Spinocerebellar ataxia 17 (SCA17) and Huntington’s disease-like 4 (HDL4)

Abstract

Spinocerebellar ataxia 17 (SCA17) or Huntington's disease-like-4 is a neurodegenerative disease caused by the expansion above 44 units of a CAG/CAA repeat in the coding region of the TATA box binding protein (TBP) gene leading to an abnormal expansion of a polyglutamine stretch in the corresponding protein. Alleles with 43 and 44 repeats have been identified in sporadic cases and their pathogenicity remains uncertain. Furthermore, incomplete penetrance of pathological alleles with up to 49 repeats has been suggested. The imperfect nature of the repeat makes intergenerational instability extremely rare and de novo mutations are most likely the result of partial duplications. This is one of the rarer forms of autosomal dominant cerebellar ataxia but the associated phenotype is often severe, involving various systems (cerebral cortex, striatum, and cerebellum), with extremely variable age at onset (range: 3-75 years) and clinical presentation. This gene is thought to account for a small proportion of patients with a Huntington's disease-like phenotype and cerebellar signs. Parkinson's disease-like, Creutzfeldt-Jakob disease-like and Alzheimer disease-like phenotypes have also been described with small SCA17 expansions. The abnormal protein is expressed at the same level as its normal counterpart and forms neuronal intranuclear inclusions containing other proteins involved in protein folding or degradation. The increase in the size of the glutamine stretch enhances transcription in vitro, probably leading to transcription deregulation. Interestingly, the TBP protein mutated in SCA17 is recruited in the inclusions of other polyglutaminopathies, suggesting its involvement in the transcription down-regulation observed in these diseases.

Spinocerebellar ataxia type 31 exists in Northeast China

“…This is quite similar to a few sporadic Japanese cases of SCA31 previously reported [7,8]. Because of the possibility of incomplete penetrance, it may be very common to find sporadic cases in many autosomal dominant hereditary diseases [17,26,27]. Therefore, we suggest that incomplete penetrance might be suspected in SCA31.…”

The proteasomal system

“…Additional to HD eight further neurodegenerative diseases are known, that are caused by the insertion of polyQ-sequences in the according expressed proteins: the spinocerebellar ataxias (SCA) 1 (Netravathi et Kieling et al, 2008), 6 (Craig et al, 2008Howell et al, 2006;Khan et al, 2005), 7 Rub et al, 2008), and 17 (Stevanin and Brice, 2008;Mariotti et al, 2007;Hubner et al, 2007), the dentatorubro-pallidoluysian atrophy (DRPLA) (Tsuji, 2007;Hashi et al, 2007;Yazawa et al, 1999) and finally the spinobular muscular atrophy (SBMA) (Tokui et al, 2008;Suzuki et al, 2008;Sobue, 2003;Zoghbi and Orr, 2000;Ross, 2002). Normally huntingtin shows a polyQ extension of about 6-35 glutamine residues, while clinical symptoms occur, when more than 40 residues are attached (The Huntington's Disease Collaborative Research Group, 1993;Andrew et al, 1993).…”

Psychosis in Spinocerebellar Ataxias: a Case Series and Study of Tyrosine Hydroxylase in Substantia Nigra

“…Though less recognized than the motor manifestations of the disease, significant cognitive impairment among SCA patients has been noted in 25–50% of cases and psychiatric symptoms (usually depression) in up to 30% [20, 21, 22, 23, 24, 25, 26]. Others have studied the longitudinal progression of cognitive impairment versus motor progression in SCAs 1 and 2 and found that there is dissociation between cognitive and motor progression [27].…”