Identification of a methylation profile for DNMT1-associated autosomal dominant cerebellar ataxia, deafness, and narcolepsy

Background: DNA methylation is an essential epigenetic mark, controlled by DNA methyltransferase (DNMT) proteins, which regulates chromatin structure and gene expression throughout the genome. In this study, we describe a family with adult-onset autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN) caused by mutations in the maintenance methyltransferase DNMT1 and assess the DNA methylation profile of these individuals. Results: We report a family with six individuals affected with ADCA-DN; specifically, patients first developed hearing loss and ataxia, followed by narcolepsy, and cognitive decline. We identified a heterozygous DNMT1 variant, c.1709C\u3eT [p.Ala570Val] by Sanger sequencing, which had been previously reported as pathogenic for ADCA-DN and segregated with disease in the family. DNA methylation analysis by high-resolution genome-wide DNA methylation array identified a decrease in CpGs with 0–10 % methylation and 80–95 % methylation and a concomitant increase in sites with 10–30 % methylation and \u3e95 % methylation. This pattern suggests an increase in methylation of normally unmethylated regions, such as promoters and CpG islands, as well as further methylation of highly methylated gene bodies and intergenic regions. Furthermore, a regional analysis identified 82 hypermethylated loci with consistent robust differences across ≥5 consecutive probes compared to our large reference cohort. Conclusions: This report identifies robust changes in the DNA methylation patterns in ADCA-DN patients, which is an important step towards elucidating disease pathogenesis

Exome Sequencing as a Diagnostic Tool for Pediatric-Onset Ataxia

Ataxia demonstrates substantial phenotypic and genetic heterogeneity. We set out to determine the diagnostic yield of exome sequencing in pediatric patients with ataxia without a molecular diagnosis after standard-of-care assessment in Canada. FORGE (Finding Of Rare disease GEnes) Canada is a nation-wide project focused on identifying novel disease genes for rare pediatric diseases using whole-exome sequencing. We retrospectively selected all FORGE Canada projects that included cerebellar ataxia as a feature. We identified 28 such families and a molecular diagnosis was made in 13; a success rate of 46%. In 11 families, we identified mutations in genes associated with known neurological syndromes and in two we identified novel disease genes. Exome analysis of sib pairs and/or patients born to consanguineous parents was more likely to be successful (9/13) than simplex cases (4/15). Our data suggest that exome sequencing is an effective first line test for pediatric patients with ataxia where a specific single gene is not immediately suspected to be causative. © 2013 The Authors. *Human Mutation published by Wiley Periodicals, Inc

Abnormal fatty acid metabolism is a core component of spinal muscular atrophy

Objective: Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra-neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease. Methods: We analyzed clinical data collected from a large cohort of pediatric SMA type I-III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA. Results: We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn2B/- mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non-alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation. Interpretation: This work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

BACKGROUND: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population. METHODS: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials. RESULTS: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner. CONCLUSION: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients

Correction: Systematic prospective electrophysiological studies of the median nerve after simple distal radius fracture.

[This corrects the article DOI: 10.1371/journal.pone.0231502.]

Systematic prospective electrophysiological studies of the median nerve after simple distal radius fracture.

Purpose: To assess whether there is a measurable impairment of median nerve conduction study parameters with uncomplicated distal radius fracture.Methods: Patients were assessed prospectively at the time of cast removal (visit 1) after a standard 6-8 week immobilization for uncomplicated distal radius fracture. Patients with prior entrapment neuropathy or polyneuropathy were excluded. Patients were asked to report sensory symptoms. Median and ulnar motor and sensory conduction studies were performed bilaterally, as well as transcarpal stimulation. All electrophysiologic studies were repeated at a follow-up visit 2, on average 7.8 weeks later.Results: 39 patients were assessed at visit 1 and 30 (77%) were available for follow-up visit 2. Paresthesia in the median territory on the fractured side were reported in 20% at visit 1 and 26% at visit 2. Electrophysiological evidence of only mild carpal tunnel syndrome was found on the fractured side in 4/39 at visit 1 and 6/30 at visit 2. There were only 2 cases of moderate-marked median neuropathy, both asymptomatic and on the unfractured side. Median motor and sensory latencies and amplitudes did not show statistically significant differences between fractured and unfractured sides with the single exception of median distal motor latency at visit 1.Conclusions: Median territory paresthesia at the time of cast removal following distal radius fracture are often not associated with electrophysiologic evidence of median neuropathy. Most median nerve electrophysiologic parameters do not significantly differ between the fractured and uninjured sides. Significant traumatic median neuropathy is not likely to be a frequent manifestation of uncomplicated distal radius fracture.Level of evidence: Diagnostic analysis, Level III

Autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) associated with progressive cognitive and behavioral deterioration

Objective: Autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN) is an emerging syndrome caused by mutations in the C-terminus end of the TS domain of the DNMT1 gene. ADCA-DN is also associated with sensorimotor polyneuropathy, extrapyramidal, and dysautonomic signs, as well as dementia. Little has been reported about the progressive cognitive impairment associated with ADCA-DN. Our objective is to provide a detailed characterization of the cognitive profile of ADCA-DN. Method: Three members of a kindred with ADCA-DN underwent comprehensive neuropsychological testing and neuroimaging. Results: At baseline, 2 individuals demonstrated cognitive profiles with executive difficulties in some areas consistent with frontalsystem dysfunction behaviorally and on standardized testing. The third individual was further in the disease course and exhibited more globally impaired cognition consistent with a diagnosis of dementia. Conclusions: This family demonstrated progressive neurodegeneration beginning with isolated areas of executive dysfunction and leading to globally impaired cognition and dementia. Cognitive decline occurred in parallel with neurological deterioration. The cognitive profile is similar to case reports of other individuals with an allelic neurological phenotype, H

Dataset for worldwide survey of cerebrospinal total protein upper reference values

This article reports data pertaining to a worldwide web-based survey referenced in the publication “Adult CSF Total Protein: Higher upper reference limits should be considered worldwide ” (P.R. Bourque, et al., 2019). This survey was distributed to corresponding authors of the journal Neurology and the Journal of neurological sciences for the period of Jan–Dec 2017. The response rate was 36.9%. Additional results were collated through networking and national associations. There were 473 unique responses from clinical hospital laboratories in 69 countries: North America 178, South America 26, Europe 139, Africa 20, Asia 102 and Oceania 8. The upper reference limit for cerebrospinal fluid total protein ranged from 0.2 g/L to 0.8 g/L. 86.8% of the survey responses were 0.45 g/L or less. Data is presented separately for tertiary/academic and non-university/community centers

Identification of a methylation profile for DNMT1-associated autosomal dominant cerebellar ataxia, deafness, and narcolepsy

Abstract Background DNA methylation is an essential epigenetic mark, controlled by DNA methyltransferase (DNMT) proteins, which regulates chromatin structure and gene expression throughout the genome. In this study, we describe a family with adult-onset autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN) caused by mutations in the maintenance methyltransferase DNMT1 and assess the DNA methylation profile of these individuals. Results We report a family with six individuals affected with ADCA-DN; specifically, patients first developed hearing loss and ataxia, followed by narcolepsy, and cognitive decline. We identified a heterozygous DNMT1 variant, c.1709C>T [p.Ala570Val] by Sanger sequencing, which had been previously reported as pathogenic for ADCA-DN and segregated with disease in the family. DNA methylation analysis by high-resolution genome-wide DNA methylation array identified a decrease in CpGs with 0–10 % methylation and 80–95 % methylation and a concomitant increase in sites with 10–30 % methylation and >95 % methylation. This pattern suggests an increase in methylation of normally unmethylated regions, such as promoters and CpG islands, as well as further methylation of highly methylated gene bodies and intergenic regions. Furthermore, a regional analysis identified 82 hypermethylated loci with consistent robust differences across ≥5 consecutive probes compared to our large reference cohort. Conclusions This report identifies robust changes in the DNA methylation patterns in ADCA-DN patients, which is an important step towards elucidating disease pathogenesis