'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization

Brain. 2012 May;135(Pt 5):1423-35. doi: 10.1093/brain/aws069. Epub 2012 Apr 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Aged
  • Aged, 80 and over
  • Brain / pathology
  • Chromosomes, Human, Pair 20 / genetics
  • DNA Mutational Analysis
  • Disease Progression
  • Family Health*
  • Female
  • Genetic Linkage
  • Genotype
  • Humans
  • Introns / genetics
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Nuclear Proteins / genetics
  • Spain / epidemiology
  • Spinocerebellar Ataxias / genetics*
  • Spinocerebellar Ataxias / pathology
  • Spinocerebellar Ataxias / physiopathology*
  • Trinucleotide Repeat Expansion / genetics*

Substances

  • NOP56 protein, human
  • Nuclear Proteins