Oculopharyngodistal myopathy is genetically heterogeneous and most cases are distinct from oculopharyngeal muscular dystrophy.

The question whether oculopharyngodistal myopathy (MIM 164310) is a distinct disease entity or a variant of oculopharyngeal muscular dystrophy (MIM 164300) persists. To answer this question, we examined five patients with the clinical characteristics of oculopharyngodistal myopathy for GCG expansion in poly(A)-binding protein nuclear 1 gene (previously called poly(A)-binding protein 2), the causative gene defect for oculopharyngeal muscular dystrophy. Only one of our five patients had the significant GCG expansion. Thus, oculopharyngodistal myopathy is a genetically heterogeneous disorder, which includes patients with oculopharyngeal muscular dystrophy but, for the most part, is different genetically from oculopharyngeal muscular dystrophy.

[A case with posterior column ataxia associated with cerebellar ataxia and sensory neuropathy].

The patient was a 72-year-old man who had a history of subtotal gastrectomy for gastric ulcer at age of 37 years. He had no familial history of hereditary disorders. In 1980 he noticed mild ataxic gait which exaggerated while he closed eyes. The symptoms increased gradually, and four years later he noticed hypoesthesia of his soles. In 1983 he was admitted to the National Center Hospital for Mental, Nervous and Muscular Disorders for the first time. Neurological examination revealed dysarthria, ataxic gait, disturbance of coordination to a slight degree, and muscle strength of the upper and lower limbs were in normal range. Mild hypoesthesia of pain and temperature sensation, and marked decrease of deep sensation and vibration of the lower extremities were demonstrated. Romberg sign was positive. EMG studies revealed low amplitude of action potential and normal motor nerve conduction velocity. Biopsy of the sural nerve showed marked decrease of both large and small myelinated fibers. In 1998 he was admitted second time for the further examination. Laboratory examination including routine blood examination, blood chemistry including CRP, TPHA, vitamin B1, B2, B12, A, E, K, hexosaminidase A in leucocyte were in normal range. CSF was normal. Genetic studies including SCA 1, 2, 3, 6, DRPLA, CMT1A, CMTX 1 were all negative. MCV of lower limbs was in normal range, though SCV was not evoked in the upper and lower limbs. MRI studies showed mild atrophy of the bilateral lobulus of the cerebellum which was not so much changed in the last 5 years. The clinical symptoms revealed dominant posterior column disturbance, ataxia and sensory neuropathy. These combination was not described in the previous literature, and this case may be a new variant of the spinocerebellar degeneration.

Satoyoshi's syndrome in an adult: a review of the literature of adult onset cases.

Satoyoshi syndrome consists of painful intermittent muscle spasms, alopecia and diarrhea. The age of onset is commonly less than 20 years of age. Adult onset of this syndrome is rare. We report a 65-year-old Japanese woman with Satoyoshi's syndrome of adult onset. Satoyoshi's syndrome of adult onset shows no skeletal abnormalities, in comparison with the classical pediatric cases. The clinical features in our patient revealed the benign and long-term course of muscle spasm and alopecia. This progression differed markedly from the other patients of adult onset. Thus, the severity of Satoyoshi's syndrome is variable in adult onset cases, and this diagnosis should be considered in adults with various and unexplained muscle spasms.

[Palato-pharyngo-laryngeal myoclonus].

Palato-pharyngo-laryngeal myoclonus is well-known clinical criterion characterized by persistent, rapid, repetitive, rhythmic muscle twitch the rate of which ranges 50-200 Hz. It appears in the palate, pharynx, larynx, diaphragma, and the ocular or limb muscles, but the most common combination of the distribution is palate-pharyngo-laryngeal type or only palatal type. In most instances the movement is synchronous, but others show asynchronous myoclonus at different rates. There was a case report in which an electrical stimulation given at the ulnar nerve produced reset of myoclonus indicating that some feedback mechanism has some influence in the generation of pacemaker activity in the brainstem. This myoclonus has been considered to result from interruption of any one fiber system in a olivocerebellorubrotegment-olivary equipotential reverating circuit, so-called Guillain-Mollaret triangle. As etiological factors, cerebrovascular accidents are the most common, but various other causes have been encountered including tumor, trauma, inflammation, multiple sclerosis, electroshock, dialysis encephalopathy, and other degenerative neurological diseases. Analysis of the symptoms is the most important cure of the diagnosis, and this myoclonus is relatively easily differentiated from other involuntary movement, but recently MRI is a very effective examination to detect a lesion in the medulla visualizing the degenerative changes of the lower olivary nucleus. Clonazepam, trihexyphenidyl, carbamazepine, 5HTP and caeruletin have been reported as effective agents for this movement.

Skeletal abnormalities in Satoyoshi's syndrome: a radiographic study of eight cases.

Skeletal abnormalities of eight patients with Satoyoshi's syndrome, a rare condition of unknown etiology characterized by progressive muscle spasms, alopecia, and diarrhea, were studied radiographically. Various skeletal changes were observed including metaphyseal lesions, slipping of multiple epiphyses, cystic lesions, acroosteolysis and osteolysis, bone fragmentation at tendinous insertions, fatigue fractures, and early osteoarthrosis. This wide range of lesions is likely to be due to repeated injuries to the growth plates, epiphyses, and tendon attachments in the growing skeleton caused by recurrent vigorous muscle spasms.

[Divergence paralysis due to a lesion of the lateral tegmentum of the midbrain caused by thalamic hemorrhage].

A 66-year-old diabetic and hypertensive man suddenly developed right hemiplegia. Examination revealed right hemiplegia including his face, vertical gaze palsy, and divergence paralysis. The cranial CT scan disclosed a left thalamic hemorrhage as large as 40 mm in diameter, which extended to the midbrain. He was treated medically and his divergence paralysis improved. But all other symptoms remained for the next 11 months and he eventually died of acute retroperitoneal hemorrhage. The autopsy revealed spongy state and gliosis extending from the left thalamic nuclei to the left midbrain. In the tegmentum, dorsolateral part around the left oculomotor nucleus was involved. The precise location of the human divergence center of the eyes is still unknown. According to previous reports, the divergence center may locate in the tegmentum of the midbrain or pons. Recently, animal experiments detected the neurons which fire for divergent in the mesencephalic reticular formation just dorsal and lateral to the oculomotor nuclei. Our case had a lesion of gliosis and spongy state, namely the old hematoma, in the same portion. Therefore, we considered that the human divergence center of the eyes might exist in the lateral tegmentum of the midbrain, just lateral and dorsal to the oculomotor nucleus.

Therapeutic trials on progressive muscular dystrophy.

The special medical care in the National Sanatorium prolonged the life span of the patients with progressive muscular dystrophy from 15.8 years to 20.4 years over the last 20 years. Various new drug trials for muscular dystrophy have been implemented in the last 12 years in Japan. Bestatin and Loxistatin, protease inhibitors, showed definite improvement on dystrophic mice or hamsters, animal models of muscular dystrophy. However clinical application of these drugs failed to prove the effects on patients with Duchenne muscular dystrophy. The difficulty of clinical evaluation and judgement of effects in progressive neurological diseases is discussed.

1-[11C]pyruvate turnover in brain and muscle of patients with mitochondrial encephalomyopathy. A study with positron emission tomography (PET).

We examined pyruvate turnover using 1-[11C]pyruvate in the brain and epicranial muscle of 6 patients with mitochondrial encephalomyopathy (MEM), diagnosed by muscle biopsy and mitochondrial enzyme assay. The radioactivity was measured by positron emission tomography (PET). The time-activity curve for 11C in both brain and muscle generated after i.v. injection of 1-[11C]pyruvate consisted of 2 components in normal subjects and patients, i.e. a fast and a slow component which were assumed to represent the aerobic (mitochondrial) and anaerobic (glycolytic) metabolism of pyruvate, respectively. In the brain and muscle of patients, the aerobic component was smaller and the anaerobic larger than in normals. The extent of this abnormality seemed to reflect the severity of the disease. The same slight abnormality for [11C]pyruvate turnover was also observed in the brain of MEM patients who were without cerebral symptoms. Cerebral blood flow (CBF) and cerebral oxygen consumption (CMRO2) of most patients were lower than those of normals, and the oxygen extraction fraction (OEF) was decreased in many patients.

Distal myopathy.

Various types of the distal myopathy except Welander's late distal myopathy of Swedish type were described. There were many reports in the past concerning the varieties of the distal myopathy. Distal myopathy is a rather rare disorder and it may be difficult to diagnose these cases. Among these various distal myopathy, an emphasis was made upon the clinical and pathological characteristics of the diseases, particularly distal muscular dystrophy of Miyoshi, Distal myopathy with rimmed vacuole formation of Nonaka and ours, and Oculo-pharyngo-distal myopathy. All these diseases show the distal muscle involvement but the clinical features, heredity, course and pathological features are quite different, and prognosis is also different. Accordingly when we examined these distal myopathy cases, clinical characteristics and histo-pathological findings should be carefully studied. It should be also emphasized that the level of serum CPK dose not indicate the severity of the myopathy. In muscular dystrophy or myositis, serUm CPK elevates remarkably and we can consider the level of CPK as a sign of the severity or condition of the disease. However, in myopathy as "rimmed vacuole distal myopathy" serum CPK remains in normal level even though weakness is severe. This is due to absence of the membrane abnormalities of muscle cells. Leakage of the CPK from muscle cells, therefore, does not reflect the degree of the cell destruction. In this point we have to remember the fact that serum CPK is not a indicator of all muscle diseases and even if the CPK is normal, we have to consider the presence of myopathy.

[Two cases of mitochondrial myopathy (focal cytochrome c oxidase deficiency), long-term follow-up on a diagnosis of ocular type myasthenia gravis].

Two patients (a 50-year-old and a 35-year-old men) with focal cytochrome c oxidase deficiency, manifesting ptosis and external ophthalmoplegia of 13 and 6 years' duration, respectively, were reported. Patient 1 (a 50-year-old male) had also slight muscular weakness of the proximal limb and neck flexor muscles. Diagnosis of myasthenia gravis had been made on the clinical findings including ptosis and external ophthalmoplegia, diurnal fluctuation of symptoms, and equivocal positive Tensilon test. However, waning phenomenon on repetitive nerve stimulation or elevation of titer of the anti-acetylcholine receptor antibody was not detected on both patients. Needle EMG showed mild myopathic changes. Finally, pathological and biochemical analyses of the biopsied muscles confirmed the diagnosis of mitochondrial myopathy (focal cytochrome c oxidase deficiency).

Neurotoxicity of human eosinophils towards peripheral nerves.

The toxicity of eosinophils towards peripheral nerves was examined using cultures of posterior ganglion cells from chick embryos. Eosinophils were also derived from a patient with significant "hyper-eosinophilia", peripheral neuropathy, bronchial asthma, myocardial damage and skin involvement. A sural nerve biopsy showed a severe to almost complete loss of myelinated fibers without pathological changes suggesting necrotizing vasculitis. Surviving neurons in a culture containing the patient's eosinophils or serum were markedly decreased in number as compared with those in normal subjects. These results support the possibility that the peripheral neuropathy in the patient caused by toxic agents derived from eosinophils.

[A case of symptomatic adrenoleukodystrophy heterozygote manifested by spastic paraparesis of late onset].

A case of symptomatic adrenoleukodystrophy (ALD) heterozygote, manifested by spastic paraparesis, was reported. The patient's 9 year-old grandson had ALD, and her 34 year-old daughter, who was the mother of the case of ALD, was asymptomatic but accompanied by elevation of serum very long chain fatty acid (VLCFA). The patient's gait disturbance appeared at age 62 and that gradually worsened. On admission, she showed spasticity on the lower limbs with bilateral Babinski's reflexes, muscle weakness of the lower limbs and interossei muscles of the hand, and mild sensory disturbance on the distal part of all limbs. Serum VLCFA was markedly elevated. There was no abnormal adrenal function. Sensory and motor nerve conduction velocities were within normal limits. A needle EMG examination disclosed long-duration and high-amplitude potentials. Auditory brainstem response (ABR) revealed elongation of III-V wave intervals bilaterally, and somatosensory evoked potential (SEP) showed delayed N20. Brain CT scan revealed no abnormality but MRI (T2 weighted image) showed mild high intensity areas in the capsula interna and cerebral peduncles. The abnormality of MRI suspected that spastic paraparesis may result from involvement of the corticospinal tract of the cerebrum or brainstem though the symptom has been considered due to the lesion of the spinal cord. Examinations of ABR, SEP and MRI were useful methods to make a diagnosis of symptomatic ALD heterozygote.

Positron emission tomography using pyruvate-1-11C in two cases of mitochondrial encephalomyopathy.

Positron emission tomography (PET) using pyruvate-1-11C was carried out to investigate the in vivo metabolism of pyruvate in the brains of patients with mitochondrial encephalomyopathy and Leigh's disease. Two epileptic patients were studied as control subjects. Radioactivity was eliminated from the brain tissue of the epileptic patients soon after injection of pyruvate-1-11C. PET images of mitochondrial encephalomyopathy patients showed an increase in radioactivity in the cerebral cortex, basal ganglia and thalamus, with elimination of radioactivity being slower than that of epileptic patients. One patient with Leigh's disease showed similar PET images. PET using pyruvate-1-11C is useful for the evaluation of mitochondrial energy metabolism in the brain.

Supranuclear paralysis preventing lid closure in amyotrophic lateral sclerosis.

We report a case of amyotrophic lateral sclerosis (ALS) in which the ability to close the eyes on command or voluntarily, was lost in spite of retention of reflex activity. A electrophysiological study of the blink reflex revealed a prominent R1 component with normal latency, which confirmed that the blink reflex was exactly preserved and also suggested a hemispherical lesion. Postmortem examination disclosed prominent cortical and subcortical lesions of the precentral areas on both sides. These lesions seem to be very closely related to the inability to initiate lid closing.

[Positron emission tomography in two cases of transient global amnesia].

We encountered two cases of typical transient global amnesia (a 53-year-old woman and a 50-year-old man). Both cases showed no evidence of abnormal findings which caused the attack on examinations of CSF, EEG, brain CT, brain MRI and cerebral angiography. Examinations of positron emission tomography, using 15O labeled CO2 and O2, were performed on 14 and 8 days after the attack in the female and male cases, respectively, and those disclosed decreased regional blood flow (CBF), increased oxygen extraction ratio (OER), and decreased oxygen metabolic ratio (CMRO2) in the bilateral medial temporal and occipital lobes, which were supplied by the bilateral posterior cerebral arteries. PET, performed on about one month after the attack, revealed normalized values of CBF, OER, CMRO2 in both cases. These findings strongly suggested that transient global amnesia in our cases may be related to ischemia of the bilateral posterior cerebral arteries.

Catecholamines increase nerve growth factor mRNA content in both mouse astroglial cells and fibroblast cells.

Previous studies have shown that catecholamines increase the nerve growth factor (NGF) content in medium conditioned by mouse L-M fibroblast cells and mouse astroglial cells. In this study, the NGF mRNA levels in these cells were measured by Northern blot analysis. In astroglial cells treated with epinephrine (EN), the cellular NGF mRNA level increased prior to accumulation of NGF in the culture medium. 3-Hydroxytyramine (DA) and norepinephrine (NE) also increased the cellular NGF mRNA content. An increased level of NGF mRNA elicited by EN was also observed in mouse L-M cells. These results indicate that catecholamines enhance NGF synthesis of L-M fibroblast cells and astroglial cells by increasing the cellular content of NGF mRNA. The present results also indicate that the effects of catecholamines are not mediated by adrenergic receptors.

Distal myopathy with rimmed vacuole formation. A follow-up study.

A long-term follow-up study of patients with familial distal myopathy with rimmed vacuole formation and a review of the literature indicates that the prognosis of the disorder was extremely poor as to daily life. Although the initial symptom appearing in early adulthood was muscular wasting and weakness in the legs, especially the distal muscles, severe generalized skeletal muscle involvement with sparing of the facial, extraocular, bulbar, intercostal and diaphragm muscles was recognized in the advanced stage. The disease is probably inherited as an autosomal recessive trait, while there is a considerable female preponderance, the female-to-male ratio being 2:1. The disorder is distinguishable from various types of distal myopathy on the basis of clinical and pathological findings, and other myopathies with rimmed vacuole formation, including inclusion body myositis, from a prognostic viewpoint.