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.

Mutations inPOLR3Aare characterized by high phenotypic heterogeneity, with manifestations ranging from severe childhood-onset hypomyelinating leukodystrophic syndromes to milder and later-onset gait disorders with central hypomyelination, with or without additional non-neurological signs. Recently, a milder phenotype consisting of late-onset spastic ataxia without hypomyelinating leukodystrophy has been suggested to be specific to the intronic c.1909 + 22G > A mutation inPOLR3A. Here, we present 10 patients from 8 unrelated families withPOLR3A-related late-onset spastic ataxia, all harboring the c.1909 + 22G > A variant. Most of them showed an ataxic-spastic picture, two a “pure” cerebellar phenotype, and one a “pure” spastic presentation. The non-neurological findings typically associated withPOLR3Amutations were absent in all the patients. The main findings on brain MRI were bilateral hyperintensity along the superior cerebellar peduncles on FLAIR sequences, observed in most of the patients, and cerebellar and/or spinal cord atrophy, found in half of the patients. Only one patient exhibited central hypomyelination. ThePOLR3Amutations present in this cohort were the c.1909 + 22G > A splice site variant found in compound heterozygosity with six additional variants (three missense, two nonsense, one splice) and, in one patient, with a novel large deletion involving exons 14–18. Interestingly, this patient had the most “complex” presentation among those observed in our cohort; it included some neurological and non-neurological features, such as seizures, neurosensory deafness, and lipomas, that have not previously been reported in association with late-onsetPOLR3A-related disorders, and therefore further expand the phenotype.

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.

The complexity in diagnosing hereditary degenerative ataxias lies not only in their rarity, but also in the variety of different genetic conditions that can determine sometimes similar and overlapping clinical findings. In this light, Magnetic Resonance Imaging (MRI) plays a key role in the evaluation of these conditions, being a fundamental diagnostic tool needed not only to exclude other causes determining the observed clinical phenotype, but also to proper guide to an adequate genetic testing. Here, we propose an MRI-based diagnostic algorithm named CHARON (Characterization of Hereditary Ataxias Relying On Neuroimaging), to help in disentangling among the numerous, and apparently very similar, hereditary degenerative ataxias. Being conceived from a neuroradiological standpoint, it is based primarily on an accurate evaluation of the observed MRI findings, with the first and most important being the pattern of cerebellar atrophy. Along with the evaluation of the presence, or absence, of additional signal changes and/or supratentorial involvement, CHARON allows for the identification of a small groups of ataxias sharing similar imaging features. The integration of additional MRI findings, demographic, clinical and laboratory data allow then for the identification of typical, and in some cases pathognomonic, phenotypes of hereditary ataxias.