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.
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.
Autosomal recessive forms of limb-girdle muscular dystrophy are caused by biallelic loss of function variants. Haplosufficient carriers are hypothesized to have sufficient protein expression to maintain normal physical function. This study aims to determine relative protein expression in haplosufficient carriers of 3 subtypes of autosomal recessive LGMD: LGMDR1 (CAPN3, calpain-3), LGMDR9 (FKRP, FKRP), and LGMDR3 (SGCA, α-sarcoglycan). In addition, this study clarifies fukutin-related protein (FKRP) enzymatic functionality in LGMDR9 carriers. Individuals affected with LGMDR1, R9, and R3 and corresponding carriers provided a muscle biopsy following a physical examination. RNA-seq analysis was performed to determine global gene-expression patterns. Gene expression of CAPN3, FKRP, and SGCA were determined using RNA-seq normalized counts, and relative quantification of disease-associated proteins was determined by western blotting. Carriers of LGMDR1 were found to have approximately 25% total calpain-3 expression compared with noncarrier controls, while LGMDR9 carriers had nearly 50% functionality of FKRP. LGMDR3 carriers exhibited α-sarcoglycan and β-sarcoglycan protein levels comparable with controls. Carriers of several autosomal-recessive LGMDs have reduced expression of disease-related proteins compared with noncarrier controls with associated reduced protein functionality. Since these haplosufficient carriers have normal physical strength, this degree of protein expression may represent the threshold to restore haplosufficient status after gene replacement therapy.
Structural neurovascular lesions (SNVLs)-arteriovenous malformations, cavernous malformations, and vein of Galen aneurysmal malformations, among others-have historically been treated using neurosurgical, radiotherapeutic, and endovascular approaches. However, lesion size, location, and presence of high-risk angioarchitectural features preclude many patients from receiving these treatments. Advances in human genetics and cerebrovascular biology have redefined SNVLs as dynamic, genetically driven lesions where sporadic cases are caused by somatic variants. Intriguingly, many SNVL-causing variants are also oncogenic and active drug targets. These data provide the rationale for a genetically driven taxonomy to guide targeted therapeutic selection. In this commentary, we synthesize efforts toward pharmacologic treatments of SNVLs and highlight how variant-specific or pathway-modulating therapies may be investigated, incorporating key considerations in molecular diagnosis, cerebrovascular biology, and molecular and phenotypic outcome measures, in forthcoming clinical trials. Together, these advances support the investigation of pharmacologic treatment strategies in carefully selected patients with SNVLs.
Background and Objectives Next-generation phenotyping (NGP) tools, such as GestaltMatcher, have revolutionized the diagnosis of rare genetic disorders through computational facial analysis. While NGP has been widely integrated into differential diagnosis workflows, its application in variant reclassification within the ACMG framework remains underexplored.Methods We applied GestaltMatcher to a 4-year-old patient with an undiagnosed neurodevelopmental disorder, suspected Mowat-Wilson syndrome (MWS), and a de novo ZEB2 variant. In addition to facial image analysis, we used the PEDIA framework, integrating Human Phenotype Ontology (HPO) terms and simulated exome data to refine variant prioritization. Bayesian likelihood modeling was used to establish Gestalt score thresholds for PP4 evidence levels (supporting, moderate, strong, and very strong). Brain MRI analysis was also performed to assess structural abnormalities characteristic of MWS.Results GestaltMatcher ranked MWS as the top differential diagnosis, and PEDIA integration further confirmed ZEB2 as the most likely disease-causing gene. Three of the patient's 4 facial images met the PP4 moderate threshold, while one met PP4 supporting. MRI analysis revealed subtle corpus callosum thinning, consistent with MWS. In addition, an exploratory case of an infant with molecularly confirmed MWS demonstrated the capability of GestaltMatcher to prioritize the diagnosis solely based on infant facial features.Discussion This study highlights the potential of NGP-driven facial phenotyping and multimodal integration in dysmorphology. The results support the broader application of AI-assisted phenotyping to improve diagnostic accuracy, particularly in neurodevelopmental disorders with distinct facial features.
Background and Objectives:Emerging genetic therapies and the expansion of genetic testing are identifying individuals carrying amyotrophic lateral sclerosis (ALS) risk variants who would benefit from surveillance and early intervention. Anticipating the geographic distribution and clinical needs of this population is essential for optimizing care delivery and ensuring readiness as new therapies become available. We estimate the number of individuals in the United States carrying ALS risk variants and project the clinical engagement required to support this population. This is especially timely because ALS clinics are already grappling with rising numbers of patients with symptomatic ALS and deep funding cuts. Methods:We developed a population model to estimate the number of symptomatic individuals with gene-positive ALS and asymptomatic gene carriers across US states over the next decade (year 1: 2026). State-level ALS prevalence and incidence were calculated using 2 approaches: (1) race-adjusted ALS rates from the Atlanta metropolitan study applied to 2023 Census demographics and (2) observed state-level ALS case counts from the National ALS Registry (2011-2018). Gene-positive cases were estimated using published frequencies of SOD1, C9orf72, FUS, and TARDBP pathogenic variants. At-risk relatives were modeled assuming autosomal-dominant inheritance with ∼5 first-degree and ∼7 second-degree living relatives per proband, and broad uptake of cascade genetic testing. Surveillance needs were modeled as 1 annual visit per asymptomatic carrier, which was normalized by the number of ALS centers per state. Results:In year 1 (2026), the model estimated 2,704 symptomatic gene-positive ALS carriers. With an average of 4.25 carrier relatives per proband, 10,944 asymptomatic carriers were projected nationwide. Most states required <50 additional visits per clinic annually, with 12 states in the 50-99 range and none exceeding 100. By year 10 (2035), the model projected 7,474 symptomatic and 26,111 asymptomatic carriers. State-level demand shifted substantially: only 6 states remained below 50 visits per clinic annually; 22 reached 50-99; 18 reached 100-199; and 3 exceeded 200. Discussion:Gene-targeted testing is projected to substantially increase ALS clinic visits among asymptomatic gene carriers. While current infrastructure may accommodate the initial rise, within a decade, most states will require significant expansion. Anticipating and planning for this growth now is essential to ensure seamless integration of gene-positive individuals into ALS care.
Background and Objectives:Hemizygous variants in B-cell receptor-associated protein 31 (BCAP31) can cause deafness, dystonia, and cerebral hypomyelination syndrome, which typically presents in infancy. Methods:We performed whole-exome sequencing in a family with 2 affected individuals who exhibited congenital hearing loss and adult-onset motor symptoms, including Parkinson disease (PD) and cerebellar ataxia. To assess the frequency of BCAP31 variants, we analyzed 234 Japanese individuals with either recessively inherited familial PD or early-onset PD using Sanger sequencing. Results:Whole-exome sequencing identified a novel BCAP31 variant (c.302G>A; p.Arg101Lys) shared by both individuals. The proband developed parkinsonism in early adulthood; responded well to levodopa; and later exhibited wearing-off phenomena, dyskinesias, and cerebellar signs. Sanger sequencing of a Japanese population with PD identified 3 additional BCAP31 variants; however, all 3 variants were predicted to be benign and showed no enrichment compared with public databases. Discussion:This report links a BCAP31 variant to adult-onset PD. Our findings suggest that BCAP31 should be considered in male patients with early-onset PD and atypical features such as congenital deafness and cerebellar involvement.
Background and ObjectivesThe ABCC9 gene encodes the widely expressed SUR2 subunit of ATP-sensitive potassium (KATP) channels. Autosomal recessive loss-of-function variants in ABCC9 cause ABCC9-related Intellectual disability and Myopathy Syndrome (AIMS). Here, we sought to compile multiple case reports from previously unidentified individuals with the primary objective of further establishing the clinical consequences of ABCC9 variants.MethodsWe combine multiple case reports with genetic diagnoses and functional tests of recombinant KATP channels.ResultsWe report 5 cases of AIMS, including a neonate, and a woman who presented as a sexagenarian with signs of dementia. All variants are predicted to lead to nonsense mediated decay of ABCC9 transcripts and/or drastic truncation of SUR2. Functional tests of recombinant channels confirm that disease-associated SUR2 truncations cause a complete loss-of-function. These new cases further demonstrate the prominence of white matter abnormalities resembling periventricular leukomalacia or small vessel disease as a key hallmark of the disorder, alongside developmental delay, intellectual impairment, seizures, and fatigability. These latest findings also highlight neonatal presentation of disease, deterioration following surgical procedures, and the potential for motor and cognitive decline, which should be monitored in older individuals.DiscussionThese findings provide new insights into the spectrum of pathology and natural history of AIMS. This new cohort underscores that AIMS is characterized by the combination of periventricular leukomalacia, developmental delay and intellectual disability, and muscle weakness and fatigability - and is driven by biallelic loss-of-function variants in ABCC9.
Background and ObjectivesAutosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease caused by pathogenic variants in SACS. ARSACS is characterized by mitochondrial abnormalities and disruptions of the neurofilament cytoskeleton. In other conditions, these features have been linked to activation of Sterile Alpha and TIR Motif Containing 1 (SARM1), an enzyme that can trigger axon degeneration and neuronal death. Inhibition of SARM1 is an attractive therapeutic strategy because SARM1 is inactive in healthy cells and knockout of SARM1 has little or no deleterious effects. We therefore asked whether SARM1 activity contributed to Purkinje cell degeneration and motor defects present in a Sacs-/- mouse model of ARSACS.MethodsWe studied 4 cohorts of mice: (1) Sacs -/-; Sarm1+/+; (2) Sacs +/+; Sarm1+/-; (3) Sacs -/-; Sarm1 +/-; and (4) Sacs -/-; Sarm1 -/-. In 9-month-old mice, we analyzed protein markers of Purkinje cells (n = 3-4 mice per genotype) and counted surviving Purkinje cells in folia III, IV, and VIII of cerebellar sections (n = 3 mice per genotype, 6 sections per mouse), and tested motor function at 3, 6, and 9 months by quantifying parameters of gait (Digigait) and coordination and balance (Rotarod) (8 male, 8 female mice of each genotype).ResultsProbing of cerebellar extracts showed that the Purkinje cell protein markers Calbindin-1, RGS8, and PCP2 were decreased in Sacs-/- mice but restored to normal levels in Sacs -/-; Sarm1-/- mice. Purkinje cell loss in Sacs-/- mice was most prominent in anterior folia, as previously noted. Sarm1 loss partially mitigated the Purkinje cell death in folium III of 9-month-old Sacs-/- mice. Similarly, longitudinal behavioral assessment of motor functions showed that disturbances in gait pattern (slower cadence, prolonged swing, and stance phases) were partially alleviated. Rotarod tests gave more ambivalent results, as the homozygous loss of Sarm1 was less effective than heterozygous loss in ameliorating the Sacs-/- phenotype.DiscussionWe conclude that SARM1 contributes to neurodegeneration in ARSACS, and its downregulation or inhibition could constitute a significant therapeutical strategy in the treatment of the disease.
Background and ObjectivesColony-stimulating factor receptor 1-related disorder (CSF1R-RD) is an underrecognized, adult-onset genetic leukodystrophy with a devastating clinical course. Disease monitoring is critical as patients with CSF1R-RD can benefit from hematopoietic stem cell transplantation. Here, we aimed to compare blood neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels between patients with CSF1R-RD and those with alternative diagnoses and to correlate blood biomarkers values with clinical severity.MethodsWe analyzed 22 patients with CSF1R-RD and patients with fronto-temporal lobar degeneration due to GRN pathogenic variants (GRN-FTLD, n = 22), CADASIL (N = 9), cerebral adrenoleukodystrophy (13), and primary progressive multiple sclerosis (n = 14).ResultsNfL and GFAP were elevated in CSF1R-RD and GRN-FTLD as compared with the other groups. After adjusting for age, GFAP was higher in patients with CSF1R-RD compared with those with GRN-FTLD (p = 0.035). Among CSF1R-RD patients, both NfL (p = 0.0054) and GFAP (p = 0.0065) correlated with Expanded Disability Status Scale scores. For a subset of patients with cognitive testing, GFAP correlated with the processing speed index of the Wechsler adult intelligence scale (p = 0.025) and state anxiety (p = 0.0088).DiscussionOur results show that blood NfL and GFAP are promising biomarkers of disease progression in patients with CSF1R-RD.
