Spinocerebellar Ataxia Type 1 Clinical Trial
Official title:
Identification of Biomarkers in Patients With Autosomal Dominant Cerebellar Ataxia
Autosomal dominant cerebellar ataxias (ADCA) are a group of neurodegenerative disorders that are clinically and genetically various. BIOSCA study aims to identify markers of the metabolism (energy production inside the cells) in the blood and the brain of ADCA 1,2,3 and 7 patients and control subjects, in the perspective of future therapeutic trials.
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.
Study period. BIOSCA is a prospective study for which each participant is enrolled for 24
months. The study duration is 36 months. The start date is November 2011.
Funding. BIOSCA is funded by a national funding hospital program in clinical research (PHRC)
from APHP institution.
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