Biomedical subjects
Publications and source records attributed to N Sunohara.
The cytogenetic analysis of 23 Japanese patients with amyotrophic lateral sclerosis is reported. G-banded chromosomes of cultured peripheral blood lymphocytes of one subject had a constitutional chromosomal translocation, t(7;13)(p22;q21). No constitutional chromosome abnormality was found in any of the other 22 Japanese patients with amyotrophic lateral sclerosis tested.
We describe two brothers with early onset cerebellar ataxia associated with hypoalbuminemia (EOCAH). Choreo-athetoid movements preceded the cerebellar ataxia, and serum pseudocholinesterase elevation preceded the hypoalbuminemia. The parents are first cousins. Patient 1, the 22-year-old elder brother, developed choreoathetoid movements of the neck and extremities at the age of eighteen months. He later developed slowly progressive cerebellar ataxia with decreased tendon reflexes. The choreoathetoid movements ceased at about 16 years of age. A recent examination revealed cerebellar ataxia, action myoclonus of the neck and upper limbs, diminished tendon reflexes, mild sensory disturbance in the lower extremities, and very slight amyotrophy of the feet. Patient 2, the 18-year-old younger brother, developed choreo-athetoid movements at the age of 6 years, followed by slowly progressive cerebellar ataxia with disminished tendon reflexes. No scoliosis, ECG abnormalities, or edema was detected. Serum biochemistry studies revealed elevated pseudocholinesterase (6,226 to 2,390 IU) in the patient's early teens. Serum albumin levels tended to be low (3.7 to 4.1 g/dl). Serum triglyceride and beta-lipoprotein levels were elevated in the patients' late teens. Genetic studies showed slight linkage of D9S15. The maximum lod score was 0.289 (recombination fraction rate was 0.14).
Diffusion MRI studies were performed on 14 patients with diffuse high-signal lesions of the cerebral white matter on T2-weighted MR images. There were two patients with adrenoleukodystrophy, four with dentato-rubro-pallido-luysian atrophy, three with familial spastic paraplegia, two with myotonic dystrophy and three with dementia of unknown origin. In addition, a patient with of Sanfilippo disease and one of the three patients who exhibited dementia of unknown origin were also found to be low-signal in the cerebral cortex T2-weighted MR images. In every case except the last two, diffusion-weighted MR images yielded significantly higher apparent diffusion coefficients perpendicular to nerve fibers in the frontal white matter and the corpus callosum than in the normal controls. The lesions displayed increased diffusion anisotropy, calculated as the ratio of the diffusion coefficient perpendicular to the nerve fibers to the diffusion coefficient parallel to the nerve fibers, i.e., diffusion anisotropy was lost in the white matter, suggesting a demyelinating process in the lesion. In the last two cases, on the other hand, the diffusion coefficient and diffusion anisotropy were within normal range. The white matter lesions in these cases were thought to represent degeneration secondary to the cortical involvement. Thus, it was confirmed that diffusion-weighted MR images, unlike T2-weighted MR images, were confirmed to allow differentiation between at least two types of white matter lesions.
Magnetic resonance images in some cases of amyotrophic lateral sclerosis (ALS) revealed abnormal signals in both the paraventricular white matter and in the posterior limbs of the internal capsule. We examined T2- and diffusion-weighted MR images of these lesions in 18 cases of ALS. There were symmetrical high-signal areas in the posterior limbs of the internal capsule in all of the cases. The high-signal areas in the internal capsule corresponded to the pyramidal tracts in the anatomical atlas by Talairach. In 5 of the cases of ALS, T2- weighted MR images showed discrete paraventricular white matter lesions as well. The mean age of the ALS patients with paraventricular white matter lesions was higher than that of the ALS patients without such lesions. Proton densities calculated from the conventional MR images were higher in both the capsular and paraventricular lesions. The diffusion coefficients perpendicular to the pyramidal tract in the internal capsula lesions were within the normal range, where as the diffusion coefficients in the paraventricular lesions were increased in all directions. Thus, diffusion anisotropy was lost in the paraventricular lesions. These findings are similar to those observed in the white matter lesions of cerebro-vascular origin. As a result, the pathology of the paraventricular lesions in ALS was confirmed to be different from that of the internal capsular lesions.
FLAIR (fluid-attenuated inversion recovery) images are MR images obtained with an inversion recovery sequence having a long inversion time (TI) and a long echo time (TE). Twenty healthy adults and twenty patients with multiple cerebral infarction, multiple sclerosis, temporal epilepsy, or brain trauma were examined with FLAIR sequences of several types having repetitive times (TR) of 4000-8000 msec, inversion times of 1200-2400 msec and echo times (TE) of 140-200 msec, and the results were compared with spin-echo sequences (TE = 20 msec and TE = 90 msec). With a long repetitive time of 6000 msec and a long inversion time of 1400-1600 msec, the cerebrospinal fluid signals in the lateral ventricles and the cerebral sulci were low-intensity with brain tissue appearing as high signal intensity areas with good T2 contrast. The FLAIR image signal intensities correlated well with T2 relaxation times under 100 msec. Cystic lesions with long T2 relaxation times over 100 msec in multiple sclerosis and cerebral infarction appeared as low-signal areas, and the lesions surrounding the cystic lesions as high-signal areas. In patients with temporal lobe epilepsy, the hippocampus was visualized as a high-signal area. Hippocampal lesions were demonstrated better with FLAIR images than with conventional T2-weighted images or proton-density images. In a cerebral contusion patient, the FLAIR images revealed a lobulated structure with the residual cortex appearing as high-signal areas. The lesions surrounding the cystic change were imaged as high-signal areas. These structural changes were demonstrated better with FLAIR images than with conventional T2-weighted sequences.(ABSTRACT TRUNCATED AT 250 WORDS)
Clinical, radiological, and histological examinations were performed on eight patients with autosomal-dominant dentato-rubro-pallido-luysian atrophy (DRPLA) including an autopsy case, to investigate the abnormal findings of the cerebral white matter in DRPLA. Three of the eight patients were found to have diffuse low density on CT or diffuse high-signal areas on T2-MRI in the white matter of the brain. There were no correlations between abnormal findings in the white matter and the following factors; age of onset, duration of the disease, clinical manifestations, disease severity, Hachinski score, or EEG abnormality. Single-photon emission tomography failed to reveal any relative decrease in cerebral blood flow in the white matter, even in the three patients with abnormal findings in the white matter. MRI perfusion studies did not suggest any decrease in cerebral blood volume in any of the patients examined, but in the DRPLA patients the latency, i.e., the interval from the time of injection to the time of the minimum signal intensity, was significantly prolonged in comparison with the results in normal controls. On histopathological investigation, there was diffuse decreased staining in the centrum semiovale and deep white matter of the temporal lobes bilaterally, but no gliosis, or arteriolar thickening or hyalinization were detected. These findings confirmed that the lesions in the white matter in DRPLA are not attributable to cerebral ischemia. The abnormal findings are presumably the result of the degeneration which occurs in DRPLA itself.(ABSTRACT TRUNCATED AT 250 WORDS)
Clinical, neurophysiological and neuropathological investigations were performed on five patients from two families with autosomal dominant distal amyotrophy followed by spastic paraplegia and with a positive history in two generations of these two families. All cases in the two families had a benign clinical course, although two mothers could not walk without support at around 60 years old. Neurophysiological studies revealed normal maximum conduction velocities of peripheral sensory and motor nerves, and the central spinal sensory pathway. Distribution of motor nerve conduction velocities in the ulnar nerve had a normal pattern except for one patient who had severe deformities of the cervical vertebrae. The biopsied sural nerve disclosed no distinct abnormalities in any cases. From these results, we confirmed preservation of the myelinated nerve fibers of motor and sensory peripheral nerves.
We analyzed diffusion weighted magnetic resonance images (diffusion MRI) of the basal ganglia, which were obtained from four patients with Wilson's disease, and compared them with the images from ten age-matched normal individuals. In all patients, T2-MRI of the basal ganglia disclosed low or iso-signals, but diffusion MRI revealed abnormal high signals in some areas of the basal ganglia in each case. Pathological changes except for copper and/or iron deposits are difficult to estimate by T2-MRI because the low signal on T2-MRI emphatically reflects the deposits, while the abnormal high signal on diffusion MRI is thought to reflect parenchymal lesions such as cell loss, demyelination and/or increase of the extracellular fluid. From our results, we confirmed that diffusion MRI was very useful for estimating parenchymal lesions with metal deposits.
We reported a 55-year-old man, whose T2-weighted MR images disclosed abnormal high signal band along the left pyramidal tract 6 months after cerebral infarction of the left centrum semiovale. Brain CT revealed low intensity areas in the centrum semiovale, the posterior limb of the internal capsule on left side. On T2-weighted MR images, there were an irregular high signal area on the left centrum semiovale, a high signal band from the left centrum semiovale to the medullary pyramid, and a high signal band from the left centrum semiovale to the cerebral cortex. These lesions were observed as high signal areas on proton weighted images and low signal areas on T1-weighted MR images. Diffusion coefficient perpendicular to the pyramidal tract in the patient, which was calculated from diffusion weighted images at the posterior limb of the internal capsule, was higher than that in normal individuals. Diffusion anisotropy at the lesion, which is the rate between the diffusion coefficient parallel and perpendicular to nerve fiber, was higher than that of normal individuals. These data suggested that the lesion had demyelinating process, which was consistent with the pathology at stage 2 of the Wallerian degeneration.
We report a case of 33-year-old man with multiple sclerosis, showing piano playing movement in both hands. His course of multiple sclerosis was remittent/progressive during 2 years and the clinical manifestation suggested the spinal cord involvement. On July 15, 1991, he was admitted with numbness of the right limbs, and then developed piano playing movement in both hands, more marked in the right side. Neurological examination revealed mild weakness in the right upper extremity, and rough touch, pain, and temperature sensation were slightly decreased. However, there was no deep sensory abnormalities, such as vibration, fine touch, and position senses. Vibration sense was lost below ilium. CSF examination showed elevation of IgG index (1.6), three oligoclonal bands and myelin basic protein content of 2.4 ng/ml. There was no HTLV-I antibody in CSF. SSEP, elicited by median nerve stimulation at the right wrist, showed no N13 and low amplitude of N20. T2-weighted images of cervical MRI revealed area of high signal intensity at the C3-C4 level. The piano playing movement gradually improved and disappeared by the initiation of steroid hormone therapy. It was considered that involuntary movement in this patient was due to the spinal cord lesion caused by multiple sclerosis. These findings suggested that the involuntary movement like pseudoathetosis could present without deep sensory abnormalities.
Serial examination of magnetic resonance images (MRI) for two months were carried out on two cases of multiple cerebral infarction during the acute stage. The T2-weighted MR images at the onset of the infarction showed both acute (new) and chronic (old) lesions appearing as high signal area. While on the diffusion weighted images only an acute lesion was detected as a high signal area with good contrast. The diffusion coefficient of the acute lesion was lower than that of normal white matter. Diffusion coefficient of the chronic lesions were higher than that of normal white matter. Therefore, on the apparent diffusion coefficient mapping images (ADC images) only an acute lesion appeared as a low signal area. The examination of diffusion images was very useful for distinguishing an acute lesion from a chronic lesion during the acute stage of multiple infarction. The diffusion weighted images after 4 weeks from the onset showed the diffusion coefficient of the "acute" lesion to be the same level of normal white matter. And after 8 weeks from the onset, increased to a level higher than that of normal white matter to the same level of the "chronic" lesion.
Site-specific mutants of human myoglobin (Mb) have been prepared, in which Leu29 (B10) is replaced by Ala(L29A) or Ile(L29I), in order to examine the influence of this highly conserved residue in the hydrophobic clusters of the heme distal site on the heme environmental structure and ligand binding properties of Mb. Structural characterizations of these recombinant Mbs are studied by electronic absorption, infrared (IR), one- and two-dimensional proton nuclear magnetic resonance spectroscopies, and ligand-binding kinetics by laser photolysis measurements under ambient and high pressures (up to 2000 bar). Multiple split carbon monoxide (CO) stretch bands in the IR spectra of mutant Mbs exhibit a relative decrease of the 1945 cm-1 band (approximately 50%) which is associated with an upright binding geometry of CO, accompanied by an increase of the tilted CO conformer at 1932 cm-1. On the basis of these results, replacement of Leu29(B10) by Ala or Ile appears to allow bound CO to rotate from a conformation pointing toward the beta meso carbon of the heme group to the one pointing toward the alpha meso carbon atom, presumably filling the space left by removal of the delta 2 carbon atom of Leu29(B10). These substitutions cause the rate constants for CO and O2 association to decrease almost 3-5-fold. Present results show that CO and O2 bindings to the heme iron of Mb are controlled by Leu29(B10) by influencing the structure of close vicinity of the heme and the geometry of iron-bound ligand. Further, mutant Mbs (Leu72(E15)----Ala and Leu104 (G5)----Ala) which have altered residues in another hydrophobic clusters around proximal and distal site are also examined.
We reported a 29-year-old woman with autoimmune polyglandular deficiency (APGD) type 1 accompanied by progressive myopathy. She had chronic mucocutaneous candidiasis at the age of 3, primary hypothyroidism at 12, insulin dependent diabetes mellitus at 27, and adrenal insufficiency at 29 years. Laboratory findings indicated an underlying defect in cell mediated immunity. Meanwhile, she had progressive muscular weakness and wasting at the age of 22 years which brought her to our hospital at 29 years. On admission, she could not walk without support and raise her arms up to the level of shoulders. Moderate to severe muscle wasting as well as weakness was observed in the limb girdle muscles. Serum CK levels were mildly elevated. A needle EMG examination disclosed short-duration and low-amplitude polyphasic motor units at voluntary contraction with few fibrillations and positive sharp waves at rest. On muscle CT examination, decreased density was detected in the neck extensor, paravertebral, rectus femoris, vastus intermedius, biceps femoris and soleus muscles. Muscle biopsy was performed on the biceps brachii and rectus femoris muscles. The former showed chronic dystrophic changes including marked variation in fiber size with necrotic and degenerating process, interstitial fibrosis, and lobulated and right fibers. In the latter, in addition to variation in fiber size with some necrotic fibers and occasional multi-core structures, nemaline bodies were seen in approximately 30% of muscle fibers. The progressive muscle involvement in our patient might be induced from 1) endocrine abnormality, 2) autoimmune disorder, and/or 3) coincidental complication of nemaline myopathy or limb girdle muscular dystrophy. The clinical and laboratory examinations, however, failed to support any of them.(ABSTRACT TRUNCATED AT 250 WORDS)
Follow-up magnetic resonance imaging (MRI) and computed tomography (CT) examinations were performed on five patients with Wilson's disease at intervals from 6 to 29 months. We studied the clinical correlation with MRI and CT, and whether the examination of MRI and CT could be useful for evaluation of the therapeutic effect. Positron emission tomography (PET) was also carried out on 4 cases except for an asymptomatic case (patient 2, sister of patient 1). Close relationship has been observed by MRI between dystonia and the lesion of the lenticular nuclei, abnormality of smooth pursuit eye movements and the brain stem lesion, and severe dysarthria/dysphagia and the lesion of the caudate and lenticular nuclei, respectively. In patient 4, repeated MRI of an interval of 18 months demonstrated decrease of the abnormal high signal in the lateral part of the putamen on T2-weighted image in accordance with marked improvement of clinical manifestations. In patient 3, who had severe dystonia of the extremities and trunk, T2-weighted image showed high signals in the lenticular nuclei. Marked decrease of the high signal in the lenticular nuclei was observed by MRI in this patient after 29 months, when her neurological manifestations were markedly improved. Patient 5 with severe cerebellar signs disclosed abnormal signals in the middle cerebellar peduncles, brain stem and dentate nuclei in addition to low signals in the caudate and lenticular nuclei, and high signals in the lateral part of the putamen on T2-sequence.(ABSTRACT TRUNCATED AT 250 WORDS)
We examined dystrophin, the protein product of the Duchenne muscular dystrophy gene, in muscle biopsy specimens from 4 male patients with quadriceps myopathy, all of whom showed a mild and slowly progressive myopathy confined to the quadriceps muscles. All 4 patients had clear abnormalities of dystrophin, and were diagnosed as having Becker muscular dystrophy by both immunofluorescence and immunoblot examinations; that is, dystrophin of an abnormal molecular mass was visualized in muscle cryosections as "patchy" or discontinuous immunostaining at the surface membrane of the muscle fibers. One patient had a brother who showed widespread myopathic changes consistent with typical Becker muscular dystrophy. We conclude that the syndrome called quadriceps myopathy includes a group of forme fruste Becker muscular dystrophy.
In wobbler mice, histometric features and the response to injury in the less affected hindlimb nerves were compared with the severely affected forelimb nerves which were studied previously. The frequency of vacuolated anterior horn cells was not different at the individual ages studied (3 and 6 weeks, 3 months), but with the three ages combined, the frequency in the two systems differed significantly, being 1.7 +/- 0.9% in the cervical and 0.6 +/- 0.7% in the lumbar anterior horns (P = 0.005). The number of large myelinated nerve fibres (greater than or equal to 6 microns in diameter) became progressively reduced in ventral roots as the disease advanced, particularly for the forelimb. The total number of myelinated axons was well preserved in the hindlimb ventral roots because of an increase in the number of small myelinated nerve fibres. The regenerative capacity of motor neurons after axotomy (tested by radiolabelling growth cones) was well preserved. In the hindlimb, the increased numbers of small myelinated fibres in ventral roots and the normal regenerative capacity in the sciatic nerve and its branches contrast with the severely affected forelimb system. Our studies suggest that cervical and lumbar anterior horn cells have different susceptibilities to the wobbler gene, producing vulnerability in one system and disease resistance in the other.
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Was reported a 23-year-old man with Becker muscular dystrophy (BMD), manifesting heart failure as an initial symptom. He had admitted to a hospital because of his sudden exertional dyspnea due to dilated cardiomyopathy. Because of elevated serum CK level, he had admitted to our hospital for further clinical evaluation. His uncle and male cousin were affected by a mild progressive muscle weakness since second decades. Physically, his intelligence was slightly below the average (WAIS total IQ 71). There was a slight weakness in his pelvic and shoulder girdle muscles. Pseudohypertrophy was observed in calves and tongue. Serum CK level was markedly elevated to ten times of the upper normal limits. Both EMG and muscle biopsy examinations revealed mild myopathic changes. Electrocardiogram showed tall R waves in leads V1 and V2, abnormal Q waves in I, aVL, V5 and V6 and flattened T waves in V5 and V6. On immunostaining of the biopsied skeletal muscle, patchy appearance of dystrophin on the surface membrane of the fiber was detected, which is consistent with BMD. Myocardiac damages in BMD are not always related either to the duration or the severity of the skeletal muscle weakness, as shown in our present case. The possibility that subclinical BMD is one of causes for dilated cardiomyopathy always must be considered.