High-dose vitamin C therapy for inclusion body myositis.

OBJECTIVES: The efficiency of high-dose vitamin C therapy for inclusion body myositis (IBM) was assessed. SUBJECTS & METHODS: The subjects were five patients with IBM confirmed pathologically. After the intravenous administration of 40 mg/kg vitamin C five times/week for four weeks, muscle weakness was found to improve in three cases. The average muscle score improved from 8.1 to 8.8, from 7.0 to 8.1 and from 6.2 to 6.8. Magnetic resonance imaging (MRI) demonstrated a reduction in the size of T2 high lesions and gadolinium enhancement in the thigh muscles in one case. Based on our findings, high-dose vitamin C therapy is considered to be effective in some cases of IBM.

Identification of human MutY homolog (hMYH) as a repair enzyme for 2-hydroxyadenine in DNA and detection of multiple forms of hMYH located in nuclei and mitochondria.

An enzyme activity introducing an alkali-labile site at 2-hydroxyadenine (2-OH-A) in double-stranded oligonucleotides was detected in nuclear extracts of Jurkat cells. This activity co-eluted with activities toward adenine paired with guanine and 8-oxo-7,8-dihydroguanine (8-oxoG) as a single peak corresponding to a 55 kDa molecular mass on gel filtration chromatography. Further co-purification was then done. Western blotting revealed that these activities also co-purified with a 52 kDa polypeptide which reacted with antibodies against human MYH (anti-hMYH). Recombinant hMYH has essentially similar activities to the partially purified enzyme. Thus, hMYH is likely to possess both adenine and 2-OH-A DNA glycosylase activities. In nuclear extracts from Jurkat cells, a 52 kDa polypeptide was detected with a small amount of 53 kDa polypeptide, while in mitochondrial extracts a 57 kDa polypeptide was detected using anti-hMYH. With amplification of the 5'-regions of the hMYH cDNA, 10 forms of hMYH transcripts were identified and subgrouped into three types, each with a unique 5' sequence. These hMYH transcripts are likely to encode multiple authentic hMYH polypeptides including the 52, 53 and 57 kDa polypeptides detected in Jurkat cells.

[A case of limb-girdle type myasthenia gravis in whom rheumatoid arthritis appeared immediately after thymectomy].

We report a 48-year-old female who presented limb-girdle type myasthenia gravis with inflammatory lung lesions and rheumatoid arthritis. She demonstrated a rapidly progressive muscle weakness of extremities. Neurological examination revealed facial muscle weakness, and proximal dominant limb muscle atrophy and weakness. Ptosis, ophthalmoplegia, and bulbar palsy were not observed. The edrophonium test and serum anti-acetylcholine receptor antibody were positive. The repetitive nerve stimulation showed 55% waning in the thenar muscles. From these findings, she was diagnosed as having myasthenia gravis. Plain chest X-P and body CT showed tumor-like lesions in the lung. Lung biopsy revealed the infiltration of lymphocytes. These lesions decreased in size after thymectomy and corticosteroid administration. Immediately after thymectomy, she began to have morning stiffness with pain and swelling of the finger and knee joints. RAHA test, which was negative before thymectomy, became highly positive. These findings were consistent with rheumatoid arthritis. In this patient, thymus probably played a role to suppress the development of rheumatoid arthritis.

A novel mutation of the GTP-cyclohydrolase I gene in a patient with hereditary progressive dystonia/dopa-responsive dystonia.

We report a 37-year-old Japanese woman with hereditary progressive dystonia with marked diurnal fluctuation and dopa-responsive dystonia. She developed dystonia in the lower limbs at the age of 11 years, followed by spasmodic torticollis and resting tremor of the feet, which responded remarkably to low doses of levodopa (100 mg/day). Concentrations of biopterin and neopterin in CSF were decreased. Polymerase chain reaction analysis of the guanosine 5'-triphosphate cyclohydrolase I gene revealed a novel mutation (Thr186-->Lys).

[Gerstmann-Sträussler-Scheinker syndrome with a Pro102Leu mutation in the prion protein gene and atypical MRI findings, hyperthermia, tachycardia, and hyperhidrosis].

A 64-year-old Japanese woman with Gerstmann-Sträussler-Scheinker syndrome (GSS) is reported. She was admitted to our hospital for progressive amnesia, twitching of the right upper limb, and difficulty in speaking and walking for 5 months. Physical examination revealed a fever, tachycardia, and hyperhidrosis without any evidence of inflammation or infection. Neurological examinations demonstrated dementia, frontal lobe signs, and spontaneous myoclonus. She developed akinetic mutism 4 months later. The levels of neuron-specific enolase and 14-3-3 protein were elevated in the cerebrospinal fluid, and serial EEG showed periodic synchronous discharges. DNA analysis of the prion protein gene revealed a Pro102Leu mutation and therefore she was diagnosed as GSS102. Head MRI showed abnormal high signal intensity by T2 weighted image in bilateral caudate nuclei, putamen, frontal lobes, and white matter around the posterior horn of lateral ventricles at admission, and extension to global cerebral cortex and diffuse deep white matter with marked atrophy of bilateral frontal and cerebellar cortices 4 months later. In 123I-IMP SPECT study, uptake of RI decreased slightly only in left frontal region at admission, but decreased markedly in bilateral frontal region 4 months later. Analysis of autonomic function (analysis of noradrenarine in plasma and urine, coefficient of variation of R-R intervals before and after giving atenolol, Aschner's eyeball pressure test, intracutaneous atropine and adrenaline injection test) revealed sympathetic hyperactivity but normal parasympathetic activity. This is a very rare case of GSS102 with atypical MRI findings and clinical features like Creutzfeldt-Jakob disease rather than GSS102, presenting hyperthermia, tachycardia, and hyperhidrosis caused presumably by sympathetic hyperactivity as well as fatal familial insomnia. Therefore it is suggested that some factors besides the codon mutation in the prion protein gene may influence clinical symptoms in prion disease.

[A case of stiff-man syndrome with an antineuronal autoantibody against an 80 kDa protein].

A 23-year-old Japanese man had noted intermittent muscle stiffness in his lower limbs and trunk in addition to painful muscle cramps in his back over one year. The muscle stiffness continued and eventually spread to his upper limbs. Neurological examinations revealed saccadic ocular movement and stiffness in the masseter, neck and four limbs and truncal muscles, enhanced by both voluntary and passive movements. Although the mobility of his joints was severely limited, the muscle strength was preserved. Electromyograms showed the continuous firing of normal motor units at rest, which disappeared both during sleep and after the intravenous administration of 10 mg of diazepam. An oral glucose tolerance test showed a normal pattern. Both the adrenal and thyroid functions were normal. No antibody against glutamic acid decarboxylase was detected in either the patient's serum or cerebrospinal fluid (CSF). The serum antibody against the voltage-gated potassium channel was also negative. Western blot analysis revealed the presence of an antibody in his serum and CSF which reacted with an 80kDa protein in the rat cerebrum, cerebellum and human spinal cord, but not in the rat liver. This patient was thus diagnosed as having stiff-man syndrome. Treatment with oral diazepam (50 mg/day), a GABAA agonist, proved to be effective, whereas baclofen (75 mg/day), a GABAB agonist, was not. These results suggest the dysfunction of the GABA neurons in this case, similar to that as previously observed in other cases of stiff-man syndrome while, in addition, the function of the GABAB receptor was also markedly disturbed in this case.

Differential splicing of the GTP cyclohydrolase I RNA in dopa-responsive dystonia.

We characterized the GTP cyclohydrolase I (GTP-CH-I) gene in a patient with hereditary progressive dystonia with marked diurnal fluctuation/dopa-responsive dystonia (HPD/DRD). The sequence analysis revealed a C to A transversion, which predicts a novel missense mutation (Thr186Lys). Unexpectedly, this base change, occurring in the middle of exon 5, resulted in a production of the novel transcript lacking exon 5 and a part of exon 6. Three different transcripts of the GTP-CH-I gene, previously reported in the human liver, were also present in the peripheral lymphocytes from the patient and controls. Quantitative comparison of the truncated-subunit mRNA and the wild-type one implied that differential splicing regulates the GTP-CH-I enzyme activity, leading to the clinical variations in HPD/DRD. The patient showed a unique clinical symptom, suggesting that the nigrostriatal dopaminergic system is more affected than previously thought in HPD/DRD.

[Myelopathy due to vitamin B12 deficiency presenting only sensory disturbances in upper extremities: a case report].

We report a 54-year-old man with vitamin B12 deficiency myelopathy limited to the upper extremity region. He was well until October, 1995, when he had an onset of exertional dyspnea and general fatigue. Then he noted tingling sensation in bilateral upper extremities in March, 1996. He had undergone total gastrectomy due to gastric ulcer 15 years ago. Neurological examination revealed superficial and vibratory sensory loss in the upper extremities distal to elbows, and pseudoathetoid movement of the left fingers. Otherwise neurological examination was unremarkable. Laboratory examination revealed macrocytic anemia, and low serum vitamin B12. However, serum folate was within the normal range. In SEP studies, median nerve stimulation evoked peripheral N9 and N13 potentials, but not cortical N20 one. Posterior tibial nerve stimulation elicited normal responses. MEP, VEP, needle EMG, and nerve conduction studies gave normal findings. T2-weighted MRI showed high signal intensity lesions at the C1-Th1 level in the posterior column, especially in the cuneate fascicles. The gracile fascicles were spared. This is a very rare case of myelopathy due to vitamin B12 deficiency presenting only sensory disturbances in both upper extremities. The lesions limited in the cuneate fascicle were confirmed by electrophysiological, and neuroradiological examinations.