Mutation spectrum and phenotypic manifestation in FSHD Greek patients

Sakellariou, P.; Kekou, Kyriaki; Fryssira, Helen; Sofocleous, Christalena; Manta, Panagiota; Panousopoulou, Angeliki; Gounaris, K.; Kanavakis, Emmanuel

doi:10.1016/j.nmd.2011.11.001

Cited by 47 publications

(45 citation statements)

References 39 publications

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“…It has also been observed that FSHD affects males more severely and more frequently than females (Zatz et al , 1998; Tonini et al , 2004; Sakellariou et al , 2012). We thus evaluated whether gender influences expression and severity of motor impairment.…”

Section: Resultsmentioning

confidence: 99%

“…For the last 20 years the clinical diagnosis of FSHD has been supported by this type of D4Z4 DNA testing, which has been considered highly sensitive and specific for disease (Lunt et al , 1995 a , b ; Lunt, 1998; Tawil et al , 2010). However, several studies on FSHD families describe subjects carrying D4Z4 alleles of reduced size (DRA) and no signs of the disease, defined as non-penetrant carriers (Tawil et al , 1996; Zatz et al , 1998; Ricci et al , 1999; van Overveld et al , 2000; Goto et al , 2004; Tonini et al , 2004; Sakellariou et al , 2012; Scionti et al , 2012 a ). As a possible explanation of some non-penetrant cases, it has been proposed that reduction of D4Z4 repeats on chromosome 4q35 is pathogenic only in certain chromosomal backgrounds, defined by ‘permissive’ specific haplotypes, namely (i) reduction of D4Z4 elements; (ii) presence of the 4A(159/161/168) haplotype; and (iii) a single nucleotide polymorphism that provides a polyadenylation signal (PAS) for the DUX4 transcript (Lemmers et al , 2002, 2007, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Large scale genotype–phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy

Ricci

Scionti

Sera

et al. 2013

Brain

120

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Facioscapulohumeral muscular dystrophy has been genetically linked to reduced numbers (≤8) of D4Z4 repeats at 4q35 combined with 4A(159/161/168) DUX4 polyadenylation signal haplotype. However, we have recently reported that 1.3% of healthy individuals carry this molecular signature and 19% of subjects affected by facioscapulohumeral muscular dystrophy do not carry alleles with eight or fewer D4Z4 repeats. Therefore, prognosis for subjects carrying or at risk of carrying D4Z4 reduced alleles has become more complicated. To test for additional prognostic factors, we measured the degree of motor impairment in a large group of patients affected by facioscapulohumeral muscular dystrophy and their relatives who are carrying D4Z4 reduced alleles. The clinical expression of motor impairment was assessed in 530 subjects, 163 probands and 367 relatives, from 176 unrelated families according to a standardized clinical score. The associations between clinical severity and size of D4Z4 allele, degree of kinship, gender, age and 4q haplotype were evaluated. Overall, 32.2% of relatives did not display any muscle functional impairment. This phenotype was influenced by the degree of relation with proband, because 47.1% of second- through fifth-degree relatives were unaffected, whereas only 27.5% of first-degree family members did not show motor impairment. The estimated risk of developing motor impairment by age 50 for relatives carrying a D4Z4 reduced allele with 1–3 repeats or 4–8 repeats was 88.7% and 55%, respectively. Male relatives had a mean score significantly higher than females (5.4 versus 4.0, P = 0.003). No 4q haplotype was exclusively associated with the presence of disease. In 13% of families in which D4Z4 alleles with 4–8 repeats segregate, the diagnosis of facioscapulohumeral muscular dystrophy was reported only in one generation. In conclusion, this large-scale analysis provides further information that should be taken into account when counselling families in which a reduced allele with 4–8 D4Z4 repeats segregates. In addition, the reduced expression of disease observed in distant relatives suggests that a family’s genetic background plays a role in the occurrence of facioscapulohumeral muscular dystrophy. These results indicate that the identification of new susceptibility factors for this disease will require an accurate classification of families.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Large scale genotype–phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy

Ricci

Scionti

Sera

et al. 2013

Brain

120

View full text Add to dashboard Cite

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“…Even multiple cases of monozygotic twins with discordant FSHD phenotypes have been reported (60,149,154). Thus, there is more to developing clinical FSHD1 than the known diagnostic genetic lesion and overall, the FSHD1 clinical data are suggestive of a strong epigenetic component to disease onset, progression, and severity (3,58,78,127,128,136,140,153,170,178).…”

Section: Fshd Genetics and Clinical Presentationmentioning

confidence: 99%

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Himeda

Jones

2015

Antioxidants & Redox Signaling

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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.

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“…The systematic review identified one Class I study 33 demonstrating that in patients with FSHD, smaller D4Z4 repeat size is probably associated with more severe disease as measured by age at diagnosis and age at wheelchair dependence. Class II and Class III studies 29,[34][35][36] provided evidence that smaller fragment size is possibly associated with other measures of disease severity, including early age at onset, quantitative computerized muscle testing, severity of leg weakness, global severity scores, and earlier loss of ambulation.…”

mentioning

confidence: 99%

Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy

et al. 2015

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Objective: To develop recommendations for the evaluation, diagnosis, prognostication, and treatment of facioscapulohumeral muscular dystrophy (FSHD) from a systematic review and analysis of the evidence.Methods: Relevant articles were analyzed in accordance with the American Academy of Neurology classification of evidence schemes for diagnostic, prognostic, and treatment studies. Recommendations were linked to the strength of the evidence and other factors.

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Mutation spectrum and phenotypic manifestation in FSHD Greek patients

Cited by 47 publications

References 39 publications

Large scale genotype–phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy

Large scale genotype–phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy

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