Marked asymmetry of putaminal pathology in an MSA-P patient with Pisa syndrome.

We report on an autopsy case of a 62-year-old Japanese woman with a 2.5-year history of axial dystonia. She presented with a form of axial dystonia reminiscent of Pisa syndrome. The pathophysiological mechanism underlying forms of axial dystonia remains to be elucidated. We report here the histopathological findings of a multiple system atrophy of parkinsonian predominance (MSA-P) patient with Pisa syndrome.

Reduced voltage sensitivity of activation of P/Q-type Ca2+ channels is associated with the ataxic mouse mutation rolling Nagoya (tg(rol)).

Recent genetic analyses have revealed an important association of the gene encoding the P/Q-type voltage-dependent Ca(2+) channel alpha(1A) subunit with hereditary neurological disorders. We have identified the ataxic mouse mutation, rolling Nagoya (tg(rol)), in the alpha(1A) gene that leads to a charge-neutralizing arginine-to-glycine substitution at position 1262 in the voltage sensor-forming segment S4 in repeat III. Ca(2+) channel currents in acutely dissociated Purkinje cells, where P-type is the dominant type, showed a marked decrease in slope and a depolarizing shift by 8 mV of the conductance-voltage curve and reduction in current density in tg(rol) mouse cerebella, compared with those in wild-type. Compatible functional change was induced by the tg(rol) mutation in the recombinant alpha(1A) channel, indicating that a defect in voltage sensor of P/Q-type Ca(2+) channels is the direct consequence of the tg(rol) mutation. Furthermore, somatic whole-cell recording of mutant Purkinje cells displayed only abortive Na(+) burst activity and hardly exhibited Ca(2+) spike activity in cerebellar slices. Thus, in tg(rol) mice, reduced voltage sensitivity, which may derive from a gating charge defect, and diminished activity of the P-type alpha(1A) Ca(2+) channel significantly impair integrative properties of Purkinje neurons, presumably resulting in locomotor deficits.

Variation in the number of CAG repeats in the Machado-Joseph disease gene (MJD1) in the Japanese population.

Variation in the number of CAG repeats in the Machado-Joseph disease gene (MJD1) was examined by polymerase chain reaction and denaturing polyacrylamide gel electrophoresis analysis of 2134 normal and 135 affected chromosomes of Japanese individuals. The number of repeats ranged from 14 to 47 in normal alleles and from 61 to 84 in disease-associated alleles. The most frequent and lowest number of repeats was 14. The size distribution of normal MJD1 alleles did not fit a normal distribution curve, but was tetramodal. Repeats from 14 to 17, 18 to 23, 24 to 25, and 26 to 47 units were designated groups A through D, respectively. When examined Hardy-Weinberg equilibrium by chi-square analysis of goodness of fit: no evidence of significant deviation from the Hardy-Weinberg equilibrium was observed [x2=4.248<16.919 (P=0.05), df=9]. The observed distribution peak of normal MJD1 alleles corresponding to peptides containing 10, 15, 20, and 24 glutamine suggests that stretches of 5 and 10 glutamine might constitute a functional domain of human MJD1.

The effect of CAT trinucleotide interruptions on the age at onset of spinocerebellar ataxia type 1 (SCA1).

The effect of CAT trinucleotide interruptions in the CAG trinucleotide repeats of the SCA1 gene on the age at onset of spinocerebellar ataxia type 1 (SCA1) was investigated. The number of CAG repeats in SCA1 was determined by polymerase chain reaction (PCR) analysis, and the presence of CAT interruptions was assessed on the basis of the sensitivity of the PCR products to the restriction endonuclease SfaNI, which recognises CAT trinucleotides. Only one in 17 expanded SCA1 alleles from 17 SCA1 patients was interrupted by CAT. The SfaNI sensitive SCA1 allele from this single patient contained 58 CAG repeats, which would predict an age at onset of SCA1 of 22.0 years, in contrast to the actual 50 years. In addition, the brain stem atrophy of this patient was mild compared with that of a patient with 52 uninterrupted CAG repeats. A sequence analysis showed that the repeat portion of the patient contained (CAG)45CATCAG CAT(CAG)10. From these results, we suggest that the age at onset of SCA1 is not determined by the total number of CAG repeats (58) but by the number of uninterrupted CAG repeats.

Direct alteration of the P/Q-type Ca2+ channel property by polyglutamine expansion in spinocerebellar ataxia 6.

Spinocerebellar ataxia 6 (SCA6) is caused by expansion of a polyglutamine stretch, encoded by a CAG trinucleotide repeat, in the human P/Q-type Ca(2+) channel alpha(1A) subunit. Although SCA6 shares common features with other neurodegenerative glutamine repeat disorders, the polyglutamine repeats in SCA6 are exceptionally small, ranging from 21 to 33. Because this size is too small to form insoluble aggregates that have been blamed for the cause of neurodegeneration, SCA6 is the disorder suitable for exploring the pathogenic mechanisms other than aggregate formation, whose universal role has been questioned. To characterize the pathogenic process of SCA6, we studied the effects of polyglutamine expansion on channel properties by analyzing currents flowing through the P/Q-type Ca(2+) channels with an expanded stretch of 24, 30, or 40 polyglutamines, recombinantly expressed in baby hamster kidney cells. Whereas the Ca(2+) channels with

Spinocerebellar ataxia type 6 in relation to CAG repeat length.

UNLABELLED: The purpose of the present study was to assess the relationship between clinical characteristics of spinocerebellar ataxia type 6 (SCA6) and CAG repeat length. MATERIALS AND METHODS: We examined clinical symptoms of 54 patients with SCA6. CAG repeat length was compared among subgroups divided by clinical manifestations. RESULTS: The major symptom was progressive cerebellar ataxia. Truncal or limb ataxia, dysarthria, and nystagmus were observed in more than 80% of the patients. In analysis of CAG repeat length in patients with different types of nystagmus, CAG repeat length was the longest when both upbeat and downbeat nystagmus existed (P < 0.01). In addition, CAG repeat length was longer when the initial symptom was ataxic gait and was shorter when the initial symptom was dysarthria or ocular symptom (P < 0.05). CONCLUSION: Clinical features of SCA6 might be influenced by the length of abnormal CAG repeat.

[A sporadic case of spinocerebellar ataxia 6 (SCA 6) with large CAG expansion of the CACNL1A4 gene].

We reported a 73-year-old woman of spinocerebellar ataxia 6 (SCA 6). There was no family history of neurological diseases. She demonstrated cerebellar ataxia and scanning speech at the age of 48. These symptoms gradually developed. Brain MRI showed severe cerebellar atrophy and no abnormality in the brain stem. Her neurological symptoms and MRI findings were compatible with cerebellocortical atrophy (CCA). Analysis of the CACNL1A4 gene on chromosome 19p 13 demonstrated she had an expanded allele with 27 CAG repeats. Therefore, she was diagnosed with SCA 6. In spite of her large CAG expansion, there was no family history of SCA 6 in this case. SCA 6 needs to be ruled out in cases of clinical CCA.

Characteristic magnetic resonance imaging findings in spinocerebellar ataxia 6.

OBJECTIVE: To clarify the characteristic magnetic resonance imaging (MRI) findings in patients with spinocerebellar ataxia 6 (SCA6) diagnosed by genetic analysis. PATIENTS AND METHODS: Using MRI, we examined 10 patients genetically diagnosed as having SCA6 and 40 control subjects. RESULTS: The mean (+/-SD) CAG repeat length in 10 patients with SCA6 was 22.9 +/- 1.3. There was a significant inverse correlation between the CAG repeat size and age at onset in the SCA6 group (r = -0.86, P = .003). In patients with SCA6, the areas of the cerebellar vermis and hemispheres in sagittal MRI were significantly smaller than those in the control subjects. In transaxial MRI, the anteroposterior diameter of the pons and the diameter of the middle cerebellar peduncle were mildly decreased and the red nucleus was slightly atrophied in patients with SCA6. There was no significant difference in the diameter of the midbrain, medulla oblongata, fourth ventricle, superior cerebellar peduncles, dentate nucleus, or globus pallidus between the SCA6 and control groups. A high-signal intensity in the transverse pontine fibers was not observed in any of the patients with SCA6 on T2-weighted and/or proton-weighted axial MRI. CONCLUSIONS: The cerebellum and its afferent and efferent systems were affected in patients with SCA6. These results seem to distinguish the MRI findings of SCA6 from those of other forms of spinocerebellar ataxia.

Spinocerebellar ataxia type 6: MRI of three Japanese patients.

We describe the MRI findings in three Japanese patients with spinocerebellar ataxia type 6 (SCA6) in which a polymorphic CAG repeat was identified in the gene encoding the alpha 1A voltage-dependent P/Q-type Ca2+ channel subunit (CACNL1A4). All showed slowly progressive cerebellar ataxia and mild pyramidal signs. Neuroradiologically, they had moderate cerebellar atrophy, most prominently in the superior vermis, whereas the brain stem appeared to be spared. No abnormal signal intensity was identified.

A new mitochondrial DNA mutation associated with mitochondrial myopathy: tRNA(Leu)(UUR) 3254C-to-G.

We investigated a patient with mitochondrial myopathy accompanied by cardiomyopathy. Molecular analysis disclosed a C-to-G substitution at nucleotide position 3254 of the mitochondrial tRNA(Leu)(UUR). Pedigree analysis revealed that this mutation was inherited maternally. Mutation C3254G may also be a candidate for genetic defects in mitochondrial myopathy.

Molecular features of the CAG repeats of spinocerebellar ataxia 6 (SCA6).

Spinocerebellar ataxia 6 (SCA6) is an autosomal dominant spinocerebellar degeneration caused by the expansion of the polymorphic CAG repeat in the human alpha1A voltage-dependent calcium channel subunit gene (CACNL1A4 gene). We have analyzed 60 SCA6 individuals from 39 independent SCA6 Japanese families and found that the CAG repeat length is inversely correlated with the age of onset (n = 58, r = -0.51, P < 0.0001). SCA6 chromosomes contained 21-30 repeat units, whereas normal chromosomes displayed 6-17 repeats. There was no overlap between the normal and affected CAG repeat number. The anticipation of the disease was observed clinically in all eight parent-child pairs that we examined; the mean age of onset was significantly lower (P = 0.0042) in children than in parents. However, a parent-child analysis showed the increase in the expansion of CAG repeats only in one pair and no diminution in any affected cases. This result suggests that factors other than CAG repeats may produce the clinical anticipation. A homozygotic case could not demonstrate an unequivocal gene dosage effect on the age of onset.

Molecular features of the CAG repeats and clinical manifestation of Machado-Joseph disease.

Machado--Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration mapped to chromosome 14q32.1. The CAG expansions of the MJD1 gene was identified as the cause of the disease. We have analyzed 90 MJD individuals from 62 independent MJD families and found that the MJD1 repeat length is inversely correlated with the age of onset (r = -0.87). The MJD chromosomes contained 61-84 repeat units, whereas normal chromosomes displayed 14-34 repeats. In the normal chromosomes, 14 repeat units were the most common and the shortest. In association with the clinical anticipation of the disease, a parent--child analysis showed the unidirectional expansion of CAG repeats and no case of diminution in the affected family. The differences in CAG repeat length between parent and child and between siblings are greater in paternal transmission than in maternal transmission. Detailed analysis revealed that a large degree of expansion was associated with a shorter length of MJD1 gene in paternal transmission. On the other hand, the increments of increase were similar for shorter and longer expansion in maternal transmission. Among the three clinical subtypes, type I of MJD, with dystonia, showed a larger degree of expansion in CAG repeats of the gene and younger ages of onset than the other types.

[A case of idiopathic superficial siderosis of the central nervous system].

A 59-year-old man developed a staggering and wide based-gait in July 1990. Dysarthria, hearing loss, vexation and disturbance of memory appeared in January 1991. He consulted our clinic in May 1991, and cerebellar ataxia, neurogenic bladder, and cerebellar atrophy on brain CT were noted. Subsequently, he was followed as OPCA. Brain and spinal cord MRI (T2 and proton weighted images) revealed hypointensity on the surface of the Sylvian fissure, cerebellum, brainstem and spinal cord. We diagnosed this case as superficial siderosis because of the clinical course, i.e. cerebellar ataxia, dementia and sensorineural hearing impairment, and specific findings on MRI. We consider this case idiopathic superficial siderosis because the origin of the bleeding source was unknown. IMP-SPECT showed low perfusion in the cerebellum and frontal lobe where hemosiderin was heavily deposited. RI cisternography revealed a disturbance of CSF absorption even after 48 hours. The basic rhythm on EEG was slow alpha band with sporadic theta waves dominantly in the frontal lobe. His central conduction time on ABR and SEP was delayed, OKN was poorly elicited and ETT exhibited a staircase pattern. The physiological results as well as the clinical manifestations of the present case suggest that hemosiderin deposit on the surface of brain and spinal cord caused serious damage to the underlying structures.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of sodium bromate intoxication with cerebral lesion].

We confirmed a cerebral lesion due to sodium bromate intoxication on MRI, SPECT, auditory brainstem response (ABR) and sensory evoked potential (SEP). The patient was 34 years old, and ingested sodium bromate (14 g) to commit suicide. Vomiting, epigastralgia, watery diarrhea and anuria appeared after 30 minutes and he became deaf within 12 hours. Renal function recovered after hemodialysis. Renal biopsy revealed acute renal tubular necrosis. After one month, burning pain appeared in bilateral lower extremities. Sporadic, clear and small high intensity spots were observed in the deep white matter of the right occipitotemporal border zone and bilateral centrum semiovale on T2 and proton weighted images of brain MRI. IMP-SPECT disclosed partial low perfusion in the left parietal gray matter. Central conduction time was delayed on ABR and SEP. The clinical symptoms and course together with laboratory studies suggest that the cerebral lesion was due to direct sodium bromate intoxication.