Facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy: “Double trouble” overlapping syndrome?

Simeoni, Sara; Russo, Valentina; Gigli, Gian Luigi; Scalise, Anna

doi:10.1016/j.jns.2014.12.009

Cited by 6 publications

(6 citation statements)

References 11 publications

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“…Numerous genetic muscular disorders phenotypically overlap with LGMD, as limb-girdle weakness is one of their common symptoms. NGS-based genetic analyses can resolve clinical dilemmas and facilitate exact diagnosis [ 35 – 37 ]. Additionally, with the reporting of new cases, the spectrum of clinical manifestations of mutations in a given gene is likely to expand.…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients

et al. 2018

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BackgroundLimb girdle muscular dystrophies (LGMD) are a group of heterogeneous hereditary myopathies with similar clinical symptoms. Disease onset and progression are highly variable, with an elusive genetic background, and around 50% cases lacking molecular diagnosis.MethodsWhole exome sequencing (WES) was performed in 73 patients with clinically diagnosed LGMD. A filtering strategy aimed at identification of variants related to the disease included integrative analysis of WES data and human phenotype ontology (HPO) terms, analysis of genes expressed in muscle, analysis of the disease-associated interactome and copy number variants analysis.ResultsGenetic diagnosis was possible in 68.5% of cases. On average, 36.3 rare variants in genes associated with various muscle diseases per patient were found that could relate to the clinical phenotype. The putative causative mutations were mostly in LGMD-associated genes, but also in genes not included in the current LGMD classification (DMD, COL6A2, and COL6A3). In three patients, mutations in two genes were suggested as the joint cause of the disease (CAPN3+MYH7, COL6A3+CACNA1S, DYSF+MYH7). Moreover, a variety of phenotype-influencing variants were postulated, including in patients with an identified already known primary pathogenic mutation.ConclusionsWe hypothesize that LGMD could be better described as oligogenic disorders in which dominant clinical presentation can result from the combined effect of mutations in a set of genes. In this view, the inter- and intrafamilial variability could reflect a specific genetic background and the presence of sets of phenotype-influencing or co-causative mutations in genes that either interact with the known LGMD-associated genes or are a part of the same pathways or structures.Electronic supplementary materialThe online version of this article (10.1186/s40246-018-0167-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients

et al. 2018

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“…3 The substantial overlap and variability among each LGMD subtype in the age of onset, severity, and affected muscle groups, and the fact that cost of gene testing was previously unaffordable for patients, make definitive diagnosis highly elusive. 7 The lack of establishing a genotype prior to targeted therapeutic approaches obstructs recruitment of LGMD patients to available clinical trials. [8][9][10][11] Only five of the 12 LGMD trials are LGMD-subtype-specific.…”

Section: Introductionmentioning

confidence: 99%

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

Nallamilli

Chakravorty

Kesari

et al. 2018

Ann Clin Transl Neurol

130

165

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ObjectiveLimb‐girdle muscular dystrophies (LGMDs), one of the most heterogeneous neuromuscular disorders (NMDs), involves predominantly proximal‐muscle weakness with >30 genes associated with different subtypes. The clinical‐genetic overlap among subtypes and with other NMDs complicate disease‐subtype identification lengthening diagnostic process, increases overall costs hindering treatment/clinical‐trial recruitment. Currently seven LGMD clinical trials are active but still no gene‐therapy‐related treatment is available. Till‐date no nation‐wide large‐scale LGMD sequencing program was performed. Our objectives were to understand LGMD genetic basis, different subtypes’ relative prevalence across US and investigate underlying disease mechanisms.MethodsA total of 4656 patients with clinically suspected‐LGMD across US were recruited to conduct next‐generation sequencing (NGS)‐based gene‐panel testing during June‐2015 to June‐2017 in CLIA‐CAP‐certified Emory‐Genetics‐Laboratory. Thirty‐five LGMD‐subtypes‐associated or LGMD‐like other NMD‐associated genes were investigated. Main outcomes were diagnostic yield, gene‐variant spectrum, and LGMD subtypes’ prevalence in a large US LGMD‐suspected population.ResultsMolecular diagnosis was established in 27% (1259 cases; 95% CI, 26–29%) of the patients with major contributing genes to LGMD phenotypes being: CAPN3(17%), DYSF(16%), FKRP(9%) and ANO5(7%). We observed an increased prevalence of genetically confirmed late‐onset Pompe disease, DNAJB6‐associated LGMD subtype1E and CAPN3‐associated autosomal‐dominant LGMDs. Interestingly, we identified a high prevalence of patients with pathogenic variants in more than one LGMD gene suggesting possible synergistic heterozygosity/digenic/multigenic contribution to disease presentation/progression that needs consideration as a part of diagnostic modality.InterpretationOverall, this study has improved our understanding of the relative prevalence of different LGMD subtypes, their respective genetic etiology, and the changing paradigm of their inheritance modes and novel mechanisms that will allow for improved timely treatment, management, and enrolment of molecularly diagnosed individuals in clinical trials.

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“…Classical FSHD is primarily characterized by the asymmetric muscular deficit of the initial onset of facial and shoulder-girdle muscles, which descends to the lower limb muscle. However, D4Z4 contractions have also been reported in patients with atypical or overlapping symptoms, including SHD,[ 11 ] Duchenne muscular dystrophy[ 18 ]/Becker's muscular dystrophy (BMD),[ 19 ] limb-girdle muscular dystrophy (LGMD),[ 20 ] and caveolinopathy. [ 21 ] Interestingly, HPN was easily accompanied by muscular dystrophy or other syndromes, such as BMD[ 22 ] and dopamine beta-hydroxylase gene-related dysautonomia.…”

Section: Discussionmentioning

confidence: 99%

A “Triple Trouble” Case of Facioscapulohumeral Muscular Dystrophy Accompanied by Peripheral Neuropathy and Myoclonic Epilepsy

Lin

et al. 2018

Chinese Medical Journal

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Background:Facioscapulohumeral muscular dystrophy (FSHD) is characterized by asymmetric muscular deficit of facial, shoulder-girdle muscles, and descending to lower limb muscles, but it exists in several extramuscular manifestations or overlapping syndromes. Herein, we report a “complex disease plus” patient with FSHD1, accompanied by peripheral neuropathy and myoclonic epilepsy.Methods:Standard clinical assessments, particular auxiliary examination, histological analysis, and molecular analysis were performed through the new Comprehensive Clinical Evaluation Form, pulsed-field gel electrophoresis-based Southern blot, Multiplex Ligation-dependent Probe Amplification (MLPA), whole exome sequencing (WES), and targeted methylation sequencing.Results:The patient presented with mild facial weakness, humeral poly-hill sign, scapular winging, peroneal weakness, drop foot, pes cavus, and myoclonic epilepsy. Furthermore, electrophysiology revealed severely demyelinated and axonal injury. The muscle and nerve biopsy revealed broadly fiber Type II grouping atrophy and myelinated nerve fibers that significantly decreased with thin myelinated fibers and onion bulbs changes. Generalized sharp and sharp-slow wave complexes on electroencephalography support the diagnosis toward myoclonic epilepsy. In addition, molecular testing demonstrated a co-segregated 20-kb 4q35-EcoRI fragment and permissive allele A, which corresponded with D4Z4 hypomethylation status in the family. Both the patient's mother and brother only presented the typical FSHD but lacked overlapping syndromes. However, no mutations for hereditary peripheral neuropathy and myoclonic epilepsy were discovered by MLPA and WES.Conclusions:The present study described a “tripe trouble” with FSHD, peripheral neuropathy, and myoclonic epilepsy, adding the spectrum of overlapping syndromes and contributing to the credible diagnosis of atypical phenotype. It would provide a direct clue on medical care and genetic counseling.

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Facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy: “Double trouble” overlapping syndrome?

Cited by 6 publications

References 11 publications

Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients

Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

A “Triple Trouble” Case of Facioscapulohumeral Muscular Dystrophy Accompanied by Peripheral Neuropathy and Myoclonic Epilepsy

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