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Huntington disease (HD) and spinocerebellar ataxia type 1-2-17 (SCA1-2-17) are adult-onset autosomal dominant diseases, caused by triplet repeat expansions in the HTT, ATXN1, ATXN2, and TBP genes. Alleles with a repeat number just below the pathological threshold are associated with reduced penetrance and meiotic instability and are defined as intermediate alleles (IAs). We aimed to determine the frequencies of IAs in healthy Italian subjects and to compare the proportion of the IAs with the prevalence of the respective diseases. We analyzed the triplet repeat size in HTT, ATXN1, ATXN2, and TBP genes in the DNA samples from 729 consecutive adult healthy Italian subjects. IAs associated with reduced penetrance were found in ATXN2 gene (1 subject, 0.1%) and TBP gene (0.82%). IAs at risk for meiotic instability were found in HTT (5.3%) and ATXN2 genes (2.7%). In ATXN1, we found a low percentage of IAs (0.4%). Alleles lacking the common CAT interruption within the CAG sequence were also rare (0.3%). The high frequencies of IAs in HTT and ATXN2 genes suggest a correlation with the prevalence of the diseases in our population and support the hypothesis that IAs could represent a reservoir of new pathological expansions. On the opposite, ATXN1-IA were very rare in respect to the prevalence of SCA1 in our country, and TBP- IA were more frequent than expected, suggesting that other mechanisms could influence the occurrence of novel pathological expansions.

The diagnosis of sporadic adult onset ataxia is a challenging task since a large collection of hereditary and non-hereditary disorders should be taken into consideration. Sporadic adult onset ataxias include degenerative non-hereditary, hereditary, and acquired ataxias. Multiple system atrophy and idiopathic late cerebellar ataxia are degenerative non-hereditary ataxias. Late-onset Friedreich's ataxia, spinocerebellar ataxia type 6 and 2, and fragile X-associated tremor/ataxia syndrome account for most sporadic hereditary ataxias. Alcoholic cerebellar degeneration, paraneoplastic and other autoimmune cerebellar degeneration, vitamin deficiencies, and toxic-induced and infectious cerebellar syndrome are the main causes of acquired cerebellar degeneration. The diagnostic approach should include a history taking, disease progression, general and neurological examination, brain MRI, and laboratory and genetic tests. Novel opportunities in massive gene sequencing will increase the likelihood to define true etiologies.