This is the first European consensus recommendation for starting and stopping ERT in adult patients with Pompe disease, based on the extensive experience of experts from different countries.
Instability of simple DNA repeats has been known as a common cause of hereditary ataxias for over 20 years. Routine genetic diagnostics of these phenotypically similar diseases still rely on an iterative workflow for quantification of repeat units by PCR-based methods of limited precision.
We established and validated clinical nanopore Cas9-targeted sequencing (Clin-CATS), an amplification-free method for simultaneous analysis of ten repeat loci associated with clinically overlapping hereditary ataxias. The method combines target enrichment by CRISPR/Cas9, Oxford Nanopore long-read sequencing, and a bioinformatics pipeline utilizing the tools STRIque and Megalodon for parallel detection of length, sequence, methylation, and composition of the repeat loci.
Clin-CATS allowed for the precise and parallel analysis of 10 repeat loci associated with adult-onset ataxia and revealed additional parameter such as FMR1 promotor methylation and repeat sequence required for diagnosis at the same time. Using Clin-CATS we analyzed 100 clinical samples of undiagnosed ataxia patients and identified causative repeat expansions in 28 patients. Parallel repeat analysis enabled a molecular diagnosis of ataxias independent of preconceptions based on clinical presentation. Biallelic expansions within RFC1 were identified as the most frequent cause of ataxia. We characterized the RFC1 repeat composition of all patients and identified a novel repeat motif, AGGGG.
Our results highlight the power of Clin-CATS as a readily expandable workflow for the in-depth analysis and diagnosis of phenotypically overlapping repeat expansion disorders.
Genetic diagnosis of facioscapulohumeral muscular dystrophy (FSHD) remains a challenge in clinical practice as it cannot be detected by standard sequencing methods despite being the third most common muscular dystrophy. The conventional diagnostic strategy addresses the known genetic parameters of FSHD: the required presence of a permissive haplotype, a size reduction of the D4Z4 repeat of chromosome 4q35 (defining FSHD1), or a pathogenic variant in an epigenetic suppressor gene (consistent with FSHD2). Incomplete penetrance and epistatic effects of the underlying genetic parameters as well as epigenetic parameters (D4Z4 methylation) pose challenges to diagnostic accuracy and hinder prediction of clinical severity.
In order to circumvent the known limitations of conventional diagnostics and to complement genetic parameters with epigenetic ones, we developed and validated a multistage diagnostic workflow that consists of a haplotype analysis and a high throughput methylation profile analysis (FSHD-MPA). FSHD-MPA determines the average global methylation level of the D4Z4 repeat array as well as the regional methylation of the most distal repeat unit by combining bisulfite conversion with next-generation sequencing (NGS) and a bioinformatics pipeline and uses these as diagnostic parameters. We applied the diagnostic workflow to a cohort of 148 patients and compared the epigenetic parameters based on FSHD-MPA to genetic parameters of conventional genetic testing. In addition, we studied the correlation of repeat length and methylation level within the most distal repeat unit with age-corrected clinical severity and age at disease onset in FSHD patients. The results of our study show that FSHD-MPA is a powerful tool to accurately determine the epigenetic parameters of FSHD, allowing discrimination between FSHD patients and healthy individuals, while simultaneously distinguishing FSHD1 and FSHD2. The strong correlation between methylation level and clinical severity indicates that the methylation level determined by FSHD-MPA accounts for differences in disease severity among individuals with similar genetic parameters. Thus, our findings further confirm that epigenetic parameters rather than genetic parameters represent FSHD disease status and may serve as a valuable biomarker for disease status.
SARS-CoV-2/COVID-19 und neuromuskuläre ErkrankungenBestandsaufnahme der DGN (Deutsche Gesellschaft für Neurologie) Kommission Motoneuron-und neuromuskuläre ErkrankungenIn dieser Bestandsaufnahme werden das aktuell publizierte Wissen zu den primären Auswirkungen einer SARS-CoV-2-Infektion/COVID-19-Erkrankung auf das periphere Nervensystem und die Muskulatur sowie zu den sekundären Verschlechterungen präexistenter neuromuskulärer Erkrankungen durch eine SARS-CoV-2-/COVID-19-Erkrankung zusammengefasst und Empfehlungen daraus abgeleitet.
Infektion mit SARS-CoV-2 als neuromuskuläre PrimäraffektionHäufig fragen Patient*innen mit einer neuromuskulären Erkrankung ihre behandelnden Ärzt*innen nach dem persönli-
Rippling muscle disease is a rare autosomal dominant disorder first described in 1975. Recently, it could be classified as a caveolinopathy; in European families, mutations in the caveolin-3 gene were revealed as causing this disease. Although clinical symptoms were almost all described in adulthood, we are now reporting clinical data of seven children with rippling muscle disease owing to mutations in the caveolin-3 gene. Initial symptoms were frequent falls, inability to walk on heels, tiptoe walking with pain and a warm-up phenomenon, calf hypertrophy, and an elevated serum creatine kinase level. Percussion-/pressure-induced rapid contractions, painful muscle mounding, and rippling could be observed even in early childhood. The diagnosis can be confirmed by molecular genetic analysis. Muscle biopsy must be considered in patients without muscle weakness or mechanical hyperirritability to differentiate between rippling muscle disease and limb-girdle muscular dystrophy 1C.
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