Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

Pascual‐Morena, Carlos; Cavero‐Redondo, Iván; Saz‐Lara, Alicia; Sequí‐Domínguez, Irene; Lucerón‐Lucas‐Torres, Maribel; Martínez‐Vizcaíno, Vicente

doi:10.3390/ph14080798

Cited by 14 publications

(11 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The phenotypic discordant between brothers in terms of serum CK levels was observed since infancy, suggesting the involvement of congenital modi ers. Several modi er genes are being identi ed for DMD [13][14][15], and their involvement in the phenotypic discordant between the brothers should be investigated in the future.…”

Section: Discussionmentioning

confidence: 99%

Brothers with Becker muscular dystrophy, born a year apart, show marked difference in atrophy of the glutes maximus and vastus femoris muscles at adulthood

Nambu

Shirakawa

Osawa

et al. 2022

Preprint

View full text Add to dashboard Cite

Background Becker muscular dystrophy (BMD) is characterized by a progressive muscular atrophy caused by a truncated dystrophin produced by the mutant DMD gene. The onset and progression patterns of muscle atrophy in BMD are diverse, and previous reports attribute this to differences in the structure of the dystrophin produced. Therefore, it is expected that patients with BMD in the same family express the same truncated dystrophin and grow up in a similar environment, resulting in a similar progression of muscle atrophy. However, we report on brothers with BMD, who were only one year apart in age, showed marked differences in atrophy of the gluteus maximus and vastus femoris muscles on computed tomography (CT) scan at adulthood. Case presentation A retrospective analysis of clinical data from nine pairs of BMD siblings under follow-up at the Department of Pediatrics, Kobe University Hospital, revealed significant differences in clinical findings in only one pair. Brothers who were 1 year apart had identical deletions of exon 45-47 (Δ45-47) in the DMD gene, yet serum creatine kinase (CK) levels were higher in the older brother than in the younger brother at most ages from infancy to adulthood, and the median CK level was significantly higher in the older brother (4763 versus 3513 U /L, p < 0.01). Both the older brother (age 20) and younger brother (age 19) were able to walk independently, and motor function did not differ markedly between the brothers. To examine skeletal muscle damage in the brothers, CT examinations were performed to measure and compare cross-sectional area (CSA) and average CT values of a total of 10 different muscles in the upper arm, gluteal, and thigh. No significant differences in CSA and mean CT values were found between the brothers in the two upper arm muscles, but there were marked differences in CT values between the brothers in the gluteus maximus muscle in the gluteal region and the vastus femoris muscle in the thighs. The CSA of the gluteus maximus and vastus femoris muscles of the older brother was only 1/2 (2,380 vs. 4,756 mm2) and 1/3 (1,506 vs. 4,507 mm2) of that of the younger brother, respectively, and his gluteal and vastus atrophy was more pronounced than that of his younger brother. The mean CT values of the gluteus maximus and vastus femoris of the older brother were very low compared to those of the younger brother (-9.9 vs. 11.8 HU and -18.1 vs. 33.5, respectively), and despite the 1-year age difference, the adiposity of the gluteus maximus and vastus femoris of the older brother was more pronounced than that of the younger brother. Conclusions Brothers with BMD having identical DMD mutations, a 1-year age difference, and nearly identical growing environment developed significant differences in the gluteus maximus and vastus femoris atrophy. It strongly suggests that muscle atrophy in BMD may be regulated by factors other than DMD genotype or environmental factors.

show abstract

Section: Discussionmentioning

confidence: 99%

Brothers with Becker muscular dystrophy, born a year apart, show marked difference in atrophy of the glutes maximus and vastus femoris muscles at adulthood

Nambu

Shirakawa

Osawa

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Genetic modifiers are separate genetic loci that alter the phenotype of a genetic disorder. SPP1 , CD40 , and LTBP4 are among the genes recently recognized as genetic modifiers of the dystrophinopathies 21,22 …”

Section: Geneticsmentioning

confidence: 99%

The Dystrophinopathies

Lee¹

2022

CONTINUUM: Lifelong Learning in Neurology

View full text Add to dashboard Cite

PURPOSE OF REVIEW: This article reviews the history, epidemiology, genetics, clinical presentation, multidisciplinary management, and established and emerging therapies for the dystrophinopathies.RECENT FINDINGS: The multidisciplinary care of individuals with dystrophinopathies continues to improve in many ways, including early surveillance and implementation of respiratory, cardiac, and orthopedic health management. The era of genetic therapeutics has altered the treatment landscape in neuromuscular disorders, including the dystrophinopathies.SUMMARY: The dystrophinopathies are a spectrum of X-linked genetic disorders characterized by childhood-onset progressive weakness and variable cardiac and cognitive involvement. Corticosteroids are the mainstay of therapy to slow disease progression. Additional strategies for disease amelioration and dystrophin restoration, including gene replacement therapy, are under investigation.

show abstract

“…Additionally, there is evidence of progressive reduction of satellite cells (SC) and their myogenic capacity due to constant muscle injury and turnover, which leads to myofiber loss and replacement by fibrotic tissue in DMD patients 13,14 . Chronic inflammation and ECM degradation also alters the muscle niche that supports SC function, while genetic modifiers that affect the ECM alter disease severity in DMD patients [15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

Altered muscle niche contributes to myogenic deficit in the D2-mdxmodel of severe DMD

Mázala

Hindupur

Moon

et al. 2023

Preprint

View full text Add to dashboard Cite

Lack of dystrophin is the genetic basis for the Duchenne muscular dystrophy (DMD). However, disease severity varies between patients, based on specific genetic modifiers. D2-mdx is a model for severe DMD that exhibits exacerbated muscle degeneration and failure to regenerate even in the juvenile stage of the disease. We show that poor regeneration of juvenile D2-mdx muscles is associated with enhanced inflammatory response to muscle damage that fails to resolve efficiently and supports excessive accumulation of fibroadipogenic progenitors (FAPs). Unexpectedly, the extent of damage and degeneration of juvenile D2-mdx muscle is reduced in adults and is associated with the restoration of the inflammatory and FAP responses to muscle injury. These improvements enhance myogenesis in the adult D2-mdx muscle, reaching levels comparable to the milder (B10-mdx) mouse model of DMD. Ex vivo co-culture of healthy satellite cells (SCs) with the juvenile D2-mdx FAPs reduced their fusion efficacy and in vivo glucocorticoid treatment of juvenile D2 mouse improved muscle regeneration. Our findings indicate that aberrant stromal cell response contributes to poor myogenesis and greater muscle degeneration in dystrophic juvenile D2-mdx muscles and reversal of this reduces pathology in adult D2-mdx mouse muscle, identifying these as therapeutic targets to treat dystrophic DMD muscles.

show abstract

Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

Cited by 14 publications

References 63 publications

Brothers with Becker muscular dystrophy, born a year apart, show marked difference in atrophy of the glutes maximus and vastus femoris muscles at adulthood

Brothers with Becker muscular dystrophy, born a year apart, show marked difference in atrophy of the glutes maximus and vastus femoris muscles at adulthood

The Dystrophinopathies

Altered muscle niche contributes to myogenic deficit in the D2-mdxmodel of severe DMD

Contact Info

Product

Resources

About