Dataset Information

Case Report: Whole-Exome Sequencing With MLPA Revealed Variants in Two Genes in a Patient With Combined Manifestations of Spinal Muscular Atrophy and Duchenne Muscular Dystrophy.

ABSTRACT: Spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are two common kinds of neuromuscular disorders sharing various similarities in clinical manifestations. SMA is an autosomal recessive genetic disorder that results from biallelic mutations of the survival motor neuron 1 gene (SMN1; OMIM 600354) on the 5q13 chromosome. DMD is an X-linked disorder caused by defects in the DMD gene (OMIM 300377) on the X chromosome. Here, for the first time, we report a case from a Chinese family who present with clinical manifestations of both two diseases, including poor motor development and progressive muscle weakness. We identified a homozygous deletion in exons 7 and 8 of the SMN1 gene and a deletion in exon 50 of the DMD gene by whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA). This case expands our understanding of diagnosis for synchronous SMA and DMD and highlights the importance of various genetic testing methods, including WES, in differential diagnosis of neuromuscular diseases.

SUBMITTER: Xia Y

PROVIDER: S-EPMC7987946 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Case Report: Whole-Exome Sequencing With MLPA Revealed Variants in Two Genes in a Patient With Combined Manifestations of Spinal Muscular Atrophy and Duchenne Muscular Dystrophy.

Xia Yu Y Feng Yijie Y Xu Lu L Chen Xiaoyang X Gao Feng F Mao Shanshan S

Frontiers in genetics 20210310

Spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are two common kinds of neuromuscular disorders sharing various similarities in clinical manifestations. SMA is an autosomal recessive genetic disorder that results from biallelic mutations of the survival motor neuron 1 gene (<i>SMN1</i>; OMIM 600354) on the 5q13 chromosome. DMD is an X-linked disorder caused by defects in the <i>DMD</i> gene (OMIM 300377) on the X chromosome. Here, for the first time, we report a case from a C ...[more]

PMID: 33777091

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Project description:BackgroundNeuromuscular disorders (NMD) commonly affect the upper extremity. Due to muscle weakness, performance of daily activities becomes increasingly difficult, which leads to reduced independence and quality of life. In order to support the performance of upper extremity tasks, dynamic arm supports may be used. The Yumen Arm is a novel dynamic arm support specially developed for people with NMD. The aim of this study is to evaluate the feasibility and effectiveness of the Yumen Arm in persons with Duchenne Muscular Dystrophy (DMD) and persons with Spinal Muscular Atrophy (SMA).MethodsThree persons with DMD and three persons with SMA participated in this study. All participants conducted a set of measures with and without the Yumen Arm. Outcome measures were: active range of motion of the arm and trunk (i.e. Reachable Workspace, Functional Workspace, and trunk movement), fatigue (OMNI-RPE), Performance of Upper Limb (PUL) scale and some additional activities of daily living. User experiences were collected using a questionnaire.ResultsThe Yumen Arm could be used by all participants. Results showed a median increase in active range of motion (4% relative surface area), and a median increase of function ability (> 11% PUL score) when using the Yumen Arm. In addition, three out of four (data from 2 participants was missing) participants indicated that activity performance was less fatiguing when using the Yumen Arm. Four out of five (data from 1 participant was missing) participants indicated that they would like to use the Yumen Arm in their daily lives.ConclusionThis study is one of the first studies describing a range of objective measures to examine the effectiveness of a dynamic arm support. Based on these measurements we can conclude that the Yumen Arm effectively improves arm function in NMD patients, however the effectiveness varies a lot between individual subjects. We provided detailed recommendations for the improvement of the Yumen Arm, and possible also for the development of other dynamic arm supports. This study showed a lot of variability between individual subjects, which emphasizes the importance of tuning dynamic arm supports based on individual user characteristics, such as scoliosis, functional capacity and muscle strength.

Project description:Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA's metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.

Dataset Information

Case Report: Whole-Exome Sequencing With MLPA Revealed Variants in Two Genes in a Patient With Combined Manifestations of Spinal Muscular Atrophy and Duchenne Muscular Dystrophy.

Publications

Case Report: Whole-Exome Sequencing With MLPA Revealed Variants in Two Genes in a Patient With Combined Manifestations of Spinal Muscular Atrophy and Duchenne Muscular Dystrophy.

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