Myoclonus and Dystonia as Recurrent Presenting Features in Patients with the SCA21-Associated TMEM240 p.Pro170Leu Variant.

Background: Spinocerebellar ataxia 21 (SCA21) is a rare neurological disorder caused by heterozygous variants in TMEM240. A growing, yet still limited number of reports suggested that hyperkinetic movements should be considered a defining component of the disease. Case Series: We describe two newly identified families harboring the recurrent pathogenic TMEM240 p.Pro170Leu variant. Both index patients and the mother of the first proband developed movement disorders, manifesting as myoclonic dystonia and action-induced dystonia without co-occurring ataxia in one case, and pancerebellar syndrome complicated by action-induced dystonia in the other. We reviewed the literature on TMEM240 variants linked to hyperkinetic disorders, comparing our cases to described phenotypes. Discussion: Adding to prior preliminary observations, our series highlights the relevance of hyperkinetic movements as clinically meaningful features of SCA21. TMEM240 mutation should be included in the differential diagnosis of myoclonic dystonia and ataxia-dystonia syndromes.

Sex distribution and classification of GBA1 variants in an Italian cohort of Parkinson's disease patients analyzed over the last seventeen years.

INTRODUCTION: Heterozygous GBA1 variants are among the most frequent genetic risk factors for Parkinson's disease (PD). Male sex is a risk factor in the development of PD but the sex prevalence of GBA1 carriers in PD patients remains debatable. Molecular analysis of the GBA1 gene is complicated by the presence of a highly homologous pseudogene GBAP1. METHOD: Starting from 2006, we screened GBA1 gene in a large cohort of 1762 PD patients through different techniques developed over the years. Identified variants were classified employing the GBA1-PD browser and compared on the basis of frequency and sex distribution. RESULTS: Within a group of 684 patients (40.2% Males -M-) analyzed with RFLP technique looking for the two most common GBA1 mutations L444P and N370S, 29 resulted positive (4.23%). Out of 537 patients (67.4% M) analyzed with PCR that amplifies the portion of the gene between exon 8 and exon 11, we found 53 positive carriers (9.87%). Out of 424 patients (60.8% M) analyzed with NGS custom gene panel with allele-specific PCR, 50 resulted positive (11.79%). Since 2022, we also analyzed 117 patients (56.4% M) with long PCR sequenced with NGS, identifying 17 positive samples (14.52%). CONCLUSION: In our study, we highlight that screening the entire GBA1 gene with specific techniques increases the diagnostic rate. Regarding variants distribution, males have shown a higher frequency of the severe variants and complex alleles, whereas mild variants are equally distributed in both sexes and risk variants are more frequent in females especially the T369 M.

Harmonizing Genetic Testing for Parkinson's Disease: Results of the PARKNET Multicentric Study.

BACKGROUND AND OBJECTIVE: Early-onset Parkinson's disease (EOPD) commonly recognizes a genetic basis; thus, patients with EOPD are often addressed to diagnostic testing based on next-generation sequencing (NGS) of PD-associated multigene panels. However, NGS interpretation can be challenging in a diagnostic setting, and few studies have addressed this issue so far. METHODS: We retrospectively collected data from 648 patients with PD with age at onset younger than 55 years who underwent NGS of a minimal shared panel of 15 PD-related genes, as well as PD-multiplex ligation-dependent probe amplification in eight Italian diagnostic laboratories. Data included a minimal clinical dataset, the complete list of variants included in the diagnostic report, and final interpretation (positive/negative/inconclusive). Patients were further stratified based on age at onset ≤40 years (very EOPD, n = 157). All variants were reclassified according to the latest American College of Medical Genetics and Genomics criteria. For classification purposes, PD-associated GBA1 variants were considered diagnostic. RESULTS: In 186 of 648 (29%) patients, the diagnostic report listed at least one variant, and the outcome was considered diagnostic (positive) in 105 (16%). After reanalysis, diagnosis changed in 18 of 186 (10%) patients, with 5 shifting from inconclusive to positive and 13 former positive being reclassified as inconclusive. A definite diagnosis was eventually reached in 97 (15%) patients, of whom the majority carried GBA1 variants or, less frequently, biallelic PRKN variants. In 89 (14%) cases, the genetic report was inconclusive. CONCLUSIONS: This study attempts to harmonize reporting of PD genetic testing across several diagnostic labs and highlights current difficulties in interpreting genetic variants emerging from NGS-multigene panels, with relevant implications for counseling. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

NGS-Based Genetic Analysis in a Cohort of Italian Patients with Suspected Inherited Myopathies and/or HyperCKemia.

Introduction/Aims HyperCKemia is considered a hallmark of neuromuscular diseases. It can be either isolated or associated with cramps, myalgia, weakness, myoglobinuria, or rhabdomyolysis, suggesting a metabolic myopathy. The aim of this work was to investigate possible genetic causes in order to help diagnose patients with recurrent hyperCKemia or clinical suspicion of inherited metabolic myopathy. Methods A cohort of 139 patients (90 adults and 49 children) was analyzed using a custom panel containing 54 genes associated with hyperCKemia. Results A definite genetic diagnosis was obtained in 15.1% of cases, while candidate variants or variants of uncertain significance were found in a further 39.5%. Similar percentages were obtained in patients with infantile or adult onset, with some different causative genes. RYR1 was the gene most frequently identified, either with single or compound heterozygous variants, while ETFDH variants were the most common cause for recessive cases. In one patient, mRNA analysis allowed identifying a large LPIN1 deletion missed by DNA sequencing, leading to a certain diagnosis. Conclusion These data confirm the high genetic heterogeneity of hyperCKemia and metabolic myopathies. The reduced diagnostic yield suggests the existence of additional genes associated with this condition but also allows speculation that a significant number of cases presenting with hyperCKemia or muscle symptoms are due to extrinsic, not genetic, factors.

ACTB gene mutation in combined Dystonia-Deafness syndrome with parkinsonism: Expanding the phenotype and highlighting the long-term GPi DBS outcome.

We report a Dystonia-Deafness syndrome patient treated by pallidal Deep Brain Stimulation with significant long-term benefits. Our study expands and confirms the complex phenotypic spectrum of ACTB gene-related disorders and supports the effectiveness of pallidal stimulation on motor outcomes and quality of life in dystonia due to ACTB p.Arg183Trp heterozygosity.