Mitochondrial impairment in patients with spinocerebellar ataxia type 3

Background: Impaired mitochondrial function is supposed to be involved in the pathogenesis of neurodegenerative diseases like Parkinson's disease and Huntington's disease. 31P magnetic resonance spectroscopy (31P-MRS) has been established as a non-invasive method to assess mitochondrial impairment in vivo. Using 31P-MRS mitochondrial deficits have been demonstrated in primary mitochondrial disorders including Friedreich's ataxia as well as in diseases caused by polyglutamine expansions like Huntington's disease and dentato-rubral pallido-luysian atrophy.

Methods: We assessed the energy metabolism in 15 patients with gengetically proven spinocerebellar ataxia type 3 (SCA3) using 31P-MRS. Phosphocreatine recovery after exercise has been analysed as a direct measure of ATP synthesis in vivo. Additionally, the maximum rate of ATP synthesis (Vmax) has been determined according to the formula Vmax=Vi*(1 + Km/[ADP]Ki).

Results: In a standardized calf muscle test we found slowed phosphocreatine recovery after exercise under ischemic conditions (healthy controls: 43.3±16.2s versus SCA3: 58.2±16.7s; p<0.01). Under aerobic conditions differences did not quite reach significance (controls: 37.8±15.9 vs. SCA3: 50.3±28.6s). The maximum rate of mitochondrial ATP synthesis (Vmax) was decreased after aerobic (Controls: 34.6±15.7 vs. SCA3: 21.8±15.3 mM/min) as well as ischemic exercise (Controls: 35.8±15.8 vs. SCA3: 19.4±11.4 mM/min; p<0.01). Severity of mitochondrial impairment was partially determined by CAG repeat length but did not correlate with age, age at onset of symptoms or severity of the disease assessed by the international co-operative ataxia rating scale.

Conclusions: 31P magnetic resonance spectroscopy is feasible to demonstrate mitochondrial impairment in SCA3 patients in vivo. Our findings suggest impaired oxidative function as a so far unrecognized factor in the pathogenesis of SCA3 that occurs independent of the severity of clinical symptoms but increases with larger CAG repeat expansions.