Sasaki H

A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter.

Dominantly inherited, late‐onset pure cerebellar ataxia is a group of genetically heterogeneous neurodegenerative disorders. Approximately half of these disorders in the Japanese population are caused by moderate expansion of a CAG repeat in the coding region of the CACNA1A gene on chromosome 19p13 (SCA6). However, neither the loci nor the specific mutations for the remaining disorders have been determined. We performed systematic linkage analysis in a three‐generation Japanese family with a locus or mutation that differed from those of known spinocerebellar ataxias. The family members with a late onset (≥39 years old) exhibited pure cerebellar ataxia, whereas those with an early onset (≤27 years old) first showed intermittent axial myoclonus followed by ataxia. Other neurological signs were sparse, and neuroimaging studies revealed that atrophy was confined to the cerebellum. Multipoint analysis and haplotype reconstruction ultimately traced this novel spinocerebellar ataxia locus (SCA14) to a 10.2‐cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4‐qter (Zmax = 4.08, corrected for age‐dependent penetrance). Ann Neurol 2000;48:156–163

Neuropathological and molecular studies of spinocerebellar ataxia type 6 (SCA6)

Abstract SCA6 is an autosomal dominant spinocerebellar ataxia (SCA) caused by a small CAG repeat expansion of the gene encoding an α-1a-voltage-dependent Ca channel gene subunit on chromosome 19p13. A Japanese woman with SCA6, with a 7-year history of progressive pure cerebellar ataxia, died of malignant lymphoma. Systematic neuropathological examination showed that neuronal degeneration was confined to the cerebellar Purkinje cells and, to a lesser degree, the granular cells, without any involvement of other central nervous system structures. Such pathological selectivity correlates with the localized expression of the responsible gene, and coincides with the neurological manifestation. These findings might contribute to establishing the phenotype of the SCA6 via comparison with other dominant ataxias.

SCA6 mutation analysis in a large cohort of the Japanese patients with late-onset pure cerebellar ataxia

Spinocerebellar ataxia type 6 (SCA6) is caused by small CAG repeat expansion in the gene encoding the alpha1A-voltage-dependent-calcium channel subunit (CACNLIA4) on chromosome 19p13, and is a subgroup of the late-onset pure cerebellar ataxia (ADCA III). To investigate the prevalence of SCA6 in the Japanese, we analyzed this mutation in 23 families and 12 probands with ADCA III. The specificity and stability of the CAG repeat were examined in additional individuals and families with other miscellaneous dominant SCAs. The CAG expansion of SCA6 gene was exclusively observed in 12 of 23 families (52%) and 12 proband cases with ADCA III, but not in others. The CAG repeat was 21-33 in the disease-associated alleles (n=56), and 4-18 in normal alleles (n=1148). Expanded alleles were stable during transmission, and a significant inverse correlation for CAG repeat number with age at onset was noted. Our results indicate that SCA6 shares approximately half of the ADCA III in the Japanese, and that gene mutations causing the remaining, have yet to be identified.

Clinical trial of acetazolamide in SCA6, with assessment using the Ataxia Rating Scale and body stabilometry

Objective– To investigate the effect of acetazolamide on spinocerebellar ataxia type 6 (SCA6). Methods– Acetazolamide (250–500 mg/day) was administered orally for 88 weeks to 6 patients with SCA6, and its effect was quantitatively monitored using the Ataxia Rating Scale (ARS) and body sway analysis by stabilometry. Results– During administration of acetazolamide, the ARS score and the amplitude of body sway were significantly reduced compared with before administration. However, the response became weaker after 1 year of treatment. Conclusion– Although this was an open trial, the results suggested that acetazolamide can temporarily reduce the severity of symptoms during the progression of SCA6.

Erdheim-Chester disease and slowly progressive cerebellar dysfunction

A 59 year old woman developed pronounced thirst, increased water intake, and increased urinary output followed by slowly progressive cerebellar symptoms. Brain MRI showed abnormal hyperintensity on T2 weighted studies in the region of both dentate nuclei without atrophy of the cerebellum or the brainstem. A 99mTC diphosphonate bone scan showed bone lesions in the distal parts of both femurs as well as distal and proximal parts of both tibias. The diagnosis of Erdheim-Chester disease was made by bone biopsy. This is the first case of Erdheim-Chester disease presenting as a slowly progressive cerebellar syndrome and diabetes insipidus, and also showing high signal lesions in deep cerebellar nuclei on MRI. Skeletal surveys are indicated for patients with otherwise unexplained slowly progressive cerebellar symptoms.

Mosaicism of unstable CAG repeats in the brain of spinocerebellar ataxia type 2

Abstract Spinocerebellar ataxia type 2 (SCA2) is caused by expansion of unstable CAG repeats within the coding region of the novel gene, ataxin-2, on chromosome 12q24.1. We analyzed CAG repeat size of the SCA2 allele in two deceased patients (father and daughter) to investigate the repeat mosaicism in CNS regions. The CAG repeat size was examined using lymphoblastoid cell lines, frozen brain tissues, and paraffin-embedded tissues. In each patient the major repeat size of the expanded allele varied within the brain or spinal cord (father, 39–42; daughter, 39–47 repeats), and was smaller by three to eight repeats in the cerebellum than in other CNS regions. Our results are in agreement with the findings in other polyglutamine disorders showing somatic mosaicism.

Spinocerebellar ataxia 1 (SCA1) in the Japanese in Hokkaido may derive from a single common ancestry.

Spinocerebellar ataxia 1 (SCA1) is caused by expansion of an unstable CAG triplet repeat located on the short arm of chromosome 6. Precise mapping has shown a positional relationship to closely linked markers in the order of D6S109-D6S274-D6S288-SCA1-AM10GA-D6S89+ ++-EDN1 from centromere to telomere. The haplotype which cosegregated with the disease was determined in 12 Japanese pedigrees with SCA1. Although the alleles of the SCA1 haplotype varied from pedigree to pedigree, depending on the distance from the SCA1 locus, the affected and presymptomatic subjects carried the same alleles at D6S288 and D6S274. All the families with SCA1 had migrated from either Miyagi or Yamagata Prefectures, neighbouring areas in the Tohoku District, the northern part of Honshu which is the main island of Japan. It seems highly likely that SCA1 in the Japanese, at least those residing in Hokkaido, derives from a single common ancestry.

Dissociation of smooth pursuit and vestibulo-ocular reflex cancellation in SCA-6.

Objective: To study gaze in SCA-6 patients during pursuit and passive whole-body rotation. Background: Smooth pursuit and vestibularly induced eye movements interact to maintain the accuracy of eye movements in space (i.e., gaze). Previous studies have implicated the cerebellum, particularly the floccular lobe and dorsal vermis, in the control of gaze velocity during pursuit and vestibulo-ocular reflex (VOR) cancellation. SCA-6 has recently been identified genetically and characterized as pure cerebellar ataxia that affects the cerebellar cortex selectively. Methods: Using infrared oculography, eye movements of five SCA-6 patients and five age-matched normal control subjects were recorded during sinusoidal pursuit and passive whole-body rotation in the horizontal plane (amplitude, ±10 deg; frequency, 0.2 Hz). Eye and gaze gain (eye and gaze velocity/stimulus velocity) were calculated after deleting saccades. Results: Eye gain of all SCA-6 patients during pursuit was significantly lower than those of the control subjects (mean ± SD, 0.26 ± 0.06 versus 0.91 ± 0.07). In contrast, eye gain of the patients was not significantly different from that of the control subjects either during VOR cancellation, when the subjects tracked a target that moved with the same amplitude and phase, like a chair (0.21 ± 0.05 versus 0.12 ± 0.07), or during visually enhanced VOR (×1), when the target remained stationary in space (0.85 ± 0.06 versus 0.95 ± 0.05). Moreover, there was no significant difference in mean VOR gain in total darkness between the two groups. Gaze gain of patients (0.26 ± 0.06 versus 0.81 ± 0.06) but not control subjects (0.91 ± 0.07 versus 0.88 ± 0.08), was significantly different during pursuit and VOR cancellation. Conclusion: SCA-6 patients show dissociation in the control of gaze tracking during smooth pursuit and VOR cancellation.

Electrophysiological features of central motor conduction in spinocerebellar atrophy type 1, type 2, and Machado-Joseph disease

OBJECTIVES To characterise electrophysiologically the central motor conduction of spinocerebellar atrophy type 1 (SCA1), type 2 (SCA2), and Machado-Joseph disease (MJD). METHODS Motor evoked potentials (MEPs) triggered by transcranial magnetic stimulation (TMS) was used to investigate the functions of corticospinal tracts of 10 patients with SCA1, 10 with MJD, and eight with SCA2 in addition to pathological study of the spinal cord in a patient with SCA1. RESULTS Central motor conduction time (CMCT) was extremely prolonged and the MEP threshold increased in all patients with SCA1, whereas both were normal in patients with SCA2 or MJD. The MEP size in MJD was larger than normal, but was normal in SCA1 and SCA2. A pathological investigation of the corticospinal tract of the spinal cord of a patient with SCA1 showed selective loss of large diameter fibres. CONCLUSIONS SCA1, SCA2, and MJD differ in their pathophysiological features of the central motor tract and can be differentiated from each other by MEP values for the lower limb muscles, even though their neurological symptoms are sometimes similar.

CAG repeat expansion of Machado-Joseph disease in the Japanese: analysis of the repeat instability for parental transmission, and correlation with disease phenotype

Machado-Joseph disease (MJD) is caused by abnormal expansion of an unstable CAG repeat in a novel gene locating on chromosome 14q32.1. We analysed this CAG repeat polymorphism with 66 Japanese MJD patients. All the patients were selectively associated with abnormal expansion of the CAG repeat. Repeat length of the mutant allele did not overlap that of normal allele and closely correlated with not only age at onset but also with clinical phenotypes. CAG repeat size is apparently related to a wide variety of phenotypic presentations in MJD.