Abstract: The authors describe an unusual case of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) without leg spasticity, which is a core clinical feature of ARSACS. This is the second family with a spasticity-lacking phenotype in ARSACS. A peripheral nerve conduction study disclosed decreases in motor and sensory nerve conduction velocities with the disease progression. Although the leg spasticity is reported to become progressively worse during the disease and is prevalent in older patients, we first observed that the symptom had disappeared, probably due to the progressive peripheral nerve degeneration in the disease course. Thus, we should analyze the SACS gene even in cases of early-onset cerebellar ataxia without spasticity. The patient had a novel homozygous 2-base pair deletion mutation (c.5988-9 del CT) of the SACS gene, but the genotype was different from that in our first family of this phenotype. A further genotype-phenotype correlation study is required to clarify the molecular mechanism underlying 'sacsinopathies'.
Abstract: OBJECTIVE: To report the autoantigens of a new category of treatment-responsive paraneoplastic encephalitis. METHODS: Analysis of clinical features, neuropathological findings, tumors, and serum/cerebrospinal fluid antibodies using rat tissue, neuronal cultures, and HEK293 cells expressing subunits of the N-methyl-D-aspartate receptor (NMDAR). RESULTS: Twelve women (14-44 years) developed prominent psychiatric symptoms, amnesia, seizures, frequent dyskinesias, autonomic dysfunction, and decreased level of consciousness often requiring ventilatory support. All had serum/cerebrospinal fluid antibodies that predominantly immunolabeled the neuropil of hippocampus/forebrain, in particular the cell surface of hippocampal neurons, and reacted with NR2B (and to a lesser extent NR2A) subunits of the NMDAR. NR2B binds glutamate and forms heteromers (NR1/NR2B or NR1/NR2A/NR2B) that are preferentially expressed in the adult hippocampus/forebrain. Expression of functional heteromers (not single subunits) was required for antibody binding. Eleven patients had teratoma of the ovary (six mature) and one a mature teratoma in the mediastinum; five of five tumors examined contained nervous tissue that strongly expressed NR2 subunits and reacted with patients' antibodies. Tumor resection and immunotherapy resulted in improvement or full recovery of eight of nine patients (paralleled by decreased antibody titers); two of three patients without tumor resection died of neurological deterioration. Autopsies showed extensive microgliosis, rare T-cell infiltrates, and neuronal degeneration predominantly involving, but not restricted to, the hippocampus. INTERPRETATION: Antibodies to NR2B- and NR2A-containing heteromers of the NMDAR associate with a severe but treatment-responsive encephalitis. Our findings provide a diagnostic test and suggest a model of autoimmune NMDAR-related encephalitis with broad implications for other immune-mediated disorders of memory, behavior, and cognition.
Abstract: We reported a Japanese case of spinocerebellar ataxia type 6 (SCA6) with episodic ataxia type 2 (EA2) phenotype. A 28-year-old woman was admitted to our hospital because of episodic unsteadiness of gait and dysarthria for 4 years. Neurological examination revealed truncal ataxia and dysarthria during attacks, but no abnormal findings in interictal phases. A brain MRI showed no obvious cerebellar atrophy, whereas proton MR spectroscopy (1H-MRS) disclosed decrease of the N-acetylaspartate/ceatine (NAA/Cr) ratio in the cerebellar hemisphere. We identified the expanded 22 CAG repeats without a missense mutation in the CACNA1A gene. After one year from the discharge, her gait ataxia became gradually obvious even in the interictal phase. To our knowledge, although a few foreign papers had reported the SCA6 cases with EA2 phenotype, there is no particular report on such cases in Japan. 1H-MRS, in addition to CAG repeats analysis, might enable us to differentiate SCA6 from EA2, because the latter showed no decrease of NAA/Cr ratio in cerebellar hemisphere according to the previous reports.
Abstract: The autosomal dominant cerebellar ataxias (ADCAs) comprise a genetically and clinically heterogenous group of neurodegenerative disorders. Very recently, a C-to-T single nucleotide substitution in the puratrophin-1 gene was found to be strongly associated with a form of ADCA linked to chromosome 16q22.1 (16q-linked ADCA; OMIM 600223). We found the C-to-T substitution in the puratrophin-1 gene in 20 patients with ataxia (16 heterozygotes and four homozygotes) and four asymptomatic carriers in 9 of 24 families with an unknown type of ADCA. We also found two cases with 16q-linked ADCA among 43 sporadic patients with late-onset cortical cerebellar atrophy (LCCA). The mean age at onset in the 22 patients was 61.8 years, and that of homozygous patients was lower than that of heterozygous ones in one family. Neurological examination revealed that the majority of our patients showed exaggerated deep tendon reflexes in addition to the cardinal symptom of cerebellar ataxia (100%), and 37.5% of them had sensorineural hearing impairment, whereas sensory axonal neuropathy was absent. The frequency of 16q-linked ADCA was about 1/10 of our series of 110 ADCA families, making it the third most frequent ADCA in Japan.
Abstract: The authors describe a Japanese autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) patient with a compound heterozygous mutation (32627-32636delACACTGTTAC and 31760delT) in a new exon of the SACS gene. The new exons upstream of the gigantic one should be analyzed when a case is clinically compatible with ARSACS, even without any mutation in the gigantic exon.
Abstract: A 54-year-old man with a history of partially dissected epidermoid cyst in the left cerebellopontine angle suffered from a slowly progressive dysesthesia and weakness in the lower extremities and trunk. Neurological examination revealed segmental muscular weakness and sensory disturbance in those regions, giving rise to the possibility of monoradiculopathy multiplex, as well as loss of tendon reflexes, dysuria and right facial nerve palsy. Electrophysiological studies indicated irregular motor axonopathy or neuronopathy and interruption of more central sensory pathways than the lumbosacral spinal nerve roots with spared peripheral sensory nerves. Although MRI demonstrated enhanced lesions in the cauda equina and lumbosacral leptomeninges, CSF cytology or a cauda equina biopsy showed no malignancy. His symptoms gradually progressed and he died 15 months after the onset. The autopsy failed to reveal any tumors in the general systemic internal organs. Histopathology demonstrated meningeal carcinomatosis with squamous-type carcinoma cells scattered in the cerebrospinal leptomeninges, and perineurium in almost all the spinal and cranial nerve roots, causing severe axonal degeneration. The dorsal root ganglions escaped tumor cell invasion. Absence of the malignant tumors in the systemic organs and the history of the operated epidermoid cyst indicate that the tumor may be the cause of the meningeal carcinomatosis in this case. Meningeal carcinomatosis almost always shows rapid progression and extremely poor prognosis with several month survival in general, and little attention has been paid that it can exhibit symptoms and signs of segmental involvement in the lumbosacral regions. Our present case prompts us to bear in mind that patients with this condition can survive fairly long, and raises the possibility that a careful neurological examination with segmental involvement will reveal such a feature more frequently than considered so far in this condition.
Abstract: The authors describe two Japanese siblings with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) without spasticity, usually a core feature of this disorder. They had a novel homozygous missense mutation (T987C) of the SACS gene, which resulted in a phenylalanine-to-serine substitution at amino acid residue 304.
Abstract: High prevalence of a form of autosomal recessive spastic ataxia with early onset was originally described among French Canadians in the Charlevoix-Saguenay region, in northeastern Quebec. Since the responsible gene (SACS) was identified, mutations in the SACS gene have been described in Tunisia, Italy, Turkey, and Japan. The mutation sites found outside Quebec are different from the ones in Quebec. All patients outside Quebec, except one Italian patient, have been reported to have homozygous mutations. The authors report here identical twin sisters with novel compound heterozygous mutations (c.[2951_2952delAG]+[3922delT]) in the SACS gene.
Abstract: Progressive myoclonus epilepsy of the Unverricht-Lundborg type is an autosomal recessive disorder that is characterized clinically by myoclonic seizures and ataxia. The majority of affected individuals carry repeat expansions of a dodecamer in the promoter region of the cystatin B gene. The unusually high GC content of this tract is refractory to conventional polymerase chain reaction (PCR), and, as a result, a circumventive procedure involving the deamination of DNA with sodium bisulfite has been proposed. This study evaluates the effectiveness of this deamination modification for the detection of dodecamer repeat variants. An analysis of 258 healthy Japanese individuals revealed an allele with four copies of the dodecamer repeat with a frequency of 0.01, in addition to the more commonly observed two and three copy repeat alleles. Homozygous repeat expansions 600 and 680 base pairs in length were detected in the analyses of two affected individuals. For these cases, sequencing, along with an alternative PCR-stutter formation, revealed 41 and 48 copies, respectively, of the dodecamer repeat. The complete conversion of C to T was observed in the expanded tracts, indicating that no methylation occurred at the CpG sites. Based on these results, it was concluded that the use of deaminated DNA allows for a precise analysis of consecutive GC tracts.
Abstract: The authors describe two patients in a Japanese family with autosomal recessive spastic ataxia of Charlevoix-Saguenay. They presented early onset spastic ataxia, sensorimotor neuropathy, nystagmus, slurred speech, and hypermyelinated retinal nerve fibers. The authors identified a homozygous missense mutation (T7492C) in the SACS gene, which resulted in the substitution of arginine for tryptophan at amino acid residue 2498 (W2498R).
Abstract: Aceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by mutations in the ceruloplasmin (Cp) gene. We reported the results of clinical and molecular studies on a Japanese family with aceruloplasminemia. A 58-year-old man who had had diabetes mellitus for more than 30 years developed cerebellar ataxia several years before. He was found to have mild retinal degeneration too. Laboratory findings revealed a complete deficiency of serum ferroxidase activity and undetectable serum Cp. Magnetic resonance imaging showed a pronounced hypointensity in the bilateral putamina, caudate, thalamus and dentate nuclei on both T1- and T2-weighted images suggesting the presence of iron overload. We identified a homozygous deletion mutation (nt2602 delG) of the Cp gene in the patient, and the same heterozygous mutation in his unaffected father. To date, at least 29 mutations in the Cp gene have been identified. Although an individual with a heterozygous mutation has been believed to be an asymptomatic carrier like his father, some patients with such a condition were recently described to show neurological deficits. The variation in clinical findings may be explained partly by the difference in the severity of generation of free radicals caused by iron deposition or the environmental factors such as aging. Further investigations would be required to elucidate the molecular mechanisms of this late onset neurodegeneraion.
Abstract: BACKGROUND: Early-onset ataxia with hypoalbuminemia is regarded as a variant form of Friedreich ataxia in Japan. Early-onset ataxia with hypoalbuminemia and ataxia with ocular motor apraxia have been considered as the same clinical entity because of the recent identification of a common mutation in the aprataxin gene. A new clinical entity named early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) has been proposed to explain these two diseases. OBJECTIVE: To disclose the clinical features of EAOH and to identify the mutations in the aprataxin gene in six patients in four Japanese families with EAOH. METHODS: The clinical features, laboratory findings, sural nerve biopsy results, and brain MRI or CT findings for these patients were evaluated, and molecular analysis was performed, which involved sequencing of the aprataxin gene directly or use of the subcloning method. RESULTS: Cerebellar ataxia and peripheral neuropathy were noted in all six patients. Ocular motor apraxia was observed in five patients; two of these patients had obvious head thrust. Choreiform movements of the limbs and mental deterioration were observed in five patients. Although foot deformity was noted in five patients, kyphoscoliosis was noted only in one patient. In all patients, hypoalbuminemia and hypercholesterolemia were evident, and brain MRI or CT showed marked cerebellar atrophy. Nerve biopsy revealed depletion of large myelinated fibers in three of the five patients examined. Molecular analysis of the aprataxin gene revealed an insertion mutation (insT at nt167) and two missense mutations (A-to-G transition at nt80 and C-to-T transition at nt95, the former being novel). CONCLUSION: We found clinical heterogeneity in the patients with EAOH in this study. With the disease course, the choreiform movements tended to reduce in degree, and hypoalbuminemia became evident. Molecular analysis identified one insertion and two missense mutations including a novel missense one, which was located at a highly conserved amino acid residue in the aprataxin gene product.
Abstract: Alexander's disease, a leukodystrophy characterized by Rosenthal fibers (RFs) in the brain, is categorized into three subtypes: infantile, juvenile, and adult. Although most are sporadic, occasional familial Alexander's disease cases have been reported for each subtype. Hereditary adult-onset Alexander's disease shows progressive spastic paresis, bulbar or pseudobulbar palsy, palatal myoclonus symptomatologically, and prominent atrophy of the medulla oblongata and upper spinal cord on magnetic resonance imaging. Recent identification of GFAP gene mutations in the sporadic infantile- and juvenile-onset Alexander's disease prompted us to examine the GFAP gene in two Japanese hereditary adult-onset Alexander's disease brothers with autopsy in one case. Both had spastic paresis without palatal myoclonus, and magnetic resonance imaging showed marked atrophy of the medulla oblongata and cervicothoracic cord. The autopsy showed severely involved shrunken pyramids, but scarce Rosenthal fibers (RFs). Moderate numbers of Rosenthal fibers (RFs) were observed in the stratum subcallosum and hippocampal fimbria. In both cases, we found a novel missense mutation of a G-to-T transition at nucleotide 841 in the GFAP gene that results in the substitution of arginine for leucine at amino acid residue 276 (R276L). This is the first report of identification of the causative mutation of the GFAP gene for neuropathologically proven hereditary adult-onset Alexander's disease, suggesting a common molecular mechanism underlies the three Alexander's disease subtypes.
Abstract: OBJECTIVES: We report the results of clinical and genetic studies on a Japanese SPG4 family. MATERIAL AND METHODS: Family N included eight patients in four generations with autosomal dominant transmission. We performed neurological and molecular analyses on the SPG4 gene in the family members comprising three patients, 12 at-risk individuals, and three normal spouses. RESULTS: The three patients showed pure spastic paraplegia, two of them exhibiting a decrease in vibration sense. There was marked intrafamilial variability in age at onset and clinical severity in the present family. On molecular analysis, a novel missense mutation (nt1579 C-->T) in exon 12 of the SPG4 gene was found in the three patients, three probably affected, and an asymptomatic carrier. CONCLUSION: The present SPG4 family, which was shown to have a novel SPG4 mutation, exhibited marked variability in the clinical features, indicating the participation of additional factors in the phenotypic appearance of this family.
Abstract: We studied a large Japanese family with autosomal dominant pure hereditary spastic paraplegia (ADPHSP) clinically and genetically. To date, seven loci causing ADPHSP have been mapped to chromosomes 14q, 2p, 15q, 8q, 12q, 2q, and 19q. Among these loci, the SPG4 locus on chromosome 2p21--p22 has been shown to account for approximately 40% of all autosomal dominant hereditary spastic paraplegia (ADHSP) families. Very recently, Hazan et al. identified the SPG4 gene encoding a new member of the AAA (ATPases associated with diverse cellular activities) protein family, named spastin. We found a novel insertion mutation (nt1272--1273insA) in exon 8 of the SPG4 gene in the present family. Our study is the first to confirm the causative mutation of the SPG4 gene in Japanese. Clinically, it is noteworthy that the disease progression in the patients of this family was slow in spite of the late onset, and more than half of the patients showed severe constipation in addition to pure spastic paraplegia.
Abstract: Intergenerational stability of the CAG repeat number has been considered to be a specific molecular feature of SCA6 compared with other CAG repeat diseases. Nevertheless, we showed meiotic instability of the CAG repeats in the SCA6/CACNL1A gene in two Japanese SCA6 families, including de novo expansion. In one family, the CAG20 allele expanded to the CAG26 one during paternal transmission, and in the other family, the CAG19 allele expanded to the CAG20 one during maternal transmission. Although it is controversial as to whether the CAG20 allele is pathological or not, this is the first case of haplotype analysis-proven de novo expansion in SCA6, confirming the derivation of an expanded allele from one normal allele. We should carefully follow up the individuals carrying the CAG20 allele in our family who show normal neurological and radiological findings at present.
Abstract: We studied the relationship between the number of CAG repeat units in the MJD1 gene and clinical features of Machado-Joseph disease (MJD) in eight patients from two generations of a Japanese MJD family. Because of lack of characteristic clinical signs of MJD such as dystonia, bulging eyes or facial myokymia, clinical diagnosis of MJD in this family was difficult to make prior to molecular testing for the CAG repeat expansion in the MJD1 gene. All the patients exhibited maternal transmission of MJD, and the intergenerational change in the number of CAG repeat units in the MJD1 gene was very small (+0.5+/-0.3, mean+/-S.E.M., n=4) in spite of marked genetic anticipation (-17.0 years/generation). In the present family, the degree of anticipation per repeat unit in maternal transmissions was much larger than that in maternal transmissions in the other six MJD families. This indicates that some maternal factors other than the increase of the number of CAG repeat units, which is known to be the basis of anticipation, may play a role in genetic anticipation in this MJD family.
Abstract: 1. We studied the physiology of the neuronal projection from the striatum to the external and internal segments of the globus pallidus (GPe and GPi, respectively) in macaque monkeys. The objective of the study was to answer the following specific questions. 1) Which classes of the electrophysiologically identified striate neurons project to GPe and GPi? 2) What kind of information is transferred from the striatum to GPe and GPi during learned movement? 3) What are the physiological actions of striate projection neurons on target neurons in GPe and GPi? 4) What is the spatial pattern of the striatopallidal projections? 2. Sequential arm and orofacial movements were used as behavioral tasks. Visual stimuli triggered a sequence of three flexions-extensions of the elbow joint across the target, and the click of a solenoid valve triggered repetitive licking movements. 3. Striatopallidal projection neurons were electrophysiologically identified by antidromic activation after focal stimulation of either GPe or GPi. Of two classes of striate neurons, tonically active neurons (TANs) with tonic spontaneous discharges (2-8 imp/s) and broad action potentials, and phasically active neurons (PANs) with a very low spontaneous discharge rate (< 0.5 imp/ s) and high-frequency discharges in relation to behavioral tasks, PANs were identified as the projection neurons to either GPe or GPi. In 325 TANs examined by stimulation of GPe or GPi, no neuron was activated antidromically, even in the case of TANs located in the close vicinity of PANs that were identified as striatopallidal projection neurons. 4. The physiologically identified projection neurons (52 cells) in the striatum exhibited either discharges related to movement (30 cells) or discharges related to preparation for movement (4 cells) during performance of learned motor tasks. The activities of the remaining 17 striatopallidal neurons either were not related to the behavioral tasks used or could not be characterized sufficiently in the tasks. However, all of the unidentified striatopallidal neurons were PANs, on the basis of the spontaneous discharge rate and the shape of the action potential. 5. PANs with movement-related activity and those with preparation for movement-related activity were antidromically activated from the globus pallidus (GP). Not only the PANs that show burst discharges specifically at the beginning of a sequence of movement but also PANs that show phasic discharges time-locked to each movement of a sequence were identified as putaminopallidal projection neurons. On the other hand, no neurons that showed responses to sensory stimulus were identified as putaminopallidal neurons. 6. The conduction velocities of the putaminopallidal axons were estimated at approximately 1 m/s on the basis of the latency of antidromic activation and conduction distance. The PANs with activity only at the beginning of a sequential movement were more frequently found to project to GPi than to GPe, whereas the PANs with burst activity at each movement were more frequently found to project to GPe than to GPi. Among the GPi-projecting PANs, neurons with initial activity only showed a tendency to have longer latencies of activation from GPi than neurons with activity time-locked to each movement. 7. The physiological action of the striatopallidal projection was examined by switching from recording to microstimulation after identification of striatopallidal projection neurons in the putamen while recording evoked field potentials or spike discharges of single GP neurons located where the electrical stimulation evoked antidromic activation of the striate neurons with the lowest threshold. A small majority of GP neurons that exhibited increase of discharges during motor tasks received facilitatory putaminopallidal influences, whereas the vast majority of GP neurons that exhibited decrease of discharges during motor tasks received suppressive putaminopallidal influences.
Abstract: A 23-year-old man was admitted because of vomiting and severe, progressive headache. After admission, he suffered from a generalized clonic seizure, and developed right hemiparesis. Contrast-enhanced CT of the brain showed empty delta sign in the posterior part of the superior sagittal sinus and filling defect in the straight sinus. T2-weighted MRI demonstrated high intensity area in the left parieto-occipital subcortical region. Delayed venous phase of the right carotid angiography confirmed the diagnosis of thrombosis of the superior sagittal sinus. Coagulation studies gave a protein C activity of 35.3% (normal range 55-140%), protein C antigen of 45% (normal range 70-150%). Same results were obtained from the studies of his father and one of his sisters, indicating hereditary protein C deficiency. We started warfarin therapy under the administration of heparin for a week, then he has been followed up with no subsequent problems.
Abstract: Machado-Joseph disease (MJD) is an autosomal dominant, multisystem neurodegenerative disorder involving predominantly cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. Although it was first reported in families of Portuguese-Azorean descent, MJD has also been described in non-Azorean families from various countries, being one of the most common hereditary spinocerebellar degenerations. With the use of highly polymorphic microsatellite DNA polymorphisms, we have assigned the gene for MJD to the long arm of chromosome 14 (14q24.3-q32) by genetic linkage to microsatellite loci D14S55 and D14S48 (multipoint lod score Zmax = 9.719).
Abstract: In order to study neuronal information transfer from the striatum to the globus pallidus (GP) during voluntary movement, we recorded activity of electrophysiologically identified projection neurons in the putamen to the GP while the monkey was performing learned movement tasks. Two categories of putamen neurons were recorded: one with tonic spontaneous discharges at about 2-7 impulses/s responded to external sensory stimuli (type I); the other with very low spontaneous discharge rates less than 0.5 impulses/s showed phasic burst discharges which were time-locked to limb or orofacial movements (type II). All of the putamen neurons identified as projecting to the GP (external and/or internal segment) by an antidromic activation from electrical stimulation of the GP were type II cells. It was concluded that the movement-related activity of type II putamen neurons is transferred to GP and/or SN during voluntary movement but tonically active type I cells do not project to the GP.
