Progression of Nigrostriatal Denervation in Cerebellar Multiple System Atrophy: A Prospective Study.

OBJECTIVES: Nigrostriatal dopaminergic denervation (NSDD) remains poorly characterized in cerebellar multiple system atrophy (MSA-C). We aimed to study NSDD progression in MSA-C and evaluate the capacity for [123I]-FP-CIT-SPECT and parkinsonism to differentiate MSA-C from idiopathic late-onset cerebellar ataxia (ILOCA). METHODS: We included 85 patients successively referred for sporadic late-onset cerebellar ataxia (SLOCA). Every 6 months, SARA, UPDRS-III, and SDFS scores were measured, and MSA-C diagnostic criteria were searched for. Striatal/occipital dopaminergic binding ratio was evaluated every year with [123I]-FP-CIT-scintigraphy. RESULTS: After a mean follow-up of 33.8 months, 33 patients had probable MSA-C, 8 possible MSA-C, and 44 ILOCA. SARA and UPDRS-III scores worsened faster in the probable MSA-C group (p < 0.01) compared with the ILOCA group. The baseline striatal/occipital ratio was lower (2.3 vs 2.97; p < 0.01) and more decreasing among patients with probable MSA-C (p < 0.01). Weighting dysautonomia and parkinsonism and/or NSDD as additional and principal criterion, respectively, in the possible MSA-C diagnostic criteria slightly improved their specificity (81.6% vs 76.9%) and sensitivity (77.8% vs 72.2%) to predict a final diagnosis of probable MSA-C. DISCUSSION: Rapid symptom worsening and NSDD existence and progression predict MSA-C among patients with SLOCA. Parkinsonism, NSDD, and dysautonomia should be considered equivalent for possible MSA-C diagnosis.

Biallelic RFC1-expansion in a French multicentric sporadic ataxia cohort.

OBJECTIVE: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the RFC1 gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C). METHODS: 163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C. RESULTS: A pathogenic biallelic RFC1 AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two RFC1 AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found. CONCLUSION: Our study confirms the genetic heterogeneity of the CANVAS and that RFC1 repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.

Relevance of corpus callosum splenium versus middle cerebellar peduncle hyperintensity for FXTAS diagnosis in clinical practice.

Fragile X-associated tremor ataxia syndrome (FXTAS) is caused by FMR1 premutation. The features include ataxia, action tremor and middle cerebellar peduncle (MCP) hyperintensity, the latter being the only major radiological criterion in the diagnosis of definite FXTAS until very recently. The importance of corpus callosum splenium (CCS) hyperintensity was recently reported and this sign is now considered as an additional major radiological diagnostic criterion in the diagnosis of FXTAS. However, little is known about its relevance for the diagnosis of FXTAS in clinical practice. We report a practical justification of the relevance of CCS hyperintensity in parallel with MCP hyperintensity for the diagnosis of FXTAS. Clinical and radiological study of 22 FMR1 premutation carriers with neurological signs that may be encountered in FXTAS compared to series of patients with essential tremor, multiple system atrophy of cerebellar type, Parkinson's disease, Alzheimer's disease and stroke. Among the 22 patients with FMR1 premutation [17 men, 5 women; mean age, 63 ± 7.5 (46-84)], 14 were diagnosed with definite FXTAS with the initial criteria. Considering CCS hyperintensity as a new major radiological criterion permitted the diagnosis of definite FXTAS in 3 additional patients. Overall CCS proved as frequent as MCP hyperintensity (64 versus 64 %), while 23 % of patients had CCS but not MCP hyperintensity, 14 % of patients had CCS hyperintensity but neither MCP, nor brainstem hyperintensity. In contrast with CCS hyperintensity, MCP hyperintensity proved less frequent in women than in men. CCS and MCP hyperintensity were more frequent in FXTAS than in the other neurodegenerative disorders. The combination of CCS and MCP hyperintensity was specific of FXTAS. We confirmed the relevance of CCS hyperintensity in FXTAS and we clarified its interest compared to MCP hyperintensity. Our results support the inclusion of CCS hyperintensity in the diagnostic criteria as a new major radiological criterion.