Background and Objectives:Enzyme replacement therapy has not only significantly improved motor outcome and survival in patients with classic infantile Pompe disease, but also revealed previously unrecognized central nervous system (CNS) involvement. In this international study, involving patients from the Netherlands, Italy, Argentina, Germany, the United Kingdom, and Taiwan, we investigated whether epilepsy should be considered part of the CNS phenotype. Methods:We included patients with classic infantile Pompe disease, defined by the presence of hypertrophic cardiomyopathy, symptom onset < 6 months of age, complete acid α-glucosidase (GAA) deficiency, and/or 2 severe variants in the GAA gene, who developed epilepsy. Data on epilepsy characteristics, electroencephalogram (EEG), cognitive testing, serum neurofilament light chain (NfL), and brain magnetic resonance imaging (MRI) were retrospectively collected. Results:Seventeen patients from 10 centers were identified. The median follow-up duration was 13.7 years (range 3.3-19). Seven patients had deceased at the time of analysis. The median age at first seizure was 11.5 years (range 2.5-17.5). Seizure semiology was variable: six patients experienced generalized tonic-clonic seizures and 3 focal seizures with impaired consciousness only; 6 had multiple seizure types, and 7 experienced seizures during fever or infection. Seizure frequency varied considerably (in 9 occasionally, 5 monthly, 2 weekly, 1 daily). The most common EEG findings were a slowed background activity and focal epileptiform discharges, not substantially activated by sleep. Levetiracetam was most frequently used as antiseizure medication. Overall, 70% of patients became seizure-free. Serum NfL was elevated in all 6 patients in whom it was measured, and 8 of 10 patients had an intelligence quotient ≤66 at onset of epilepsy. Although brain MRI was not always performed at the age of first seizure, 14 of 15 patients showed white matter abnormalities, which were extensive in 11 of 14 (score ≥7/12). Brain atrophy was present in 9 cases and calcifications in 4. Discussion:Our findings suggest a potential increased frequency of seizures in classic infantile Pompe disease in comparison with unaffected children, occurring predominantly after the age of 7, and that epilepsy is part of the CNS phenotype. The risk of seizures should be evaluated during follow-up in long-term survivors with classic infantile Pompe disease.
Background and Objectives:Facioscapulohumeral muscular dystrophy (FSHD) includes approximately 10%-30% sporadic cases, where de novo pathogenic variants are hypothesized to be associated with more severe phenotypes. However, the systematic clinical characteristics and natural history of these cases remain poorly defined. Methods:This retrospective observational cohort study was conducted at the Fujian Neuromedical Center, enrolling patients with genetically confirmed FSHD who were classified as de novo (dnFSHD) when no pathogenic D4Z4 contraction was detected in blood samples from either available parent. Clinical and genetic parameters at baseline and during subsequent evaluations were compared between dnFSHD and familial FSHD (fFSHD). The fFSHD cohort was matched for sex and disease duration. Mediation analysis was applied to explore the relationships among de novo pathogenic variants, the number of D4Z4 repeats, and disease progression. Results:A total of 92 patients with genetically confirmed FSHD who were classified as de novo cases were included, representing 17.8% of all FSHD type 1 cases. Compared with fFSHD, patients with dnFSHD exhibited an earlier age at onset (median: 10 years vs 16 years, p < 0.0001), higher clinical score (median: 8 vs 6, p = 0.0001), and smaller number of D4Z4 repeat units (RUs) (median: 3 vs 5, p < 0.0001). Survival analysis revealed significantly increased risks in patients with dnFSHD for lower extremity involvement (hazard ratio 1.55, p = 0.021). Mediation analysis indicated that D4Z4 RUs mediated 72% of the correlation between dnFSHD and lower extremity involvement and 48% of the association with age-corrected clinical severity scale. Discussion:This study establishes dnFSHD as a distinct, high-risk FSHD subtype characterized by unique clinical features, with its severe phenotype primarily mediated by a shorter D4Z4 repeat array.
Background and Objectives:Early-onset Parkinson disease (EOPD), defined as symptom onset before 50 years of age, accounts for approximately 10% of patients and is suggested to have a greater genetic component than typical late-onset forms of the disease. Recessive variants in PRKN, PINK1, and DJ-1, are the most common genetic cause of EOPD, however, most studies are in patients of white ancestry. This study aims to analyze genetic variants in PRKN, PINK1, and DJ-1 in Colombian patients to help address the gap in EOPD genetic research of South American populations. Methods:We analyzed 43 unrelated patients with EOPD using Sanger sequencing for the PRKN, PINK1, and DJ-1 genes and employed multiplex ligation-dependent probe amplification to detect copy number variants. Additionally, long-read whole-genome sequencing was conducted on 3 unresolved patients with age at onset before 30 years of age (long-read sequencing [LRS] patient A-C). Results:We identified known pathogenic single-nucleotide variants and copy number variants in the PRKN gene accounting for 2 patients' disease (4.6% of patients). We observed 2 pathogenic variants in PRKN (c.155delA; p.N52Mfs*29 and c.1083+1G>A) in patient 1, who reported an age at onset of 16 years. We further detected a homozygous duplication of PRKN exons 5-6 in an additional patient, age at onset of 18 years. Discussion:Our study helps characterize genetic contributors to EOPD in Colombian patients, demonstrating genetic forms (PRKN, PINK1, and DJ-1) are rare. Our results highlight a need to include diverse populations in research to improve genetic understanding of disease.
Objectives:Spinocerebellar ataxia 27B (SCA27B) is a recently discovered genetic cause of idiopathic late-onset cerebellar ataxia (ILOCA) due to guanine-adenine-adenine (GAA) repeat expansions (greater than 250) in FGF14. We aimed to identify and characterize a New Zealand cohort of patients with SCA27B. Methods:Patients with previous negative ataxia panels were identified from electronic records and tested with an updated ataxia repeat expansion panel including FGF14 and 5 other new genes. Results:Updated genetic testing for 11 of the 29 patients returned a positive result: repeat expansions in FGF14 in 9, RFC1 (associated with cerebellar ataxia, neuropathy, vestibular areflexia syndrome) in 1, and TBP (associated with SCA17) in 1. In the 9 patients with SCA27B, the clinical characteristics such as initial episodic symptoms and late age at onset (mean 56 years), were like those reported in European cohorts. Two patients in our cohort had palatal tremor. While 7 patients had a repeat expansion length greater than 250, 2 patients with a clinical phenotype consistent with SCA27B had between 200 and 250 repeats. Discussion:In our New Zealand cohort of patients with ILOCA, updated genetic testing revealed a diagnosis in 38%. SCA27B is a common cause of ILOCA in this cohort.
Background and Objectives:Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL), caused by pathogenic NOTCH3 variants, can be misdiagnosed as multiple sclerosis (MS) due to overlapping clinical and radiologic features. Although initially described in European cohorts, prevalence of pathogenic NOTCH3 variants may be higher among Asian populations. Misdiagnosis may delay appropriate management and expose patients to ineffective and potentially harmful therapies. This study aimed to estimate the proportion of CADASIL patients with prior MS misdiagnosis presenting to a multicenter tertiary-care cohort and to identify associated clinical and genetic features and consequences of this diagnostic error. Methods:We conducted a retrospective cohort study to compare genetically or histopathologically confirmed CADASIL patients with and without a prior MS misdiagnosis. Patients were classified into high-risk, medium-risk, low-risk, or unknown-risk by the location of their NOTCH3 variant in the epidermal growth factor-like repeat (EGFr) domain. Prespecified logistic regression models were used to evaluate factors independently associated with MS misdiagnosis, adjusting for age, sex, race, and prior stroke history. Results:Of 107 CADASIL patients (mean age 57.5 ± 13.4 years), 11 (10.2%) were misdiagnosed with MS. In prespecified adjusted logistic regression models, absence of prior stroke (adjusted odds ratio [OR] 4.60; 95% CI 1.02-20.68), Asian race (adjusted OR 20.74; 95% CI 3.21-134.18), asymmetric external capsule white matter hyperintensity (WMH) (adjusted OR 53.34; 95% CI 4.06-701.08), and absence of infratentorial WMH (adjusted OR 12.48; 95% CI 1.90-82.01) were independently associated with misdiagnosis. The median time to diagnostic correction was 14.45 months (range 1.18-138.07), during which 5 patients (45.5%) received unnecessary MS therapies and 2 experienced documented adverse events. Medium-risk EGFr variants were more frequent among misdiagnosed patients in unadjusted comparisons but were not independently associated after adjustment. Discussion:In this multicenter tertiary-care cohort, approximately 1 in 10 patients with CADASIL had been misdiagnosed as MS, an error associated with Asian race, absence of a stroke history, and atypical neuroimaging patterns leading to worse functional outcomes and inappropriate treatments. A high index of suspicion for CADASIL is critical in patients presenting with atypical or late-onset demyelinating disease. Larger studies are needed to understand the role of medium-risk variants in misdiagnosis.
