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We report a 57-year-old woman with familial amyotrophic lateral sclerosis (ALS) with posterior column involvement of 11 years duration. The patient had been on a respirator for more than 5 years before death. In addition to the well established pathology of this form of familial ALS, there were obvious degenerative changes in the brainstem tegmentum, including the reticular formation, cerebellar cortex, dentate and red nuclei, thalamus and mammillary body. Of great interest in this case was intracytoplasmic accumulation of neurofilaments in the remaining neurons in these areas, some of which, for instance, those in the oculomotor and abducens nuclei, still showed only minimal loss. This patient had survived considerably beyond the point of respiratory failure, which is the final stage in the natural history of the disease. We considered that in this patient the underlying degenerative process of the disease had become manifested in wider areas than recognized previously during the prolonged clinical course due to respiratory support. However, whether or not such widespread degeneration would occur in all patients with this disease who survive longer with the help of respiratory support awaits further studies.

To date, eleven independent FAD pedigrees with the 717 Val→Ile mutation have been identified. Interestingly, five pedigrees were of Japanese origin and four were of British origin. The apparent ethnic prediction of this mutation raises the possibility that there is a founder effect in these two island nations. We did not observe any significant linkage disequilibrium in any locus of APP and GT12 loci in the five Japanese FAD pedigrees with the 717 Val→Ile mutation. A founder effect would probably not be present in Japanese FAD pedgrees with the 717 Val→Ile mutation.

Several gangliosides of human nervous tissues have been reported to be potential target antigens in autoimmune neuropathies. To explain the diversity of clinical symptoms in patients with antiganglioside antibodies, we have searched for ganglioside antigens that are specific to individual nervous tissues such as motoneurons, peripheral motor nerves, and sensory nerves. Although the major ganglioside compositions were not different among human peripheral motor and sensory nerves, fucosyl-GM1 was found to be expressed in sensory nervous tissue but not in spinal cord, motor nerve, and sympathetic ganglia. Sera from several patients with sensory nerve involvement also reacted with fucosyl-GM1 as well as GM1. Thus, fucosyl-GM1 may be a responsible target antigen for developing sensory symptoms in some patients with autoimmune neuropathies.

To examine the cytotoxicity of a patient's serum with an acute relapsing sensory neuropathy syndrome, dorsal root ganglion neurons from young adult rats were cultured in the presence of the patient's serum which had an extremely higher-titer monoclonal IgM antibody recognizing B-series gangliosides, GD2, GD1b, GT1b and GQ1b. By the addition of the inactivated patient's serum, the relatively larger cells died after undergoing of metamorphosis during several hours of culture, whilst the smaller cells survived. The IgM fraction isolated from the patient's serum showed similar cytotoxicity towards the neurons as the inactivated whole serum. No cytotoxicity was observed with the IgM fraction-containing medium after it had been absorbed with ganglioside GD1b. The results suggested that the anti-B-series ganglioside-directed antibody is the causal agent for the human neurologic disease.

The linkage of the glycan chain to the beta/A4 amyloid protein precursor (APP) in cerebrospinal fluid (CSF) was studied by Western blot analysis. The apparent molecular weight of APP in CSF was reduced from 103 to 100 kDa by N-glycanase, and to 96 kDa by O-glycanase treatment, respectively. These data indicate that APP is both N- and O-glycosylated in one molecule. The extent of glycosylation of APP was not altered in the CSF from patients with Alzheimer's disease.

We measured nitric oxide synthase activity in nervous, Purkinje cell degeneration mutant mice and 3-acetylpyridine-treated mice to determine the cellular localization of nitric oxide synthase in the cerebellum. Nitric oxide synthase activity per cerebellum was reduced to less than 50% of that of controls in nervous and Purkinje cell degeneration mutants, while in 3-acetylpyridine-treated mice there was no reduction.

We investigated consecutive 1000 autopsied cases (average age 82.9 years) clinicopathologically in order to reveal the significance of cerebral amyloid angiopathy (CAA) as a cause of senile intracranial hemorrhages. We found 101 cases with intracerebral hemorrhages, and CAA accounted for 10.9% of them (31.0% of lobar cerebral hemorrhages, and 14.3% of cerebellar ones). In contrast to hypertensive hemorrhages, CAA-related ones (1) ruptured into the subarachnoid space without exception, (2) often coexisted with dementia of Alzheimer's type, and (3) frequently occurred in the night without elevated blood pressure at onset. The cerebrovascular amyloid was strongly immunoreactive with antibody to beta-protein in all of the cases with CAA-related hemorrhages, and less intensively with antibody to cystatin C in 91% of them. Our data indicate that CAA is an important etiological factor of cerebellar hemorrhages, as well as lobar cerebral hemorrhages, in normotensive, aged patients.

To clarify the contribution of cerebral amyloid angiopathy (CAA) to subarachnoid haemorrhage (SAH) in the elderly, relationships between SAH and CAA were investigated in 997 necropsy cases aged 60 years or older. Primary SAH (bleeding from subarachnoid vessels) was found in 15 cases (1.5%). There was no case in which primary SAH was clearly attributed to CAA. Secondary SAH [secondary rupture of intracerebral haemorrhage (ICH) through the cortex to the subarachnoid space] was found in 23 patients (2.3%). In 11 (48%) of them, ICH with secondary SAH was associated with CAA. The results indicated that primary SAH is rarely related to CAA, however, CAA is the most frequent cause of ICH accompanying secondary SAH in the elderly.

A 67-year-old patient with Shy-Drager syndrome (SDS), exhibited nocturnal polyuria associated with abnormal circadian rhythm of antidiuretic hormone (ADH) secretion and nocturnal polyuria. The patient excreted a larger volume of urine during the nighttime compared to that in the daytime. The specific gravity of urine at night was lower than that during the day. In contrast to normal circadian rhythm of ADH, the patient's plasma concentration of ADH was increased in the daytime. The present study raised the possibility that an altered circadian rhythm of plasma ADH secretion might be considered a result of the neurodegenerative changes involving the hypothalamus.

We used the enzyme-linked immunosorbent assay to investigate autoantibodies against the gangliosides G M1 , G D1a , G D1b , G T1b , G D2 , and G Q1b , in sera from 16 patients with Fisher9s syndrome. We found high anti-G Qlb antibody titers, mainly those of the IgG class, in the sera of 13 of these patients. The titers decreased with the clinical course of the illness. Moreover, anti-G Qlb antibody-positive patients had more severe ataxia of cerebellar type than the antibody-negative patients.

We previously reported two siblings with decreased subcutaneous adipose tissue, muscular atrophy, joint contractures, recurrent skin eruptions, hyper-γ-globulinemia, and reduced natural killer cell activity. Some of their clinical features are similar to those of partial lipodystrophy, but they are distinct in that muscular atrophy, joint contractures and recurrent skin eruptions are not found in patients with partial lipodystrophy. Thirteen other Japanese patients with similar clinical manifestations have been reported. We propose that such cases should be considered a distinct clinical entity.(Internal Medicine 32: 42-45, 1993)

X-linked spinal and bulbar muscular atrophy (SBMA), a motor neuron disease associated with androgen insensitivity, is caused by androgen receptor gene mutations with an increased number of tandem CAG repeats in exon 1. We investigated the increased number of CAG repeats in androgen receptor genes of 19 SBMA patients and found that this correlated strongly with the age at onset of muscle weakness. Thus, SBMA is the first genetic disease in which a strong correlation between the degree of genetic abnormality (number of CAG tandem repeats) and clinical phenotypic expression is demonstrable. The results further indicate that androgen gene mutation is directly involved in the degeneration of motor neurons.

A 56-year-old woman presented with severe iron-deficiency anemia and memory disturbance. She had been in a state of severe iron deficiency for many years due to an unbalanced diet. Aerobic exercise test revealed an abnormal elevation of lactate and pyruvate reflecting mitochondrial dysfunction. After iron replacement therapy, WAIS verbal IQ score improved from 63 to 83, and levels of lactate and pyruvate on aerobic exercise test were normalized. We raise the possibility that severe and long-term iron deficiency anemia may cause memory disturbance due to mitochondrial dysfunction.

Using a cosmid clone derived from human Xq28 as a probe which shows cross-species homology, we isolated cDNA clones and the nucleotide sequence analysis of the cDNA revealed that the cDNA is identical to QM cDNA. The QM cDNA has recently been reported as a cDNA with down-regulation in tumorigenic Wilms' tumor microcell hybrid. Comparison of the nucleotide sequences of the cDNA with those of the genomic DNA allowed us to determine the genomic organization of the QM gene. The QM gene consists of at least 7 exons and is located at Xq28. Southern blot analysis of a somatic cell hybrid panel indicates that the QM genes are scattered at least to chromosome 2, 3, 6, 14, 16, and possibly to other chromosomes. Northern blot analysis demonstrated the QM gene is expressed in all the examined adult human tissues as well as cell lines including HeLa cells, fibroblasts, and somatic cell hybrids with increased expression in liver, spleen, testis, and adrenal gland. The results suggest that the QM gene belongs to a new multi-gene family with yet undetermined function.

The molecular basis of a dramatically decreased steady state level of beta-hexosaminidase beta subunit mRNA in a patient with juvenile Sandhoff disease was investigated. Nucleotide sequence analysis of the HEXB gene coding for the beta subunit revealed two single base substitutions, one in exon 2 (A to G, a known polymorphism) and the other in exon 11 (C to T). Analysis of the beta subunit mRNA species demonstrated activation of a cryptic splice site in exon 11 as well as skipping of the exon. A transfection assay using a chimeric gene containing intron 10 flanked by cDNA sequences carrying the mutation confirmed that the single base substitution located at position 8 of exon 11 inhibits the selection of the normal 3' splice site. The results demonstrate a new type of exon mutation affecting 3' splice site selection.

In the present study, the effect of the adenosine uptake blocker, propentofylline (HWA 285) on the extracellular concentration of several amino acids including glutamate, glycine and taurine following 10 min of forebrain ischemia in gerbil hippocampus was investigated using in vivo microdialysis. Pretreatment with HWA 285 (20 mg/kg i.p.) significantly reduced the extracellular concentration of glutamate following ischemia but did not significantly alter levels of other amino acids such as glycine and taurine. These findings suggest that the neuroprotective effect of HWA 285 may be associated with inhibition of glutamate release in the gerbil hippocampus.

We developed a simple method for the detection of a tRNA Lys mutation in myoclonus epilepsy associated with ragged-red fibers (MERRF) by polymerase chain reaction with use of a mismatched primer. Although the tRNA Lys mutation does not alter recognition sequences for commercially available restriction enzymes, we have successfully changed two nucleotides flanking the A to G mutation at nucleotide position 8344 in a tRNA Lys gene of a mitochondrial genome. As a result, the mutation can be detected as a Nae I restriction fragment length polymorphism. With this method, all eight MERRF patients and an asymptomatic mother of a MERRF patient, from six independent families, had the same tRNA Lys mutation. Our method is simple and should also be useful for the quantitation of heteroplasmies.

An A to G transition at nucleotide position 8,344 in tRNALys of mitochondrial DNA has been recently identified as a causative mutation of myoclonus epilepsy associated with ragged-red fibers (MERRF). To investigate if the degree of heteroplasmy of mitochondrial DNA is correlated with the severity of MERRF, we have developed a novel method for quantitation of the mutant mitochondrial DNA by polymerase chain reaction using a mismatched primer. With the method, populations of mutant mtDNAs from 5 cases of MERRF carrying the tRNALys mutation were analyzed. The tight linkage of the severity of symptoms and the degree of heteroplasmies is not necessarily observed for all cases, though there is a tendency that patients with less wild type mtDNAs show severer clinical symptoms and earlier onset.

The mouse myelin-associated glycoprotein gene was isolated from a mouse gene library. This gene was split into 13 exons distributed about 15 kb in length. Each extracellular immunoglobulin-related domain was encoded by a single exon, and RNA splicing between those exons occurred between the first and second nucleotides of the junctional codon, the features of which are conserved in most of the genes of the immunoglobulin superfamily. The sequence of the 5'-flanking region appeared to have some regions homologous to other myelin proteins, which suggested that they were possible cis-elements for specific expression of oligodendrocytes.

Sialidase isolated from human placenta is associated with several proteins including acid beta-galactosidase, carboxypeptidase, N-acetyl-alpha-galactosaminidase, and others. These proteins are thought to form an aggregated complex during isolation of sialidase. One of the proteins of 60 kDa was recently identified by Potier et al. (Biochem. Biophys. Res. Comm. 173, 449-456, 1990) as a sialidase protein: this protein also cross-reacted with anti-prosaposin antibodies. We have isolated this protein and from the following evidence identified it as a heavy chain component of immunoglobulin G and not sialidase or a derivative of prosaposin. On gel filtration HPLC, sialidase activity and the 60 kDa protein were clearly separated from one another. The 60 kDa protein cross-reacted not only with antibodies raised against human saposins A, C, and D, but also with second antibody (goat anti-rabbit immunoglobulin G antibody) alone. This 60 kDa protein strongly cross-reacted with anti-human immunoglobulin G antibodies. The sequence of the initial 15 amino acids from the N-terminus of the 60 kDa protein was identical to the sequence of an immunoglobulin G heavy chain protein Tie (gamma 1).

We studied the metabolism of radioactive fatty acids in cultured skin fibroblasts from patients with adrenoleukodystrophy (ALD) and Zellweger syndrome (ZS) to clarify the physiological significance of the fatty acid elongation system in the accumulation of very long chain fatty acids (VLFA) in ALD. A substantial amount of radioactive C26:0 was synthesized from [18-14C]stearic acid by ALD and ZS fibroblasts, whereas radioactive C26:0 was not detected in control fibroblasts. Kinetic studies demonstrated that the production of radioactive C24:0 and C26:0 in ALD fibroblasts is higher than that of ZS fibroblasts, which suggests that the fatty acid elongation activity plays an important role for the accumulation of VLFA in ALD, in addition to the decreased VLFA oxidation activities. The addition of monounsaturated fatty acids including oleic acid and erucic acid specifically lowered the formation rate of VLFA without any significant effect on degradation activities of VLFA both in ALD and control fibroblasts. The results suggest that the mechanism of decrease of VLFA by administration of monounsaturated fatty acids is based on the inhibition of fatty acid elongation activity.

We performed linkage analyses of juvenile parkinsonism with autosomal recessive inheritance (AR‐JP) to chromosome 11p15.5 locus including tyrosine hydroxylase (TH), Harvey‐ ras ‐1 (HRAS), and insulin (INS) genes by analyzing genomic DNA from 28 members of seven Japanese AR‐JP families containing 10 affected individuals. We used the methods of pairwise linkage analysis (LIPED) and multipoint linkage analysis (LINKAGE) for genetic linkage to the chromosome 11p15.5 markers and detected recombination events between AR‐JP locus and TH gene. Multipoint linkage analysis excluded the linkage in the interval between TH and HRAS, as well as 11 cMo distal to TH and 8.5 cMo distal to HRAS, a total of approximately 23 cMo on chromosome 11p. NEUROLOGY 1991;41:719‐722

Two major oligosaccharides were isolated from the urine of a patient with type 3 GM1 gangliosidosis. From structural studies including compositional sugar analysis, fast-atom bombardment mass spectrometry, direct-inlet chemical ionization mass spectrometry, methylation analysis, chromium trioxide oxidation, and proton magnetic resonance spectroscopy, their structures were deduced to be as follows: [formula: see text] Both oligosaccharides have beta-linked galactose at the non-reducing ends. Oligosaccharide 1 is one of the most common urinary oligosaccharides found in type 1 and type 2 GM1 gangliosidosis. Oligosaccharide 2, lacto-N-difucohexaose II, has not been described in the urine of GM1 gangliosidosis patients. Excretion of oligosaccharide 1 in the type 3 patient was much less than that of a type 2 patient. Thin-layer chromatographic analysis revealed that the excretion of oligosaccharides with higher molecular weight than that of oligosaccharide 1 (octasaccharide) in the type 3 patient was much less than that of a type 2 patient, raising the possibility that the mutant beta-galactosidase of type 3 GM1 gangliosidosis can still act to some extent on higher molecular weight oligosaccharides containing beta-linked galactose at the non-reducing end.

The neurophysiological complications in ACTH deficiency have not been well documented. In this paper, we present a patient with isolated ACTH deficiency who developed various neurological signs. The neurophysiological abnormalities, including slow wave activity on electroencephalogram, delayed conduction velocity of the peripheral nerves and low amplitude of muscle action potentials, were improved by replacement of glucocorticoid. These findings suggested that glucocorticoid is directly involved in the function of the peripheral and central nervous systems.

We have studied the water permeability through membranes, the function of the Na pump, and glucose metabolism of erythrocytes of patients with myotonic muscular dystrophy (MyD) using 1H--, 23Na, and 13C-NMR techniques. A significant decrease in water permeability was recognized in the MyD erythrocyte membrane, and impaired Na pumping was suspected to be correlated with the former biochemical abnormalities in band III protein of MyD erythrocyte membrane. Significant acceleration of glycolysis in the erythrocyte for the first 160 minutes was also recognized in MyD; however, the production of lactate showed no difference between MyD and controls. The increased glucose uptake in MyD may be compensatory to the diminished pumping mechanism, but further information, such as inorganic phosphate permeability and the activity of the rate-limiting enzyme of erythrocyte glycolysis, is needed.

The neuropathological findings in a 13-year-old Japanese male showing decrease of sialidase and beta-galactosidase activities are reported. The patient was the product of normal pregnancy to consanguineous parents. He started to sit at 8 months, stand at 20 months and walk at age of 2; mental retardation, visual disturbance, cerebellar ataxia, myoclonus and epilepsy developed by the age of 10, and he died at 13. Neuropathological investigation revealed neuronal loss and storage. Severe loss of neurons was observed in the thalamus, globus pallidus, lateral geniculate body, gracile nucleus, Purkinje and retinal ganglion cells. Marked ballooning was seen in the Betz cells and neurons in the basal forebrain, the motor neurons in the cranial nerve nuclei and spinal cord, and in the trigeminal and spinal ganglia. The storage material varied in staining from region to region and from neuron to neuron. Electron microscopic investigation revealed a variety of intracytoplasmic and intranuclear inclusions: membranous cytoplasmic bodies, parallel, wavy-lamellar or tortuous tubular structures, lipofuscin-like irregular-shaped pleomorphic bodies, and cytoplasmic vacuoles with fine granules and lamellar materials. The severity of the neuronal loss did not seem to correlate with the amount of the storage materials, but with the presence of tortuous tubular inclusion.

We reported ocular findings of 3 patients with adult-form galactosialidosis. Diffuse fine opacities in the deep layer of the corneal stroma, an obscure cherry-red spot of the macula and optic nerve atrophy were noted in all cases. Punctate lenticular opacities were observed in 2 cases. Slowly progressive visual disturbance was seen in all cases, and it might be due to secondary optic nerve atrophy caused by retinal ganglion cell death.

We report 2 patients with Guillain-Barre syndrome (GBS) following Campylobacter jejuni enteritis. Electrophysiologic studies indicated that the predominant process was axonal degeneration of motor nerves, and clinical recovery was poor. Serum testing by thin-layer chromatography and enzyme-linked immunosorbent assay revealed that the sera from both patients contained high titers of IgG antibody against GM1 ganglioside. These cases may represent a subgroup of GBS as acute axonal polyneuropathy following C jejuni enteritis associated with anti-GM1 antibodies.

Two species of cDNAs for human α-N-acetylgalactosaminidase were isolated from a human fibroblast cDNA library. The two species differ each other by a 70 bp insertion in the coding region. Transient expression study in COS cells demonstrated that only the cDNA without the 70 bp insertion expressed α-N-acetylgalactosaminidase activity. Analysis of mRNA species utilizing polymerase chain reaction revealed that the majority of the mRNA does not contain the 70 bp insertion, and the mRNA containing the 70 bp insertion is present only in a minor amount in human brain.

In an autopsy case of galactosialidosis, G M3 , G M2 , G M1 , and G D1a were accumulated in sympathetic and spinal ganglia and grey matter of the spinal cord. Especially, the accumulations of G M3 and G M2 amounted to 41- and 86-fold increases in sympathetic ganglia, respectively, as compared to normal controls. In addition LacCer, GA 2 and GA 1 were accumulated in sympathetic and spinal ganglia. The accumulations of G M3 and G D1a are considered to be the result of defective lysosomal sialidase activity and the accumulation of G M1 , LacCer and GA 1 is also considered to be due to decreased β-galactosidase activity in this disorder. To better understand the possible mechanism of G M2 accumulation, we determined the activity of G M2 synthesizing enzyme (G M3 : UDP-GalNAc transferase), as well as hexosaminidase activity, in sympathetic ganglia, but they did not change. Abnormal ganglioside and neutral glycosphingolipid metabolism, as well as sialyloligosaccharide and sialylglycoprotein metabolism, may be involved in the pathogenesis of this disorder.

Using an immunoblotting technique, we investigated changes in the concentrations of microtubule-associated protein 2, 200-kDa neurofilament, tubulin, myelin-associated glycoprotein, and 2':3'-cyclic nucleotide 3'-phosphodiesterase in the brains of 40 rats following occlusion of the left middle cerebral artery or sham operation. Compared with those 4 hours after surgery, concentrations of all proteins decreased significantly in the left hemisphere 3 days after surgery (p less than 0.01). Microtubule-associated protein 2 was the most susceptible to ischemia, and its mean +/- SEM concentration decreased to 23 +/- 9.4% of that in concurrent sham-operated controls. Degradation products of microtubule-associated protein 2 and myelin-associated glycoprotein were detected on the blots. Furthermore, in the contralateral hemisphere (where calpain might be activated), concentrations of these two proteins decreased to 57 +/- 12.0% and 83 +/- 4.3% of those in concurrent sham-operated controls, respectively, 3 days after surgery. Changes in the concentrations of cerebral proteins in the contralateral hemisphere are important for understanding clinical symptoms not attributable solely to the ipsilateral lesion following a focal cerebral stroke.

The vacuolar degeneration of central myelin was produced in Sprague-Dawley rats by oral administration of triethyl tin. The wet weight of brain stems which seems to reflect the degree of accumulation of water increased during the administration of the toxin, whereas the activity of 2′, 3′-cyclic nucleotide 3′-phosphodiesterase altered less remarkably. When TET was withdrawn from the drinking water, the rats showed a dramatic clinical improvement along with reduction in wet weight of brain stems. Treatment with acetazolamide following TET inhibited the clinical improvement and reduction in wet weight of brain stems. The present results indicates that central myelin has plasticity in recovering from the vacuolar degeneration by removing the accumulated fluid and carbonic anhydrase is possibly involved in the dehydration, of myelin in such a recovery phase.

Two forms of myelin-associated glycoprotein (MAG) mRNA are produced by alternative splicing of the exon 12 portion. Expression of the two forms of MAG mRNA was studied here in experimentally introduced demyelination and remyelination by Cuprizone intoxication. During the demyelinating stage, both forms of MAG mRNA decreased markedly. When feeding with Cuprizone was stopped, MAG mRNA began to increase. One form of MAG mRNA without the exon 12 portion, which appears in normal development at the period of active myelination, was characteristically induced during the remyelinating stage. The other form containing the exon 12 portion was also induced but recovered only to the level in normal development.