Survival and severity in dominant cerebellar ataxias

Abstract

Inherited spinocerebellar ataxias (SCAs) are known to be genetically and clinically heterogeneous. Whether severity and survival are variable, however, is not known. We, therefore, studied survival and severity in 446 cases and 509 relatives with known mutations. Survival was 68 years [95% CI: 65-70] in 223 patients with polyglutamine expansions versus 80 years [73-84] in 23 with other mutations (P < 0.0001). Disability was also more severe in the former: at age 60, 30% were wheelchair users versus 3% with other SCAs (P < 0.001). This has implications for genetic counseling and the design of therapeutic trials.

Figure 1

(A) Lifetest in 332 patients with familial autosomal dominant ataxias, according to genotype (polyQ-SCAs in blue vs. SCAs with other mutations in black). Median age at death was 69 years [95% CI: 67–71] but polyQ-SCA patients died significantly earlier than the others (68 vs. 80 years, P < 0.0001). The probability of survival for polyQ-SCA patients was over 95% at age 40, but only 20% at 80, a tendency towards an exponential decrease in life span; most deaths occurred between age 50 and 70 years. (B) Lifetest procedure according to polyQ-SCAs genotype: SCA 1 (green), 2 (red), 3 (steel), 6 (brown), and 7 (violet). Median age at death in SCA 1 was 63 years, significantly earlier than SCA 2, 3, 6 and 7, P < 0.0001. SCA, spinocerebellar ataxias.

Figure 2

(A) Lifetest procedure for the effect of genotype (polyQ-SCAs in blue vs. other SCAs in black) on age when aid was needed for walking in 862 patients, P < 0.0001 (377 patient walked with aid, 485 were censored at last visit). (B) Lifetest procedure for the effect of genotype (polyQ-SCAs in blue vs. other SCAs in black) on age when a wheelchair was needed in 835 patients, P < 0.0001 (207 patients used wheelchair, 628 were censored at last visit). (C) Lifetest procedure for the effect of polyQ-SCAs genotype: SCA 1 (green), 2 (red), 3 (steel), 6 (brown), and 7 (violet), on age when a wheelchair was needed. SCA, spinocerebellar ataxias.