Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. Conventional genetic diagnostics are low-throughput and may miss intronic, structural, or phenocopy variants, leading to delayed or missed diagnoses. In this study, we evaluate the utility of a custom next-generation sequencing (NGS) panel targeting the full-length ATP7B gene and 10 additional copper metabolism-related genes in patients with clinically suspected WD. We conducted a prospective cohort study of 144 individuals at our neurogenetic center. Variants identified by NGS were filtered and annotated with in silico tools and classified according to American College of Medical Genetics and Genomics guidelines. Confirmatory Sanger sequencing, multiplex ligation-dependent probe amplification, and reverse transcription PCR assays were performed as needed. Genetic confirmation of WD was achieved in 129 of 144 patients (90%), including 80 typical (Leipzig score ≥4) and 49 atypical (score <4) cases. Ten novel ATP7B variants, including deep intronic, noncanonical splice, and copy number variants, were identified using this panel. Among 15 genetically unresolved cases, 6 harbored variants in other copper metabolism-related genes but no pathogenic ATP7B variants. Notably, 1 patient with a Leipzig score of 4 had been clinically diagnosed with WD for years but was reclassified as spinocerebellar ataxia type 12 after panel testing revealed only a heterozygous CP variant and a CAG repeat expansion in PPP2R2B. Our comprehensive multigene NGS panel enables precise diagnosis of WD by detecting both classical and unconventional pathogenic variants, as well as distinguishing phenocopies. This improved diagnostic accuracy underscores the value of early genetic testing to guide timely intervention, especially in atypical or early-stage cases.

Spinocerebellar ataxia type 12 (SCA12) is a late-onset, autosomal dominant neurodegenerative disorder linked to a CAG repeat expansion mutation in the PPP2R2B gene and prevalent in Indian Agarwal ancestry. The pathophysiology of SCA12 and its clinical relevance need further elucidation. Dysregulation of mitochondrial quality control (mitochondrial QC), a critical determinant of neurodegeneration, could play a central role in SCA12 pathogenesis. In this study, 20 candidate genes regulating mitochondrial biogenesis, dynamics, mitophagy, mitochondrial transport, and protein folding were studied for their expression in SCA12 patient-derived peripheral blood mononuclear cells (PBMCs). Twenty-four genetically confirmed SCA12 patients and healthy controls were recruited in the study. The patients were assessed for motor severity using the International Cooperative Ataxia Rating Scale (ICARS). PBMCs were isolated from the peripheral blood. Total RNA was extracted from the PBMCs, which were reverse transcribed to make cDNA. The relative mRNA expression was estimated using quantitative Real-time PCR. Among the 20 candidate genes, a total of 5 genes, i.e., DNM1L, PPARGC1A, OPA1, NFE2L2, and BECN1, demonstrated a significantly reduced expression in SCA12 compared to healthy controls. There was no difference in the expression of other genes between groups. This study suggests dysregulation of mitochondrial biogenesis, mitophagy, dynamics, and antioxidant system converging towards a compromised mitochondrial QC system in SCA12 patients.

Spinocerebellar ataxia 12 (SCA12) is a progressive degenerative neurological disorder, primarily characterized by impaired coordination and balance. To investigate the correlation between proton (1H) magnetic resonance spectroscopy (MRS) and structural imaging indices in patients with SCA12. T1-weighted MRI, DTI, and single voxel MRS point resolved spectroscopy (PRESS) in the left hemispheric cerebellum were acquired using a 3-T MR scanner in 40 SCA12 patients and 25 healthy controls. Correlations between metabolites, gray and white matter volume of lobules, fractional anisotropy (FA), and clinical, nonclinical, and genetic data were examined. Three machine learning algorithms (KNN, LDA, and SVM) were used to analyze the metabolic feature differences between SCA12 and HC groups. Significant decreases in choline (Cho [GPC (glycerophosphocholine) + PCh (phosphocholine)]) and N-acetyl aspartate (NAA) levels, along with increases in myo-inositol ratios to creatine, FA, and white matter volume values (p < 0.05), were observed in the cerebellum of the SCA12 group compared to healthy controls. Positive correlations were observed between NAA levels and cerebellar lobule volume, the SPM IQ score with the right crus II in the SCA12 group. The International Cooperative Ataxia Rating Scale (ICARS) score showed a negative correlation with white matter and specific cerebellar lobules. Disease duration and cytosine, adenine, and guanine (CAG) repeat length were negatively correlated with right lobule VIIIB, lobule IX, and left lobule X. Machine learning algorithms achieved an accuracy of over 95% in MRS data, and 88.89% in volumetric data. MRS, VBM, and DTI techniques reveal neuronal degeneration in SCA12 compared to healthy individuals.

Spinocerebellar ataxia type 12 (SCA12) is a neurodegenerative disorder with prominent upper limb tremors. No trials have evaluated tremor-targeted therapies in this population. We evaluated long-acting propranolol for efficacy and safety in reducing tremors and improving ataxia and quality of life in SCA12. In this single-center, randomized, double-blind, placebo-controlled trial, 60 genetically confirmed SCA12 patients (aged 18-65 years; TETRAS PS [The Essential Tremor Rating Assessment Scale Performance Subscale] upper limb component ≥2) were randomized 1:1 to receive extended-release propranolol or placebo. Propranolol was escalated by 40 mg/week (placebo by one tablet/week) up to 240 mg/day, limiting side effects or ≥30% reduction in TETRAS PS/ADL (Activities-of-Daily-Living Subscale) + PS. The stable dose was continued for 8 weeks (maintenance phase). Primary outcomes were changes from baseline in TETRAS PS and ADL + PS at maintenance weeks 4 and 8. Secondary outcomes included changes in the Scale for the Assessment and Rating of Ataxia (SARA), RAND 36-Item Short-Form Health Survey (SF-36) domains, and accelerometric tremor parameters. Propranolol significantly reduced TETRAS PS (LSM ± SE: -4.4 ± 0.3 at week 4; -4.42 ± 0.4 at week 8) and ADL + PS (-5.5 ± 0.63 at week 4; -5.56 ± 0.62 at week 8; P < 0.001 vs. placebo). Significant improvements were also noted in SARA and five of nine SF-36 domains at both time points. Accelerometry confirmed reductions in tremor peak frequency and power in all positions except rest. Fatigue and headache were the commonest adverse effects, with no discontinuations due to adverse events. Propranolol effectively reduced tremors and improved quality of life in SCA12, with good tolerability. © 2025 International Parkinson and Movement Disorder Society.