapy was unsuccessful. High fever persisted despite fluconazole treatment, however he recovered after treatment with fluconazole and vitamin D (alfacalcitol). Idiopathic hypoparathyroidism hinders the activation of vitamin D via insufficient PTH secretion, and vitamin D has some immunological effects. His decreased natural killer (NK) cell activity improved after alfacalcitol treatment. We suggest the possible immunological effects of vitamin D in this fungal infection.

[Nationwide survey of necrotizing myelopathy associated with malignancy in Japan].

Twenty-two cases of transverse myelopathy associated with malignancy were collected in nationwide survey in Japan. Paraneoplastic necrotizing myelopathy (PNM) was suspected in 9 of them and 8 cases were diagnosed as radiation myelopathy (RM), clinically and pathologically. Other 5 cases had different causes of transverse myelopathy. In comparison with PNM and RM, malignant lymphoma, flaccid paraplegia and sphincter dysfunction were highly associated in the patients with PNM. On the other hand, lung cancer, spastic paraplegia, abnormality in spinal MRI and dysesthesia in legs as an initial symptom were prevalent in the cases of RM. Six cases of them were compared pathologically. Although all cases had no metastasis of malignant cells, five cases of PMN showed acute and chronic necrosis and rarefaction of spinal cord with or without perivascular cuffing. One case of RM had focal spinal cord atrophy and no lymphocytes infiltration. Immunohistochemically, herpes simplex virus type 2 (HSV2) infection in spinal cord was shown in the 2 cases of the necrotizing myelopathy. Virus infection such as HSV2 could be one of causes of PNM and virological study must be done in the cases of necrotizing myelopathy associated with malignancy.

[A case of pharyngeal-cervical-brachial variant of Guillain-Barré syndrome with positive anti-galactocerebroside (Gal-C) IgM antibody].

A 49-year-old man presented with hoarseness, dysphagia, muscle atrophy and weakness of deltoid, trapezius, sternocleidomastoid, rhomboid, anterior serratus, infraspinatus and supraspinatus. Anti-Gal-C IgM antibody was positive in the serum. The other antiganglioside antibodies (GM1, GM2, GM3, GD1a, GD1b, GD3, GT1a, GT1b, GQ1b, GA1, GalNAc-GD1a, GM1b) were negative. Patient contracted pneumonia but whether it was due to mycoplasma was not evident. Plasmapheresis improved his clinical state including a decrease of the antibody. This case was diagnosed pharyngeal-cervical-brachial variant of Guillain-Barré syndrome, and anti-Gal-C antibody seemed to be correlated with the pathogenesis of this syndrome. Gal-C is a major glycolipid of myelin and the cell membrane of the myelin-forming cell (oligodendrocytes and Schwann cells) and is free of specific localization and distribution. The mechanism how the anti-Gal-C IgM antibody induced bulbar paralysis and the symptoms localizing neck and upper limbs remains to be known.

[Treatment of spastic paraparesis with botulinum toxin with reference to beneficial effects, disease severity and long-term treatment].

We administered local botulinum toxin injections on the leg adductors of 12 patients with spastic paraparesis (9 patients with HAM, 2 patients with spinal spastic paraparesis, 1 patient with an identified degenerative disease). Two of them were wheelchair-bound and the other patients could walk with or without help. The patients were assessed by the time to walk 10 m and the spasticity score which was derived from the degree of muscle tone and spasm frequency of leg adductors. After the initial injection, 7 of the 12 patients improved spasticity scores and 8 of the 10 patients could walk 10 m within a shorter time. The time to walk 10 m was markedly shortened in moderate cases. However, one patient complained of leg weakness and the time to walk 10 m was prolonged. Five of the 12 patients received injections 3 to 7 times, and were followed up for a mean of 16.2 months. In 4 of the 5 patients, repeated injections could maintain the improvement of spasticity score and time to walk 10 m. However, injection was discontinued in one patient because of leg weakness. The other side effects were pain and swelling at the injected site and dysarthria. However, these side effects were slight and transient and did not require treatment. No other systemic side effects were observed. In conclusion, the beneficial effects of botulinum injections to spastic paraparesis were (1) improvement of objective symptoms in mild cases, (2) improvement of ADL in moderate cases, and (3) improvement of objective symptoms and ease of nursing care in severe cases. Furthermore, we confirmed the long-term efficacy and safety of botulinum toxin.

Extrafusal and intrafusal muscle effects in experimental botulinum toxin-A injection.

The effects of botulinum toxin-A was compared on both extrafusal and intrafusal muscle fibers in the biceps femoris of Wistar rats. Four days after injection no action potentials were elicited with stimulation single-fiber electromyography on the injected side. Fourteen days after injection, jitter became measurable and these values were increased on the injected side. Extrafusal muscle fibers began to atrophy on the 4th day and this continued to the 14th day postinjection. Atrophy was also evident and progressive in intrafusal muscle fibers. Increased terminal innervation ratios, end-plate spread of cholinesterase, and increased density of very small myelinated fibers in large intramuscular nerves were observed 14 days postinjection. Both extrafusal and intrafusal fibers are cholinergically innervated, and both were progressively affected by botulinum toxin, perhaps varying in degree only. In addition to partial denervation, Botulinum toxin effects in dystonia may also be related to modified spindle afferent discharge.

A new complement factor B variant (BF S075) in Japanese.

A new slow-moving variant of the complement factor B, named BF S075, was found in a Japanese patient with cerebral thrombosis and urticaria. The variant was inherited in a codominant manner. The protein concentration and functional hemolytic activity of the complement factor B in the patient's serum were within normal limits. The BF S075 is the fourth rare BF variant found in the Japanese population.

Depression of neuromuscular transmission in methylmercury-poisoned rats: a glass microelectrode and single fiber electromyography study.

Changes in neuromuscular transmission were examined in methylmercury (MeHg)-poisoned rats, given a total oral dose of 60 mg CH3HgCl at 5 mg/kg/day. A microelectrode study was done on the 21st day. The mean quantal content and mean values of the immediately available pool of ACh in the MeHg-poisoned rats were reduced as compared to those in the control rats, but the mean values for the release probability of ACh did not differ significantly. Stimulation single fiber electromyography (SFEMG) was done on the biceps femoris muscle at 1, 5, 10 and 20 Hz on the 28th day. Both a significant and consistent increase in jitter were found at increasing stimulation rates in the MeHg-poisoned rats. The SFEMG findings suggest presynaptic involvement due to accelerated depletion of ACh. We confirmed that neuromuscular transmission is depressed in MeHg-poisoned rats in vivo and in vitro.

A case of HTLV-I-associated myelopathy with IgA nephropathy and pseudohypoparathyroidism type 1.

We report a case of HAM/TSP presenting with short stature, mental retardation, skin eruptions, uterine and ovarian hypogenesis and nephropathy. Skin erythema was noted since from the age of three years old and spasticity of lower extremities from elementary school age. Serum calcium level showed 4.1 mEq/l. Recombinant human PTH infusion resulted in no response of phosphate excretion. The persistent proteinuria prompted renal needle biopsy, which revealed IgA and C1q deposits in glomerular mesangium. A diagnosis of pseudohypoparathyroidism and IgA nephropathy was entertained. This patient with pseudohypoparathyroidism who has a deficient immune system was seized with the early onset of HAM/TSP and IgA nephropathy.

Antibodies to potassium channels of PC12 in serum of Isaacs' syndrome: Western blot and immunohistochemical studies.

We investigated the pathophysiology of nerve hyperexcitability in a patient with Isaacs' syndrome, who had typical clinical and electromyographic features and responded to plasma exchange. Immunoblotting and immunohistochemistry studies showed that antibodies from this patient reacted with the lysate of a neuronal cell line (PC12). In Western blots, constituents of the patient's serum, particularly immunoglobulin M, reacted with proteins of approximately 50 and 18 kDa, whereas the control serum did not. A cross-linking study with alpha-dendrotoxin (7 kDa) showed a 57 kDa protein-peptide complex. Immunohistochemistry showed that the patient's serum reacted with PC12 cells and human intramuscular nerve axons. Our findings indicate that in Isaac's syndrome nerve hyperexcitability is the result of the immunological involvement of the voltage-dependent potassium channels located along the distal motor nerve or at the nerve terminal.

Epidemiology of progressive muscular dystrophy in Okinawa, Japan. Classification with molecular biological techniques.

We studied the prevalence of various types of progressive muscular dystrophy (PMD) in Okinawa, Japan on December 31, 1989 and the incidence of Duchenne muscular dystrophy (DMD) in 5-year periods from 1957 to 1985. We classified patients with PMD clinically, electrophysiologically, molecular biologically and immunohistochemically with antidystrophin antibody, especially for sporadic cases of DMD, Becker muscular dystrophy (BMD) and limb-girdle muscular dystrophy (LG). The prevalence for all PMD in Okinawa was 7.13 X 10(-5) for DMD, 1.82 X 10(-5) for BMD in the male population, 1.55 X 10(-5) for LG, 1.14 X 10(-5) for congenital muscular dystrophy, 2.03 X 10(-5) for facioscapulohumeral muscular dystrophy (FSH), and 9.13 X 10(-5) for myotonic dystrophy (MD) in the total population. The incidence of DMD in the period 1957-1985 was 15.41 X 10(-5) live-born males (LBM) and 3.21 X 10(-5) LBM for BMD. The incidence has apparently declined in Okinawa since 1975. The prevalence of BMD, FSH and MD was rather high in Okinawa compared with previous reports. Molecular biological techniques for classifying patients were indispensable for the epidemiological study of PMD.

Dominantly inherited motor and sensory neuropathy with excessive myelin folding complex.

The two patients in a family having the clinical and electrodiagnostic features of hereditary motor and sensory neuropathy (HMSN) are described. The main histological features of sural nerve were segmental demyelination and remyelination with moderate to marked loss of myelinated fibers, and myelin folding complex along all of the large and small myelinated fibers. These features appeared morphologically similar to those observed in HMSN with excessive myelin outfolding, or globular neuropathy. Southern blot analysis suggests that there were neither duplication nor deletion of the peripheral myelin protein-22 gene in the patients. The presented two patients may be a rare form of dominantly inherited HMSN with myelin folding complex.

Polyneuropathy with minifascicle formation in a patient with 46XY mixed gonadal dysgenesis.

A patient with mixed gonadal dysgenesis showed glove and stocking-type sensory impairment and slowing of motor and sensory nerve conduction. Sural nerve biopsy revealed minifascicular formation with decreased density of myelinated fibers. As far as we are aware, this is the first report of polyneuropathy with minifascicular formation in 46XY mixed gonadal dysgenesis.