Phenotypic variation in a large Japanese family with Miyoshi myopathy with nonsense mutation in exon 19 of dysferlin gene.

Miyoshi myopathy, an autosomal recessive muscular dystrophy involving distal muscles, is caused by dysferlin mutations. We present clinical and genetic studies of two men and six women, aged 25-83 years, from a Japanese family with consanguineous marriages. Onset was between ages 17 and 59 years. Six of the patients had muscle involvement typical of Miyoshi myopathy, one initially had severe proximal muscle involvement, and one had scapuloperoneal-type muscle involvement. Three patients showed steppage gait. Genetic linkage analysis identified a maximum lod score of 3.34 (θ=0.00) at marker D2S292 in 2p13. Analysis of dysferlin revealed the mutation G2090T (Glu573Stop) in exon 19 in all affected patients. This is the largest Japanese family with Miyoshi myopathy showing intrafamilial phenotypic variation and sharing a common mutation in dysferlin.

[Giant-cell myocarditis without a symptom of heart failure seen in a patient with myasthenia gravis and concurrent Hashimoto's disease].

A 69-year-old Japanese woman initially noticed difficulty in squatting in the last two years, followed by nasal voice, fatiguability in mastication, and blepharoptosis. On admission to our hospital, in addition to these neurological findings, we detected ectopic arrhythmia and Levine II systolic murmur at the apex region, without any subjective symptoms. The serum titer of anti-acetylcholine receptor antibody was elevated to 28 nmol/l (normal: < 0.2), and she responded to repetitive nerve stimulation at a frequency of 3 Hz showing 13% waning, she had positive test for edrophonium administration, and was diagnosed as having myasthenia gravis (MG). There was no thymoma by radiographic examination. She also had Hashimoto's disease confirmed by the laboratory findings. Chest X-p revealed dilatation of the heart, and 24-hour Holter ECG revealed non-sustained ventricular tachcardia (VT). Ventriculography revealed prominent dilatation of the left ventricle and diffuse hypokinetic ventricular wall motility. Endomyocardial biopsy revealed muscle fiber degeneration, cellular infiltration, and scattered multinucleated giant cells, confirming a diagnosis of giant cell myocarditis (GCM). Quadriceps muscle biopsy revealed a small number of muscle fibers with giant nuclei, but no giant cells were seen. Immunological study revealed elevation of CD4/CD8 ratio and memory CD4 cells. Antibody to anti-cardiac and anti-striate muscle were strongly positive in the serum. Four months later, she developed dyspnea on effort and hypoxia, accompanied by severe bradycardia leading to sinus arrest. For acute cardiac deterioration, steroid pulse therapy was started followed by oral predonisolone and azathioprine, which aggravated myasthenic symptoms. The patient was ventilated for respiratory hypercapnia. During immunoabsobent therapy, she developed VT which caused a cardiac arrest, leading to fatal outcome. In case of MG, especially overlapped with other autoimmune diseases, evaluation of cardiac function should be conducted to detect GCM.

Preserved sympathetic skin response at the distal phalanx in patients with carpal tunnel syndrome.

OBJECTIVE: To assess the viability of sympathetic sudomotor fibers in carpal tunnel syndrome (CTS). METHODS: We recorded sympathetic skin response (SSR) with a multichannel recording system. Forty-four patients with CTS (51 hands), 7 patients (7 hands) with asymptomatic median mononeuropathy at the wrist (MMW), and 20 normal subjects (20 hands) were studied. We classified the patients into 4 grades of increasing severity. RESULTS: In the hands of normal subjects, SSR was evoked easily at all recorded sites. SSR at the wrist in patients with asymptomatic MMW decreased in amplitude. SSR was markedly distorted at the wrist in severe grades of CTS. The SSR amplitude ratio (wrist/distal phalanx) decreased significantly with more severe grade (rh=-0.4; P<0.05), but the sensitivity was lower than that of other electrodiagnostic criteria. A patient with persistent allodynia at the wrist after surgery showed the slight recovery of SSR amplitude ratio; the other two patients without allodynia showed substantial recovery of SSR amplitude ratio within 24 weeks after surgery. CONCLUSION: SSR amplitude ratio is a poor indicator of CTS diagnosis, but may be useful in assessing the viability of sympathetic sudomotor fibers and may assist in evaluating the response to surgery.

[Tracheopulmonary-subcutaneous fistula associated with anaerobic subcutaneous abscess on mechanical ventilator support in a patient with Duchenne muscular dystrophy].

A 29-year-old Japanese man with Duchenne muscular dystrophy was placed on a mechanical ventilator support at 23 years of age and admitted to our hospital at 25 years of age. He had severe neck contracture deviated to the left side which resulted in dysphagia and microaspiration. At 29 years of age, he developed left lobar pneumonia accompanied by slight fever, back pain and a foul odor from the patient's sputum. Although the patient received broad spectrum antibiotics, pneumonia disseminated to the right lung. A week later, chest computed tomography was conducted which revealed tracheopulmonary-subcutaneous fistula, and a massive subcutaneous abscess with free air production. Drainage from the subcutaneous abscess was done through a chest tube; however, respiratory hypercapnia was not corrected and the patient died. From the culture of drained fluid, anaerobic bacteria including peptostreptococcus sp. were detected. This tracheopulmonary-subcutaneous fistula was thought to be caused by chronic microaspiration of mouth anaerobes, mechanical injury of the trachea under long term ventilator support, and decreased deep back muscle bulk with substitution of adipose tissue around the chest.

Lambert-Eaton myasthenic syndrome with ophthalmoparesis and pseudoblepharospasm.

We report a patient initially diagnosed as having ocular myasthenia gravis who showed progressive ophthalmoparesis and pseudoblepharospasm together with positive acetylcholine receptor antibodies. Repeated evaluation with high-frequency repetitive stimulation revealed an incremental response and elevated titers of antibodies against presynaptic calcium channels, confirming Lambert-Eaton myasthenic syndrome. Systemic evaluation revealed no malignant neoplasm but revealed euthyroid Hashimoto's disease. Immunomodulative therapy including plasma exchange and administration of an immunosuppressent (azathioprine) combined with a potassium-channel blocker (3,4-diaminopyridine) reduced the ocular abnormalities. We conclude that the ocular manifestations in this patient were probably caused by Lambert-Eaton myasthenic syndrome.

Gene for hereditary motor and sensory neuropathy (proximal dominant form) mapped to 3q13.1.

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) has been reported as a new type of HMSN with the disease gene locus in the 3p14.1-q13 region. To further narrow down the gene locus, we performed fine linkage mapping using the linkage disequilibrium method. Analysis of DNA marker haplotypes and genetic cross-over sites showed the disease gene locus to be in the 3.1 cM interval bracketed by D3S1591 and D3S1281. Linkage disequilibrium analysis with DISMULT using 9 marker loci jointly in this region showed a lod score of 4.93 (P < 0.00000095). Consequently, the HMSN-P gene almost certainly lies on chromosome 3q13.1 and shows evidence of linkage disequilibrium.

[A patient with intractable myasthenia gravis successfully treated with total lymphoid irradiation].

We report a 20-year-old man with intractable myasthenia gravis successfully treated with total lymphoid irradiation (TLI). An encapsulated thymoma in the anterior mediastinum was resected as extended thymectomy by video-assisted thoracoscopic surgery at 2 months after the onset of ptosis and muscle weakness. Following treatments, such as ambenonium hydrochloride, an immunosuppression therapy (prednisolone and azatioprine), 5 courses of immunoadsorption therapy, and a high dose of cyclophosphamide and methylprednisolone, did not make persistent improvement of myasthenic symptoms. Ageusia occurred twice prior to myasthenic crises and subsided with other myasthenic symptoms after treatments. Steroid psychosis and secondary Cushing's syndrome made us to reduce the dose of prednisolone. Post-operative residual, recurrent, or metastatic thymus was not unveiled, then we added the low dose fractionated irradiation (1.5 Gy x 12 = 18 Gy) to the mediastinum. Three months after the irradiation, however, a crisis occurred and the titer of anti-acetylcholine receptor antibody increased up to 100 nmol/l. Therefore, we performed TLI (Mantle; 1.5 Gy x 9 = 13.5 Gy, paraaortic and inverted-Y; 1.5 Gy x 14 = 21 Gy), which brought about persistent improvement of myasthenic symptoms with decrease in the titer of anti-acetylcholine receptor antibody.

Localized scleroderma associated with progressing ischemic stroke.

We present a 73 year-old Japanese woman with localized scleroderma involving the right side of the scalp accompanied by continuous tingling pain, who developed insidiously progressive left hemiparesis. In magnetic resonance imaging of the brain, an infarct first appeared in the watershed region of the right middle cerebral artery territory and subsequently extended to deep white matter accompanied by scattered hemorrhages. Focal stenosis in the M2 portion of the right middle cerebral artery was revealed on magnetic resonance angiography, and the distal vessels were only shown faintly. A biopsy specimen from the sclerotic scalp lesion showed obvious thickening of vessel walls and mild mononuclear cell infiltration. We believe that the progressing ischemic stroke was caused by hemodynamic disturbances from localized sclerotic obstruction of the middle cerebral artery, with an autoimmune pathogenesis.

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.

Atypical rigid form of Huntington's disease: a case with peripheral amyotrophy and congenital defects of a lower limb.

We describe a patient showing an atypical phenotype of Huntington's disease (HD), including prominent generalized dystonia, peripheral amyotrophy of the legs with an inverted champagne bottle configuration and pes equinus. The patient also had congenital defects of the lower left leg. Chorea and psychiatric symptoms were not prominent. Polymerase chain reaction assessment revealed 51 CAG repeats in gene IT 15. Magnetic resonance imaging of the brain demonstrated mild atrophy of the pons and cerebellum, and hyperintensity of the transverse pontine fibers and neostriatum on spin-echo images. Peripheral amyotrophy in this case might have resulted from axonal degeneration related to neuronal damage in the central nervous system, although at the present time we cannot confirm it as a new HD phenotype.

Afterdischarges following F waves observed in a patient with tetanus.

We report a case of non-fluminent and mildly affected tetanus patient who showed afterdischarges following F waves in the affected extremity. The afterdischarges occurred following F waves and showed different configuration respond to each stimuli. Diazepam was also effective for spasms of our patient. This finding disappeared after treatment and showed a good correlation to clinical symptoms. These observations suggest that afterdischarges following F waves are induced by tetanus toxin which puts most of the motor neuron pool in a hyperactive state through its own action to the motor nerve including the spinal motor neuron.

Effects of meal ingestion and active standing on blood pressure in patients > or = 60 years of age.

Postprandial hypotension and orthostatic hypotension occur often in elderly patients. In the present study, we examined hemodynamic and humoral responses to meal ingestion and active standing in 20 patients > or = 60 years of age who were free of apparent autonomic and cardiac dysfunction. For a time-control study, water was given instead of a meal to 19 of the 20 patients. After the meal ingestion, there was a fall in systolic blood pressure (BP) in 6 patients of > 20 mm Hg, whereas the fall in systolic BP during the control study was not > 20 mm Hg in any patient. The low-frequency power of the systolic BP wave, an index of peripheral sympathetic activity, was significantly increased only in the patients without postprandial hypotension. The postprandial changes in systolic BP were correlated with the changes in the low-frequency power of the systolic BP wave (r = 0.61; p < 0.01), but they were not correlated with the changes in plasma norepinephrine, insulin, cardiac output, or parameters obtained by the spectral analysis of the RR interval. The systolic BPs in the upright position were comparable after the meal and the water ingestion. Thus, the effects of meal ingestion and upright position on BP are not additive. Dysfunction of peripheral sympathetic control of vascular tone may contribute to the postprandial hypotension in elderly patients.

[A case of tabes dorsalis observed in an HTLV-1 carrier].

We report a case of a 53-year-old female HTLV-1 carrier with tabes dorsalis. In addition to typical symptoms of tabes dorsalis, she presented HTLV-1 associated myelopathy (HAM) like clinical features such as sensory disturbance with thoracic sensory levels and bladder disturbance (pollakiuria). Although penicillin treatment did not improve in her neurological symptoms, steroid therapy was effective especially in HAM like symptoms. The CSF neopterin level was markedly decreased after steroid therapy, indicating that inflammation in the spinal cord was settled down after treatment. Our case suggests that CNS infection like tabes dorsalis may be modified by HTLV-1 infection and then present some atypical clinical features based upon altered immunological aspects of HTLV-1 carriers.

Sympathetic skin responses of the hand in normal subjects: shorter latency at distal phalanx.

We studied the conduction of the sympathetic skin response (SSR) in the hands of 35 normal subjects by simultaneous recording at five sites. The mean latency of the SSR in all subjects increased from the wrist (W) to the middle phalanx (M), but the SSR latency at the distal phalanx (D) was shorter than that at the middle phalanx. The mean conduction time and conduction velocity from W to M was 197.5 ms and 0.87 m/s, respectively, and that from W to D was 48.8 ms and 2.34 m/s, respectively. For evaluation of the cause of the shorter latency at D, digital nerve blocking was performed in two subjects. The blocking of the volar digital nerves at the proximal phalanx abolished SSR at M and D. It was postulated that the initiation or conduction of sudomotor nerve impulse to the distal phalanx would be facilitated compared with those to the other proximal sites in the hand. The SSR conduction time between W and M may be a means of detecting alteration of sympathetic sudomotor nerve activity.

[Two siblings with adult-onset sialidosis type I (cherry-red spot-myoclonus syndrome)].

Cases of two Japanese siblings with adult-onset sialidosis type I are reported. A 38-year-old man had gradually developed involuntary movement of the extremities from the age of 31. On admission, he had no skeletal abnormalities and hepatosplenomegaly, but showed myoclonus of the extremities and dyskinesia in the perioral region. We found cherry-red spots and a giant potential in a somatosensory evoked potential (SEP) study. Then, the diagnosis of sialidosis type I was confirmed by low activity of white blood cell sialidase. MRI (SE, TR 2,000/TE 100, 40) of the brain revealed a small high intensity are in the cerebral white matter adjacent to the posterior horn of the right cerebral ventricle. To our knowledge, no report on MRI findings of the brain in sialidosis type I has been reported. So far, it is uncertain whether or not such a lesion is caused by sialidosis. He was treated with clonazepam, sodium valproate, diphenylhydantoin, or haloperidol. The former two improved the symptoms, but SEP findings did not change. The subject's 43-year-old brother had also myoclonus and epilepsy since the age of 31, and low activity of sialidase. Their mother had no symptoms, but her sialidase activity level was as low as that of a carrier. These two are the eighth and ninth cases of sialidosis type I in Japan to be confirmed by enzyme activity.