Spinocerebellar Ataxia 36 is a Frequent Cause of Hereditary Ataxia in Eastern Spain.

Background: Autosomal dominant spinocerebellar ataxia 36 (SCA36) is caused by hexanucleotide repeat expansion in the NOP56 gene. Objectives: To assess frequency, clinical and genetic features of SCA36 in Eastern Spain. Methods: NOP56 expansion was tested in a cohort of undiagnosed cerebellar ataxia families (n = 84). Clinical characterization and haplotype studies were performed. Results: SCA36 was identified in 37 individuals from 16 unrelated families. It represented 5.4% of hereditary ataxia patients. The majority were originally from the same region and displayed a shared haplotype. Mean age at onset was 52.5 years. Non-ataxic features included: hypoacusis (67.9%), pyramidal signs (46.4%), lingual fasciculations/atrophy (25%), dystonia (17.8%), and parkinsonism with evidence of dopaminergic denervation (10.7%). Conclusions: SCA36 is a frequent cause of hereditary ataxia in Eastern Spain, and is associated with a strong founder effect. SCA36 analysis should be considered prior to other studies, especially in AD presentations. Parkinsonism reported here broadens SCA36 clinical spectrum.

Gait Function after High-Intensity Focused Ultrasound Thalamotomy for Essential Tremor: Searching for Technique Optimization.

INTRODUCTION: Essential tremor (ET) is one of the most prevalent movement disorders in adults and may be highly disabling for some. Magnetic resonance image-guided high-intensity focused ultrasound (MRIgFUS) has been shown to control tremor efficaciously and with acceptable risk. To date, paresthesia and ataxia are the most common adverse effects (AE). Nevertheless, the impact of MRIgFUS thalamotomy on balance is not well established. METHODS: Thirty-two patients underwent MRIgFUS for ET and completed 6 months of follow-up. Tremor severity and functional disability were assessed using the Essential Tremor Rating Scale and the Quality of Life in Essential Tremor Questionnaire. The Berg Balance Scale (BBS) was applied to objectively measure balance status. RESULTS: All treatments were successful. The sonication target was 1-2 mm above the depth of the intercommissural line. Procedures lasted less the 2 h, with an average of 8 sonications per patient. Twenty-four patients were included in the tremor analysis. The hand tremor score was improved by 76% after 6 months of follow-up and 87% of patients self-reported marked improvement (≥75%). Disability scores showed marked improvement (78%), leading to a significant improvement in quality of life. At the final follow-up, 48% of the patients reported no side effects. When present, AE were generally transient and were considered mild in 96% of affected patients. Paresthesia and subjective feeling of unsteadiness were the most common persistent complaints (23% and 20%, respectively). Regarding objective ataxia, BBS scores remained stable throughout follow-up for most patients. Only 2 patients suffered a mild worsening of balance although no patients experienced moderate or severe ataxia. CONCLUSIONS: Subjective feeling of unsteadiness is one of the most frequent AE after MRIgFUS, although objective ataxia is infrequent and mild. Selecting the most appropriate lesion location and procedural parameters should increase treatment benefits while reducing side effects.

Diagnostic Efficacy of Genetic Studies in a Series of Hereditary Cerebellar Ataxias in Eastern Spain.

Background and Objectives: To determine the diagnostic efficacy of clinical exome-targeted sequencing (CES) and spinocerebellar ataxia 36 (SCA36) screening in a real-life cohort of patients with cerebellar ataxia (CA) from Eastern Spain. Methods: A total of 130 unrelated patients with CA, negative for common trinucleotide repeat expansions (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, dentatorubral pallidoluysian atrophy [DRPLA], and Friedreich ataxia), were studied with CES. Bioinformatic and genotype-phenotype analyses were performed to assess the pathogenicity of the variants encountered. Copy number variants were analyzed when appropriate. In undiagnosed dominant and sporadic cases, repeat primed PCR was used to screen for the presence of a repeat expansion in the NOP56 gene. Results: CES identified pathogenic or likely pathogenic variants in 50 families (39%), including 23 novel variants. Overall, there was a high genetic heterogeneity, and the most frequent genetic diagnosis was SPG7 (n = 15), followed by SETX (n = 6), CACNA1A (n = 5), POLR3A (n = 4), and SYNE1 (n = 3). In addition, 17 families displayed likely pathogenic/pathogenic variants in 14 different genes: KCND3 (n = 2), KIF1C (n = 2), CYP27A1A (n = 2), AFG3L2 (n = 1), ANO10 (n = 1), CAPN1 (n = 1), CWF19L1 (n = 1), ITPR1 (n = 1), KCNA1 (n = 1), OPA1 (n = 1), PNPLA6 (n = 1), SPG11 (n = 1), SPTBN2 (n = 1), and TPP1 (n = 1). Twenty-two novel variants were characterized. SCA36 was diagnosed in 11 families, all with autosomal dominant (AD) presentation. SCA36 screening increased the total diagnostic rate to 47% (n = 61/130). Ultimately, undiagnosed patients showed delayed age at onset (p < 0.05) and were more frequently sporadic. Discussion: Our study provides insight into the genetic landscape of CA in Eastern Spain. Although CES was an effective approach to capture genetic heterogeneity, most patients remained undiagnosed. SCA36 was found to be a relatively frequent form and, therefore, should be tested prior to CES in familial AD presentations in particular geographical regions.

Clinical and genetic characteristics of 21 Spanish patients with biallelic pathogenic SPG7 mutations.

Spastic paraplegia type 7 (SPG7) is one of the most common hereditary spastic paraplegias. SPG7 mutations most often lead to spastic paraparesis (HSP) and/or hereditary cerebellar ataxia (HCA), frequently with mixed phenotypes. We sought to clinically and genetically characterize a Spanish cohort of SPG7 patients. Patients were recruited from our HCA and HSP cohorts. We identified twenty-one patients with biallelic pathogenic SPG7 mutations. Mean age at onset was 37.4 years (SD ± 14.3). The most frequent phenotype was spastic ataxia (57%), followed by pure spastic paraplegia (19%) and complex phenotypes (19%). Isolated patients presented with focal or multifocal dystonia, subclinical myopathy or ophthalmoplegia. p.Ala510Val was the most frequent pathogenic variant encountered. Compound heterozygous for p.Ala510Val displayed younger onset (p < 0.05) and more complex phenotypes (p < 0.05) than p.Ala510Val homozygotes. Two novel variants were found: p.Lys559Argfs*33 and p.Ala312Glu. In conclusion, spastic ataxia is the most common phenotype found in Spanish patients. Nonetheless, SPG7 analysis should also be considered in patients with less frequent clinical findings such as dystonia or ophthalmoplegia especially when these symptoms are associated with mild spastic ataxia.