MACHADO-JOSEPH disease (MJD) is a multisystem degeneration of the central nervous system, inherited as an autosomal dominant disease, and first reported in North American families of Portuguese-Azorean ancestry.^1-4 It is most often a highly incapacitating disease—typically, patients will become confined to a wheelchair and will later be beddriden. Disease manifestations usually start during adulthood, with a mean ± SD age of onset of 32 ± 12 years among Brazilian patients (L.B.J., I.S., M.L.P., A.F., J.S., R.G. and I. Alonso, BSc, M. C. Moreira, MSc, P. Mendonça, BSc, and F. Ferreirinha, BSc, unpublished data, 2000), or 37 ± 14 years among the Portuguese and those of Portuguese-Azorean descent.⁵ The distribution of age of onset is wide, ranging from 5 to 73 years in Portuguese patients.⁵ Penetrance is high but incomplete since there were rare obligate carriers free of symptoms until as late as the age of 90 years.⁶ The median survival time after onset varies from 14 to 25 years.^2,7

THE SPINOCEREBELLAR ataxias (SCAs) are neurodegenerative disorders that are clinically and genetically heterogeneous. Ten genetically different SCAs are known to be caused by trinucleotide repeat (TNR) expansions. In the dominant SCAs, the mutant proteins show an expanded polyglutamine tract in SCA1, SCA2, Machado-Joseph disease (MJD), SCA6, SCA7, and dentatorubropallidoluysian atrophy (DRPLA),^1-9 whereas SCA8 and SCA12 are caused by untranslated (CTG)_n and (CAG)_n expansions, respectively.^10,11 In Friedreich ataxia (FRDA), the mutant protein is deficient in homozygotes for a (GAA)_n expansion in intron 1 of the FRDA gene.¹² Recently, an expanded CAG repeat tract has been found at the TATA-binding protein gene (TBP) in an isolated patient with symptoms of ataxia and intellectual deterioration.¹³TBP repeat expansions have since been described in 4 Japanese families affected by a new type of ataxia with dementia named SCA17.¹⁴ Matsuura et al¹⁵ found a large expansion of pentanucleotide (ATTCT)_n in intron 9 of the SCA10 gene in patients with spinocerebellar ataxia type 10, thus being the first to show the existence of a new class of dynamic mutations.

Hereditary cerebellar ataxia (HCA) and hereditary spastic paraplegia (HSP) are neurodegenerative disorders that present with progressive gait impairment. Hereditary cerebellar ataxia involves mainly the cerebellar system and its connections, whereas HSP affects predominantly the corticospinal tract. Other systems are often affected, leading to complex forms. These diseases are heterogeneous groups, with considerable overlap. Often, they lead to incapacity and premature death.

Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG repeat expansion in intron 1 of NOP56. Family interview and document research allowed us to reconstruct two extensive, multigenerational kindreds stemming from the same village (Costa da Morte in Galicia, Spain), in the 17th century. We found the presence of the spinocerebellar ataxia 36 mutation co-segregating with disease in these families in whom we had previously identified an ∼0.8 Mb linkage region to chromosome 20 p. Subsequent screening revealed the NOP56 expansion in eight additional Galician ataxia kindreds. While normal alleles contain 5–14 hexanucleotide repeats, expanded alleles range from ∼650 to 2500 repeats, within a shared haplotype. Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions. We found a total of 63 individuals carrying the mutation, 44 of whom were confirmed to be clinically affected; over 400 people are at risk. We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss. There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis. Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto-cerebellar atrophy. We estimated the origin of the founder mutation in Galicia to have occurred ∼1275 years ago. Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36, while 15 (9.4%) showed other of the routinely tested dominant spinocerebellar ataxia types. Spinocerebellar ataxia 36 is thus, so far, the most frequent dominant spinocerebellar ataxia in this region, which may have implications for American countries associated with traditional Spanish emigration.