TY  - JOUR
AB  - Slowly progressive proximal muscle weakness in an otherwise healthy male posed particular challenges for the treating physicians, considering the wide range of possible differentials. Here we present a case of a 52-year-old male with paraparesis, elevated creatine kinase-levels, antibodies against the Mi-2 antigen and subtle skin lesions, leading to subsequent treatment for dermatomyositis. Beyond that, exome sequencing revealed biallelic variants in the gene encoding acid alpha-glucosidase with concordant reduced enzymatic activity in fibroblasts, indicating late onset Pompe disease. Subsequently performed magnetic resonance imaging revealed a pattern of involvement typical for LOPD, but histological workup from the vastus lateralis muscle was more indicative of an immune-mediated myopathy. After treatment for dermatomyositis and Pompe disease the patient showed an improvement in skin changes and a halt in muscular weakness. In conclusion, both entities could be seen in the patient. However, early and prolonged subclinical hyper-CK-emia hinted at Pompe disease as the primary entity.
AU  - Keritam, O.*
AU  - Haas, P.*
AU  - Klotz, S.*
AU  - Kastrati, K.*
AU  - Krenn, M.*
AU  - Wagner, M.
AU  - Hasenoehrl, T.*
AU  - Weng, R.*
AU  - Zulehner, G.*
AU  - Kasprian, G.*
AU  - Regelsberger, G.*
AU  - Kiener, H.*
AU  - Gelpi, E.*
AU  - Zimprich, F.*
AU  - Cetin, H.*
AU  - Scherer, T.*
AU  - Jengojan, S.*
C1  - 75826
C2  - 58099
TI  - Dermatomyositis masking late onset Pompe disease in a patient with proximal muscle weakness.
JO  - J. Neuromuscul. Dis.
PY  - 2025
SN  - 2214-3599
ER  - 

TY  - JOUR
AB  - HNRNPA1 variants are known to cause degenerative motoneuron and muscle diseases which manifests in middle age or later. We report on a girl with early childhood onset, rapidly progressive generalized myopathy including ultrastructural findings in line with a proteinopathy. Proteomics of patient-derived muscle and combined screening of genomic data for copy number variations identified a HNRNPA1 de novo intragenic deletion as causative for the phenotype. Our report expands the spectrum of HNRNPA1-related diseases towards early-childhood onset and adds HNRNPA1 to the growing list of ALS and myopathy genes for which certain mutations may cause severe pediatric phenotypes.
AU  - Roos, A.*
AU  - Häusler, M.*
AU  - Kollipara, L.*
AU  - Töpf, A.*
AU  - Preusse, C.*
AU  - Stucka, R.*
AU  - Nolte, K.W.*
AU  - Strom, T.*
AU  - Berutti, R.
AU  - Jiang, X.*
AU  - Koll, R.*
AU  - Lochmüller, H.*
AU  - Schacht, S.M.*
AU  - Zahedi, R.P.*
AU  - Weis, J.*
AU  - Senderek, J.*
C1  - 71443
C2  - 56176
CY  - Nieuwe Hemweg 6b, 1013 Bg Amsterdam, Netherlands
SP  - 1131-1137
TI  - HNRNPA1 de novo variant associated with early childhood onset, rapidly progressive generalized myopathy.
JO  - J. Neuromuscul. Dis.
VL  - 11
IS  - 5
PB  - Ios Press
PY  - 2024
SN  - 2214-3599
ER  - 

TY  - JOUR
AB  - BACKGROUND: The importance of early diagnosis of 5q-Spinal muscular atrophy (5q-SMA) has heightened as early intervention can significantly improve clinical outcomes. In 96% of cases, 5q-SMA is caused by a homozygous deletion of SMN1. Around 4 % of patients carry a SMN1 deletion and a single-nucleotide variant (SNV) on the other allele. Traditionally, diagnosis is based on multiplex ligation probe amplification (MLPA) to detect homozygous or heterozygous exon 7 deletions in SMN1. Due to high homologies within the SMN1/SMN2 locus, sequence analysis to identify SNVs of the SMN1 gene is unreliable by standard Sanger or short-read next-generation sequencing (srNGS) methods. OBJECTIVE: The objective was to overcome the limitations in high-throughput srNGS with the aim of providing SMA patients with a fast and reliable diagnosis to enable their timely therapy. METHODS: A bioinformatics workflow to detect homozygous SMN1 deletions and SMN1 SNVs on srNGS analysis was applied to diagnostic whole exome and panel testing for suggested neuromuscular disorders (1684 patients) and to fetal samples in prenatal diagnostics (260 patients). SNVs were detected by aligning sequencing reads from SMN1 and SMN2 to an SMN1 reference sequence. Homozygous SMN1 deletions were identified by filtering sequence reads for the ,, gene-determining variant" (GDV). RESULTS: 10 patients were diagnosed with 5q-SMA based on (i) SMN1 deletion and hemizygous SNV (2 patients), (ii) homozygous SMN1 deletion (6 patients), and (iii) compound heterozygous SNVs in SMN1 (2 patients). CONCLUSIONS: Applying our workflow in srNGS-based panel and whole exome sequencing (WES) is crucial in a clinical laboratory, as otherwise patients with an atypical clinical presentation initially not suspected to suffer from SMA remain undiagnosed.
AU  - Kleinle, S.*
AU  - Scholz, V.*
AU  - Benet-Pages, A.
AU  - Wohlfrom, T.*
AU  - Gehling, S.*
AU  - Scharf, F.*
AU  - Rost, S.*
AU  - Prott, E.C.*
AU  - Grinzinger, S.*
AU  - Hotter, A.*
AU  - Haug, V.*
AU  - Niemeier, S.*
AU  - Wiethoff-Ubrig, L.*
AU  - Hagenacker, T.*
AU  - Goldhahn, K.*
AU  - von Moers, A.*
AU  - Walter, M.*
AU  - Reilich, P.*
AU  - Eggermann, K.*
AU  - Kraft, F.*
AU  - Kurth, I.*
AU  - Erdmann, H.*
AU  - Holinski-Feder, E.*
AU  - Neuhann, T.*
AU  - Abicht, A.*
C1  - 68133
C2  - 54611
CY  - Nieuwe Hemweg 6b, 1013 Bg Amsterdam, Netherlands
SP  - 835-846
TI  - Closing the Gap - Detection of 5q-spinal muscular atrophy by short-read Next-generation sequencing and unexpected results in a diagnostic patient cohort.
JO  - J. Neuromuscul. Dis.
VL  - 10
IS  - 5
PB  - Ios Press
PY  - 2023
SN  - 2214-3599
ER  - 

TY  - JOUR
AB  - BACKGROUND: Early-onset myopathies are a heterogeneous group of neuromuscular diseases with broad clinical, genetic and histopathological overlap. The diagnostic approach has considerably changed since high throughput genetic methods (next generation sequencing, NGS) became available. OBJECTIVE: We present diagnostic subgroups in a single neuromuscular referral center and describe an algorithm for the diagnostic work-up. METHODS: The diagnostic approach of 98 index patients was retrospectively analysed. In 56 cases targeted sequencing of a known gene was performed, in 44 patients NGS was performed using large muscle specific panels, and in 12 individuals whole exome sequencing (WES) was undertaken. One patient was diagnosed via array CGH. Clinical features of all patients are provided. RESULTS: The final diagnosis could be found in 63 out of 98 patients (64%) with molecular genetic analysis. In 55% targeted gene sequencing could establish the genetic diagnosis. However, this rate largely depended on the presence of distinct histological or clinical features. NGS (large myopathy-related panels and WES) revealed genetic diagnosis in 58.5% (52% and 67%, respectively). The genes detected by WES in our cohort of patients were all covered by the panels. Based on our findings we propose an algorithm for a practical diagnostic approach.Prevalences:MTM1- and LAMA2-patients are the two biggest subgroups, followed by SEPN1-, RYR1- and Collagen VI-related diseases. 31% of genetically confirmed cases represents a group with overlap between "congenital myopathies (CM)" and "congenital muscular dystrophies (CMD)". In 36% of the patients a specific genetic diagnosis could not be assigned. CONCLUSIONS: A final diagnosis can be confirmed by high throughput genetic analysis in 58.5% of the cases, which is a higher rate than reported in the literature for muscle biopsy and should in many cases be considered as a first diagnostic tool. NGS cannot replace neuromuscular expertise and a close discussion with the geneticists on NGS is mandatory. Targeted candidate gene sequencing still plays a role in selected cases with highly suspicious clinical or histological features. There is a relevant clinical and genetic overlap between the entities CM and CMD.
AU  - Vill, K.*
AU  - Blaschek, A.*
AU  - Gläser, D.*
AU  - Kuhn, M.*
AU  - Haack, T.B.
AU  - Alhaddad, B.
AU  - Wagner, M.
AU  - Kovács-Nagy, R.*
AU  - Tacke, M.*
AU  - Gerstl, L.*
AU  - Schroeder, A.S.*
AU  - Borggraefe, I.*
AU  - Mueller, C.*
AU  - Schlotter-Weigel, B.*
AU  - Schoser, B.*
AU  - Walter, M.C.*
AU  - Müller-Felber, W.*
C1  - 53010
C2  - 44262
SP  - 315-325
TI  - Early-onset myopathies: Clinical findings, prevalence of subgroups and diagnostic approach in a single neuromuscular referral center in Germany.
JO  - J. Neuromuscul. Dis.
VL  - 4
IS  - 4
PY  - 2017
SN  - 2214-3599
ER  -