Isao Yamashita

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

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.

Prevalence of triplet repeat expansion in ataxia patients from Hokkaido, the northernmost island of Japan

Approximately 44% of cases of spinocerebellar ataxia (SCA) in Hokkaido, the northernmost island of Japan, were estimated to be inherited. To determine the prevalence of triplet repeat expansion in hereditary SCA patients, we genotyped seven genetically defined dominant SCAs in 349 patients, including 266 patients from 77 families, 78 probands from unrelated families with hereditary late-onset SCA, and five patients in whom a family history of SCA was not demonstrated. The frequency of each disorder in a total of 155 unrelated families was 23.9% for Machado-Joseph disease (MJD), 29.0% for SCA6, 9.7% for SCA1, 7.7% for SCA2, and 2.6% for dentatorubral-pallidoluysian atrophy. Abnormal expansion of triplet repeats for SCA7 and SCA8 was not detected. A total of 27.1% of the patients had still unknown SCA mutations. In addition, the GAA repeat in the frataxin gene was not abnormally expanded in 13 early-onset SCA patients with clinical features similar to those of Friedreich ataxia. Comparison of our results with those from other centers handling SCA showed that MJD is prevalent throughout Japan, but the frequencies of other dominant SCAs differ considerably even within Japan.

A rat model of human T lymphocyte virus type I (HTLV-I) infection: in situ detection of HTLV-I provirus DNA in microglia/macrophages in affected spinal cords of rats with HTLV-I-induced chronic progressive myeloneuropathy.

Abstract To investigate the pathogenetic role of human T lymphocyte virus type I (HTLV-I) in central nervous system disease, a rat model for HTLV-I-associated myelopathy/tropical spastic paraparesis, designated as HAM rat disease, has been established. Wistar-King-Aptekman-Hokudai strain rats with induced HTLV-I infection develop a chronic progressive myeloneuropathy with paraparesis of hind limbs after an incubation period of 15 months. In the affected spinal cord in these rats, white matter degeneration, demyelination and vacuolar change with microglia/macrophage infiltration are present as are the provirus DNA and the virus mRNA. To identify infected cells in the affected lesions, we carried out in situ hybridization of amplified fragments of the provirus DNA by polymerase chain reaction on thin sections, plus immunohistochemistry on the same sections. The provirus DNA was localized in some microglia/macrophages in the spinal cord lesion. In addition, the HTLV-I provirus was clearly evident not only in ED-1-negative lymphoid cells but also in ED-1-positive macrophages from lymph nodes. These observations suggest that cells of microglia/macrophage lineage may be one of dominant viral reservoirs in the spinal cords and lymph nodes in HAM rat disease. These infected microglia/macrophages may relate to cause the myeloneuropathy through neurotoxic cytokine synthesis.

Twenty CAG repeats are sufficient to cause the SCA6 phenotype.

Editor—Spinocerebellar ataxia type 6 (SCA6) is a dominantly inherited form of spinocerebellar ataxia, which usually manifests as a syndrome of progressive pure cerebellar ataxia with a late onset, and is caused by a small expansion of CAG repeats in the coding region of the αlA subunit of the P/Q type voltage dependent calcium channel gene ( CACNA1A ).1 In the original study, normal alleles were shown to have four to 16 CAG repeats, while expanded alleles with 21-27 CAG repeats were specifically associated with the clinical disorder. Subsequent studies have shown that pathogenic expansion ranges from 21-33 CAG repeats and that its size is inversely correlated with the age of onset,2-9 whereas the majority of normal alleles have 4-18 repeats and a few carriers possess 19-20 repeats.2 The frequency of relatively larger alleles in the normal population correlates with the prevalence of various forms of dominant SCA caused by tandem repeat expansion10 and the intermediate allele of SCA6 itself can potentially harbour de novo mutations.11 In all of these studies, an allele with 21 CAG repeats was considered to be the smallest expansion generating the clinical disorder.1-3 6-9 However, it is still uncertain whether 20 repeats can also cause clinical manifestations. We describe here two sibs with SCA6, who were both homozygous for 20 repeat alleles and presented with late onset pure cerebellar …

Recessively inherited spastic paraplegia associated with ataxia, congenital cataracts, thin corpus callosum and axonal neuropathy

We investigated a consanguineous Japanese family with a complicated form of familial spastic paraplegia (FSP). Three siblings were affected, probably by autosomal recessive inheritance. All showed ataxia, subnormal mentality, congenital cataracts, and slight cerebellar atrophy on CT scans. Spastic paraplegia was predominant in 2 siblings, while ataxia was more marked in the other. Slight but definite atrophy of the corpus callosum and axonal neuropathy were demonstrated in 1 sibling who underwent detailed investigation. Review of similar cases reported in the literature indicates that this recessively inherited disorder probably represents a homogeneous group within the heterogeneous cluster of complicated FSP.

Human T‐lymphocyte virus type I (HTLV‐I)‐induced myeloneuropathy in rats: Oligodendrocytes undergo apoptosis in the presence of HTLV‐I

To investigate the pathogenetic role of human T‐lymphocyte virus type I (HTLV‐I) in central nervous system disease, a rat model for HTLV‐I‐associated myelopathy/tropical spastic paraparesis, designated as HAM rat disease, was examined with regard to chronological neuropathology, from early asymptomatic phase to late disease. In the thoracic spinal cord of rats with HTLV‐I infection, the first event was the appearance of apoptosis of oligodendrocytes beginning at 7 months after induced infection, thereafter followed by the appearance of white matter degeneration, increase of macrophages/activated microglia and of gemistocytic astrocytes at 12, 15 and 20 months, respectively. In the spinal cord, HTLV‐I provirus DNA was evident as early as 4 months after the infection, and HTLV‐I pX and the tumor necrosis factor (TNF)‐α messages began to be expressed at age 7 months, just before or at the same time as the appearance of apoptotic cells. Collective evidence suggests that the apoptotic death of oligodendrocytes, which may be induced either directly by the local expression of HTLV‐I or indirectly by TNF‐α, through the transactive function of p40Tax, is the major cause of chronic progressive myeloneuropathy in Wistar‐King‐Aptekman‐Hokudai rats with HTLV‐I infection.