Infantile facioscapulohumeral muscular dystrophy revisited: Expansion of clinical phenotypes in patients with a very short EcoRI fragment

Chen, Tai‐Heng; Lai, Yu Hung; Lee, Pei Lun; Hsu, Jong Hau; Goto, Kanako; Hayashi, Yukiko; Nishino, Ichizo; Lin, Chin Wen; Shih, Hsiang-Hung; Huang, Chao; Liang, W.; Wang, Wen Fu; Jong, Yuh Jyh

doi:10.1016/j.nmd.2013.01.005

Cited by 43 publications

(51 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars apparent before 5 years, and shoulder weakness before 10 years of age (22). Muscle weakness is often accompanied by extramuscular manifestations, including high-frequency hearing loss, retinal vasculopathy, and cognitive impairment as well as occasional cardiac and respiratory symptoms (24,30,85). This severe form of FSHD1 further supports the existence of genetic or epigenetic modifiers of disease severity, as discussed next.…”

Section: Fshd Genetics and Clinical Presentationmentioning

confidence: 73%

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Himeda

Jones

2015

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Significance: Aberrant epigenetic regulation is an integral aspect of many diseases and complex disorders. Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, is caused by disrupted genetic and epigenetic regulation of a macrosatellite repeat. FSHD provides a powerful model to investigate disease-relevant epigenetic modifiers and general mechanisms of epigenetic regulation that govern gene expression. Recent Advances: In the context of a genetically permissive allele, the one aspect of FSHD that is consistent across all known cases is the aberrant epigenetic state of the disease locus. In addition, certain mutations in the chromatin regulator SMCHD1 (structural maintenance of chromosomes hinge-domain protein 1) are sufficient to cause FSHD2 and enhance disease severity in FSHD1. Thus, there are multiple pathways to generate the epigenetic dysregulation required for FSHD. Critical Issues: Why do some individuals with the genetic requirements for FSHD develop disease pathology, while others remain asymptomatic? Similarly, disease progression is highly variable among individuals. What are the relative contributions of genetic background and environmental factors in determining disease manifestation, progression, and severity in FSHD? What is the interplay between epigenetic factors regulating the disease locus and which, if any, are viable therapeutic targets? Future Directions: Epigenetic regulation represents a potentially powerful therapeutic target for FSHD. Determining the epigenetic signatures that are predictive of disease severity and identifying the spectrum of disease modifiers in FSHD are vital to the development of effective therapies.

show abstract

Section: Fshd Genetics and Clinical Presentationmentioning

confidence: 73%

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Himeda

Jones

2015

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

show abstract

“…The hypothesis that central nervous system signs present later in life is unlikely attributed to the suspected underlying genetic mechanisms 11, 50. The most likely explanation for the discrepancy with previous studies on early‐onset FSHD8, 11, 13 is selection and publication bias of the published cases.…”

Section: Discussionmentioning

confidence: 85%

“…8 In literature, early-onset FSHD is often described as a severe subtype associated with one to three D4Z4 repeats, severe muscle weakness, and frequent systemic complications, including epilepsy, hearing difficulties, retinal abnormalities (Coats' syndrome), intellectual disability, and cardiac arrhythmias. [8][9][10][11][12][13][14] Currently, FSHD in childhood is often perceived as synonymous to early-onset FSHD. Therefore, FSHD in childhood is frequently described as being a severely affected subgroup.…”

mentioning

confidence: 99%

Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study

Goselink

Schreuder

Alfen

et al. 2018

Annals of Neurology

View full text Add to dashboard Cite

ObjectiveFacioscapulohumeral dystrophy (FSHD) is one of the most frequent heritable muscular dystrophies, with a large variety in age at onset and disease severity. The natural history and molecular characteristics of FSHD in childhood are incompletely understood. Our objective is to clinically and genetically characterize FSHD in childhood.MethodsWe performed a nationwide, single‐investigator, natural history study on FSHD in childhood.ResultsMultiple‐source recruitment resulted in 32 patients with FSHD (0–17 years), leading to an estimated prevalence of 1 in 100,000 children in The Netherlands. This series of 32 children with FSHD revealed a heterogeneous phenotype and genotype in childhood. The phenotypic hallmarks of FSHD in childhood are: facial weakness with normal or only mildly affected motor performance, decreased functional exercise capacity (6‐minute walk test), lumbar hyperlordosis, and increased echo intensity on muscle ultrasonography. In addition, pain and fatigue were frequent and patients experienced a lower quality of life compared to healthy peers. In contrast to the literature on early‐onset FSHD, systemic features such as hearing loss and retinal and cardiac abnormalities were infrequent and subclinical, and epilepsy and intellectual disability were absent. Genotypically, patients had a mean D4Z4 repeat array of 5 units (range, 2–9), and 14% of the mutations were de novo.InterpretationFSHD in childhood is more prevalent than previously known and the genotype resembles classic FSHD. Importantly, FSHD mainly affects functional exercise capacity and quality of life in children. As such, these results are paramount for counseling, clinical management, and stratification in clinical research. Ann Neurol 2018;84:635–645

show abstract

“…Systemic expression is relevant because D4Z4 misexpression in FSHD has not been shown to be restricted to myoblasts or muscle fibers. Indeed, the presence of non-muscle phenotypes such as retinal vascular pathology (Fitzsimons et al, 1987; Gieron et al, 1985; Small, 1968) and sensorineural hearing loss (Brouwer et al, 1991; Lutz et al, 2013)in FSHD patients, the syndrome of phenotypes associated with very severe infantile FSHD cases with extremely short D4Z4 arrays (Chen et al, 2013), together with the demonstration of epigenetic changes also in the blood cells of FSHD patients (Hartweck et al, 2013; van Overveld et al, 2003), suggests that misexpression is not restricted to muscle and might be a global feature. Remarkably, in our novel allele, we found that low-level leaky and variable expression led to several severe phenotypes, making the iDUX4(2.7) mouse the first animal model in which FSHD allele-specific DNA has been integrated into the genome and caused a serious pathology.…”

Section: Discussionmentioning

confidence: 99%

Dominant Lethal Pathologies in Male Mice Engineered to Contain an X-Linked DUX4 Transgene

et al. 2014

View full text Add to dashboard Cite

SUMMARY Facioscapulohumeral muscular dystrophy (FSHD) is an enigmatic disease associated with epigenetic alterations in the subtelomeric heterochromatin of the D4Z4 macrosatellite repeat. Each repeat unit encodes DUX4, a gene that is normally silent in most tissues. Besides muscular loss, most patients suffer retinal vascular telangiectasias. To generate an animal model, we introduced a doxycycline-inducible transgene encoding DUX4and 3′genomic DNA into a euchromatic region of the mouse X chromosome. Without induction, DUX4 RNA was expressed at low levels in many tissues and animals displayed a variety of unexpected dominant leaky phenotypes, including male-specific lethality. Remarkably, rare live-born males expressed DUX4 RNA in the retina and presented a retinal vascular telangiectasia. By using doxycycline to induce DUX4 expression in satellite cells, we observed impaired myogenesis in vitro and in vivo. This mouse model, which shows pathologies due to FSHD-related D4Z4 sequences, is likely to be useful for testing anti-DUX4 therapies in FSHD.

show abstract

Infantile facioscapulohumeral muscular dystrophy revisited: Expansion of clinical phenotypes in patients with a very short EcoRI fragment

Cited by 43 publications

References 27 publications

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study

Dominant Lethal Pathologies in Male Mice Engineered to Contain an X-Linked DUX4 Transgene

Contact Info

Product

Resources

About