Antonella Antenora

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

Background Spinocerebellar ataxias are rare dominantly inherited neurodegenerative diseases that lead to severe disability and premature death. Objective To quantify the impact of disease progression measured by the Scale for the Assessment and Rating of Ataxia on survival, and to identify different profiles of disease progression and survival. Methods Four hundred sixty‐two spinocerebellar ataxia patients from the EUROSCA prospective cohort study, suffering from spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6, and who had at least two measurements of Scale for the Assessment and Rating of Ataxia score, were analyzed. Outcomes were change over time in Scale for the Assessment and Rating of Ataxia score and time to death. Joint model was used to analyze disease progression and survival. Results Disease progression was the strongest predictor for death in all genotypes: An increase of 1 standard deviation in total Scale for the Assessment and Rating of Ataxia score increased the risk of death by 1.28 times (95% confidence interval: 1.18–1.38) for patients with spinocerebellar ataxia type 1; 1.19 times (1.12–1.26) for spinocerebellar ataxia type 2; 1.30 times (1.19–1.42) for spinocerebellar ataxia type 3; and 1.26 times (1.11–1.43) for spinocerebellar ataxia type 6. Three subgroups of disease progression and survival were identified for patients with spinocerebellar ataxia type 1: “severe” (n = 13; 12%), “intermediate” (n = 31; 29%), and “moderate” (n = 62; 58%). Patients in the severe group were more severely affected at baseline with higher Scale for the Assessment and Rating of Ataxia scores and frequency of nonataxia signs compared to those in the other groups. Conclusion Rapid ataxia progression is associated with poor survival of the most common spinocerebellar ataxia. Theses current results have implications for the design of future interventional studies of spinocerebellar ataxia. © 2019 International Parkinson and Movement Disorder Society

Introduction: There are several reported cases of patients developing motor and cognitive neurological impairment under treatment with valproic acid (VPA). We describe a woman who developed a subacute encephalopathy after VPA intake, harboring a mitochondrial DNA variant, previously described as causing VPA sensitivity in one pediatric patient. Material and Methods: A 65-year old woman developed a progressive, severe neurological deterioration after a 3 month treatment with valproate sodium, 800 mg daily. Magnetic resonance spectroscopy (MRS), muscle histochemical analysis and assay of mitochondrial enzymatic activities, and mitochondrial DNA sequencing were performed. Results: Neurological examination showed drowsiness, vertical gaze palsy, inability to either stand or walk, diffuse weakness, increased tendon reflexes. Blood lactate was increased, EEG showed diffuse theta and delta activity, MRI subcortical atrophy and leukoencephalopathy, MRS marked reduction of the NAA spectrum, with a small signal compatible with presence of lactate. Muscle biopsy evidenced presence of ragged red fibers (20%) and reduced COX reactivity. Assay of the muscle enzymatic activities showed multiple deficiencies of the electron transport chain and reduced ATP production. The mt.8393C>T variant in the MT-ATP8 gene was found in homoplasmy. The patient considerably improved after valproate withdrawal. Conclusion: The variant we found has been reported both as a polymorphism and, in a single patient, as related to the valproate-induced encephalopathy. The present case is the first bearing this mutation in homoplasmy. In case of neurological symptoms after starting VPA therapy, once hyperammonemia and liver failure have been ruled out, mtDNA abnormalities should be considered.