Spinocerebellar ataxias in the Netherlands: Prevalence and age at onset variance analysis

• Published in: Neurology Vol. 58; no. 5; pp. 702 - 708
• Main Authors: VAN DE WARRENBURG, B. P. C, SINKE, R. J, KNOERS, N. V. A. M, KREMER, H. P. H, VERSCHUUREN-BEMELMANS, C. C, SCHEFFER, H, BRUNT, E. R, IPPEL, P. F, MAAT-KIEVIT, J. A, DOOIJES, D, NOTERMANS, N. C, LINDHOUT, D
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 12-03-2002
• Subjects: Adult; Age of Onset; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Humans; Medical sciences; Middle Aged; Mutation; Netherlands - epidemiology; Neurology; Prevalence; Regression Analysis; Spinocerebellar Ataxias - epidemiology; Spinocerebellar Ataxias - genetics; Spinocerebellar Ataxias - physiopathology; Trinucleotide Repeat Expansion; Netherlands; Europe; Human; Nervous system diseases; Prevalence; Repeated sequence; Trinucleotide; Genotype; Epidemiology; Cerebral disorder; Genetic disease; Phenotype; Age of onset; Gene; Spinocerebellar ataxia; Autosomal character; Central nervous system disease; Degenerative disease; Dominant character; Mutation; Spinal cord disease; Public health
• ISSN: 0028-3878; 1526-632X
• DOI: 10.1212/WNL.58.5.702

International prevalence estimates of autosomal dominant cerebellar ataxias (ADCA) vary from 0.3 to 2.0 per 100,000. The prevalence of ADCA in the Netherlands is unknown. Fifteen genetic loci have been identified (SCA-1-8, SCA-10-14, SCA-16, and SCA-17) and nine of the corresponding genes have been cloned. In SCA-1, SCA2, SCA3, SCA6, SCA7, SCA-12 and SCA-17 the mutation has been shown to be an expanded CAG repeat. Previously, the length of the CAG repeat was found to account for 50 to 80% of variance in age at onset. Because of heterogeneity in encoded proteins, different pathophysiologic mechanisms leading to neurodegeneration could be involved. The relationship between CAG repeat length and age at onset would then differ accordingly.
Based on the results of SCA mutation analysis in the three DNA diagnostic laboratories that serve the entire Dutch population, the authors surveyed the number of families and affected individuals per SCA gene, as well as individual repeat length and age at onset. Regression analysis was applied to study the relationship between CAG repeat length and age at onset per SCA gene. The slopes of the different regression curves were compared.
On November 1, 2000, mutations were found in 145 ADCA families and 391 affected individuals were identified. The authors extrapolated a minimal prevalence of 3.0 per 100,000 (range 2.8 to 3.8/100,000). SCA3 was the most frequent mutation. CAG repeat length contributed to 52 to 76% of age at onset variance. Regression curve slopes for SCA-1, SCA2, SCA3, and SCA7 did not differ significantly.
The estimated minimal prevalence of ADCA in the Netherlands is 3.0 per 100,000 inhabitants. Except for SCA6, the relationship between age at onset and CAG repeat expansion does not differ significantly between SCA-1, SCA2, SCA3, and SCA7 patient groups in our population, indicating that these SCA subtypes share similar mechanisms of polyglutamine-induced neurotoxicity, despite heterogeneity in gene products.