The spinocerebellar ataxias: order emerges from chaos.
In the past decade, the genetic etiologies accounting for most cases of adult-onset dominant cerebellar ataxia have been discovered. This group of disorders, generally referred to as the spinocerebellar ataxias (SCAs), can now be classified by a simple genetic nosology, essentially a sequential list in which each new SCA is given a number. However, recent advances in the elucidation of SCA pathogenesis provide the opportunity to subclassify the disorders into three discrete groups based on pathogenesis: 1) the polyglutamine disorders, SCAs 1, 2, 3, 7, and 17, which result from proteins with toxic stretches of polyglutamine; 2) the channelopathies, SCA6 and episodic ataxia types 1 and 2 (EA1 and EA2), which result from disruption of calcium or potassium channel function; and 3) the gene expression disorders, SCAs 8, 10, and 12, which result from repeat expansions outside of coding regions that may quantitatively alter gene expression. SCAs 4, 5, 9, 11, 13-16, 19, 21, and 22 are of unknown etiology, and may or may not fit into one of these three groups. At present, most diagnostic and therapeutic strategies apply equally to all of the SCAs. Therapy specific for individual diseases or types of diseases is a realistic goal in the foreseeable future.
Margolis
Russell L
RL
Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry and Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA. rmargoli@jhmi.edu
D000328:Adult; D000067696:Ataxin-1; D000067528:Ataxins; D006801:Humans; D005810:Multigene Family / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011099:Polyglutamic Acid / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000145:classification / Q000235:genetics* / Q000473:pathology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011099:Polyglutamic Acid