Identification of Biomarkers in Patients With Autosomal Dominant Cerebellar Ataxia

Rational. Autosomal dominant cerebellar ataxias (ADCA) are a clinically heterogeneous group of neurodegenerative disorders caused by unstable CAG repeat expansions encoding polyglutamine tracts. ADCA have a wide range of neurological symptoms including ataxia of gait, stance, and limbs, cerebellar dysarthria, oculomotor disturbances of cerebellar and supranuclear genesis, retinopathy, optic atrophy, spasticity, extra-pyramidal movement disorders, peripheral neuropathy, sphincter disturbances, cognitive impairment, and epilepsy. Corresponding to neuropathological findings in hereditary ataxia, there are three fundamental patterns of degeneration on MRI: spinal atrophy, olivopontocerebellar atrophy, and cortical cerebellar atrophy. We previously showed an hypercatabolism in premanifest and early stage Huntington's disease (HD), along with a systemic metabolic defect: progressive decrease of the plasmatic branched-chain amino acids (BCAA) - correlated with low serum IGF1 (insulin-like growth factor 1) - and muscle energy metabolism abnormalities measured by 31P-NMR spectroscopy. We also observed a weight loss in SCA1, 3 and mostly SCA7 patients. In addition, we underlined in a preliminary study a significant decrease of the BCAA in SCA1,2,3 and 7 patients, suggesting that an energy deficit would also be implied in SCA pathogenesis. Transcriptional interferences are likely a part of SCA physiopathology, as shown in the retinal cells of a SCA7 mouse model, or as we detected over the cerebellum growth of these mice. The hallmark of the gene expression studies in SCA1 and SCA7 mice points out the implication of IGF1 pathway and IGF1 receptor. As in HD, these transcriptional disorders might witness the metabolic defects above-mentioned.

Study objectives. The primary aim of the study is to provide metabolic and imaging biomarkers in SCA1,2,3 and 7 patients and controls in the perspective of future therapeutic trials.

The secondary aims are to determine (i) an systemic energy profile in SCA1,2,3 and 7 patients with the confirmation of an hypercatabolic status, (ii) a brain energy profile in SCA1,2,3 and 7 patients measured by in vivo 31P-NMR spectroscopy.

Study population. BIOSCA will recruit 120 participants in the Pitie Salpetriere University Hospital located in Paris, France. The target cohort will be 80 patients - divided into 4 groups of 20 participants of each mutation - and 40 controls.

Study design. All patients (SCA1,2,3,7) will be assessed at baseline (visit 1), 1 year (visit 2) and 2 years (visit 3). At visit 1 and 3, subjects will undergo clinical, MRI, a bone mineral density and a resting metabolic rate assessments, as well as donating fasted blood samples. Each visit will last approximately 6 hours. At visit 2, they will have only a clinical assessment along with a fasted blood sample. Control subjects will be seen only at visit 1 and 3 with the same assessments as the patients.