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.
Background and Objectives:Anesthetic management for Charcot-Marie-Tooth disease (CMT) is still controversial and source of concerns for both anesthetists and patients. We explored the frequency of self-reported complications following anesthesia in a large cohort of patients with CMT compared with unaffected controls. Methods:We administered an online ad hoc questionnaire to patients enrolled in the Italian CMT Registry and to unaffected controls. The questionnaire collected self-reported adverse events following any anesthetic procedure undergone during the participants' lifetime. Anesthetic procedures were categorized as general anesthesia (including endotracheal intubation or deep sedation), central neuraxial anesthesia (epidural or spinal anesthesia), and peripheral regional anesthesia (plexus or peripheral nerve blocks). Results:Overall, the questionnaire was completed by 290 patients with CMT (160 female patients; mean age 47.8 ± 13.1 years) and 94 controls (46 female patients; mean age 47.5 ± 13.2 years), and a total of 508 and 161 procedures, respectively, were analyzed. The rate of self-reported complications following general, central neuraxial, and peripheral regional anesthesia did not differ between patients with CMT and controls. All reported events in the CMT cohort were transient and fully resolved, with a favorable anesthetic outcome in all cases. Demyelinating CMT subtypes were not more likely to report complications than axonal subtypes. Moreover, experienced complications following anesthesia for cesarean delivery occurred with similar frequency in patients with CMT and controls. Discussion:Anesthesia-related complications are not reported more frequently in patients with CMT compared with controls. However, longitudinal studies incorporating objective clinical assessments and detailed information on anesthetic agents are warranted.
The genetic complexity of ATXN2 challenges conventional paradigms in neurodegeneration. While initially linked to autosomal dominant spinocerebellar ataxia type 2, ATXN2 CAG expansions have emerged as a major risk factor for amyotrophic lateral sclerosis. In a recent article, Saucier et al. describe an Acadian family with a recessive inheritance pattern of ATXN2-related disease, challenging the long-held assumption of a predominantly autosomal dominant, gain-of-function-driven mechanism. Here, we analyze how ATXN2's inheritance mode may shift based on repeat interruptions, somatic mosaicism, and gene dosage, suggesting that loss-of-function mechanisms contribute to pathogenesis in certain contexts. We discuss implications for disease classification, genetic counseling, and therapeutic strategies, emphasizing the need for genetic stratification.
Background and Objectives:The aim of this study was to present a case report of the first familial case of multiple sclerosis (MS) in an X-linked Charcot-Marie-Tooth family with a novel variant in GJB1. Methods:Clinical, neurophysiologic, neuroimaging, and genetic assessments were performed on 9 affected members of a large X-linked Charcot-Marie-Tooth (CMTX) family, including 2 who also developed MS. The 2 family members with CMTX and MS were screened for pathogenic variants in 245 genes associated with MS. We tested 150 independent patients with MS, 48 familial and 102 sporadic for rare pathogenic variants in GJB1. Results:A novel missense pathogenic variant (c.502T > G, p.Cys168Gly) in GJB1 was detected in a large CMTX family. Two 5th-degree relatives developed typical MS in addition to CMTX. No additional pathogenic genetic variants were identified in 245 MS-associated genes in 2 MS patients with exome sequencing data. Furthermore, GJB1 pathogenic variants were not found in a cohort of 48 patients with familial and 102 with sporadic MS. Discussion:This is a novel report of a familial case of MS related to the novel variant in GJB1. Although our report adds additional evidence for the increased risk of MS in carriers of pathogenic variants in GJB1, we demonstrate that genetic variation in GJB1 is not a common risk factor, neither in familial nor sporadic MS.
Background and Objectives:ATP1A3-related disorders comprise an expanding group of ultra-rare neurologic conditions, classically including rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. However, accumulating reports suggest a broader and overlapping phenotypic spectrum. In this context, we established the ATP1A3 Study Group to comprehensively characterize the phenotypic and genotypic spectrum of ATP1A3-related disorders in a Brazilian cohort. Methods:We conducted a multicenter, cross-sectional study of individuals with ATP1A3 variants. Cases were recruited across reference centers in 9 Brazilian states, with standardized extraction of demographic, genetic, neuroimaging, EEG, ECG, and clinical data. Variants were annotated using transcript NM_152296.5 (hg19). AlphaFold was used for structural visualization. Multiple correspondence analysis (MCA) was performed to explore symptom clustering. This study was approved by the Ethics Committee of Federal University of São Paulo (Approval No.: 82533124.0.0000.5505). Results:A total of 41 patients with ATP1A3 variants were included. Seven phenotypic categories were represented: AHC (17/41), RDP (10/41), CAPOS (7/41), relapsing encephalopathy with cerebellar ataxia (RECA; 4/41), fever-induced paroxysmal weakness and encephalopathy (FIPWE; 1/41), developmental and epileptic encephalopathy 99 (DEE99; 1/41), and malformation of cortical development (MCD; 1/41). Two neonatal-onset cases (DEE99 and MCD) were fatal. We identified 22 distinct ATP1A3 variants, including 4 novel variants (p.Gln920His, p.Arg827Gly, p.Glu670Ala, and c.606+5G>T). Clinical overlap was substantial: Cognitive impairment and seizures occurred across all phenotypes; hypotonia was present in 6 of 7 main phenotypes; abnormal eye movements and fever-induced symptoms occurred in all except MCD; and paroxysmal symptoms were reported in all, except DEE99. MCA demonstrated no discrete clustering by classical phenotype, reinforcing the continuous nature of the ATP1A3 spectrum. ECG abnormalities were rare in our cohort (1/20). Discussion:Our findings expand the clinical and genetic landscape of ATP1A3-related disorders and underscore major phenotypic overlap among classical syndromes. The results highlight the need for a unified diagnostic framework. This study also demonstrates the feasibility and scientific value of coordinated rare disease research in resource-limited settings.
Objectives:To report the histopathologic features seen in congenital deafness and adult-onset leukoencephalopathy (DEAPLE) caused by biallelic pathogenic variants in KARS and expand on neuroradiologic features reported in other cases. Methods:We present the clinical, neuroimaging, and histopathologic findings of a patient with adult-onset, rapidly progressive leukodystrophy. Clinical information, genetic reports, neuroimaging, and postmortem brain pathology were collected and analyzed. Results:Compound heterozygous variants in KARS were found, including the previously reported (NM_001130089.1: c.683 C > T, p.P228L) pathogenic variant and a novel (NM_001130089.1: c.1609 C > T, p.R537W) variant of uncertain significance (VUS). Brain MRI revealed extensive, frontally predominant white matter abnormalities, involvement of the corticospinal tracts extending into the midbrain, and nodular contrast enhancement primarily in the bilateral occipital cortices and leptomeninges, noncontiguous with the white matter lesions. Autopsy 1 year later revealed frontally predominant atrophy of the white matter with relative preservation of the subcortical U-fibers, brainstem, and cerebellum; microcytic parenchymal degeneration and vacuolization; and numerous axonal spheroids. No inflammatory component was present in the occipital cortex or leptomeninges. Discussion:Our findings confirm the previously reported features of DEAPLE and suggest the possibility of a transient neuroinflammatory component associated with areas of active disease.
ObjectivesEmerging evidence suggests that the genetic architecture of Alzheimer disease (AD) and Parkinson disease (PD) risk varies across ancestries. This study seeks to explore distinct and universal genetic targets across individuals of Latino, African/African-admixed, East Asian, and European populations by implementing population attributable risk (PAR) comparisons using summary statistics from genome-wide association studies (GWASs). MethodsPAR was calculated for the most significant disease variants using summary statistics derived from select multi-ancestry GWAS meta-analyses, followed by fine-mapping analysis to validate genetic contribution of disease variants to European, African/African-admixed, East Asian, and Latino individuals. ResultsFor AD, APOE4 PAR estimates were universally high across all ancestries, with TSPAN14 and PICALM emerging as other common targets. Attributable risk varied across PD-related major risk loci, including variation nearby GBA1 and LRRK2. By contrast, SNCA, MCCC1, VPS13C, and MAPT loci demonstrated comparable attributable risk across ancestries. DiscussionThis cross-ancestry evaluation of PAR reinforces the genetic heterogeneity of AD and PD. In consideration of the complex etiology of these diseases, these findings may inform the strategic prioritization of therapeutic targets and improve global health outcomes.
Background and Objectives:Disease-causing variants in the syntaxin-binding protein 1 (STXBP1) gene are among the most common genetic causes of developmental and epileptic encephalopathies and are associated with a wide phenotypic spectrum. Qualitative neuroimaging studies are usually unrevealing or uncover variable MRI findings, including cortical atrophy, thin/dysmorphic corpus callosum (CC), hypo/delayed myelination, and focal cortical dysplasia (FCD). Methods:We used quantitative MRI methods to estimate abnormal brain properties of the cortical mantle and volume of subcortical structures in patients with STXBP1 encephalopathy and age- and sex-matched controls.We performed a region-of-interest group statistical analysis between patients with STXBP1 encephalopathy and controls by multivariable linear regression models to identify morphometric patterns and to evaluate the effect of the group (patients/controls) on morphometric features. We conducted a longitudinal analysis to estimate the volumetric changes in 4 patients with serial MRI scans at different ages. We calculated the association between the structural alterations and the known STXBP1 expression levels and explored associations between morphometric and volumetric features and clinical findings (age at seizure onset, intellectual disability [ID]) and genetic variants. Results:Our analysis included 24 patients and 48 controls and revealed widespread cortical thickening, reduced frontal and occipital surface area, and reduced white matter (left/right hemisphere p value = 0.005/0.022) and CC (p value < 0.050) volumes. The longitudinal analysis highlighted that brain growth trends were lower than the average trend in the control cohort. In patients with more severe ID, we observed a significantly increased volume of the lateral ventricles (left/right p value = 0.049/0.030) and CSF (p value = 0.019). Patients with missense variants exhibited more altered morphometric values and more severe reductions of white-matter volumes, possibly because of a dominant negative effect of variants. Two patients were operated for intractable focal seizures, and the histopathologic substrate was FCD-I. Discussion:The altered cortical patterns and WM reductions we observed in STXBP1 encephalopathy might be the structural counterpart of the widespread impaired neurotransmitter release caused by a dysfunctional syntaxin-binding protein. The 2 histopathologic observations we describe, bring to 4 the number of reported patients with STXBP1 encephalopathy and FCD-I, suggesting cortical dyslamination as the architectural substrate for the abnormal morphometric parameters and reduced surface areas.
