Inflammatory facioscapulohumeral muscular dystrophy type 2 in 18p deletion syndrome

Renard, Dimitri; Taïeb, Guillaume; Garibaldi, Matteo; Paula, André Maues De; Bernard, R.; Lagha, Nadira; Cristofari, Gaël; Vovan, Catherine; Chaix, C; Lévy, Nicolas; Kien, Philippe Khau Van; Sacconi, Sabrina

doi:10.1002/ajmg.a.38843

Cited by 7 publications

(4 citation statements)

References 12 publications

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“…This is also supported by a STIR‐T1 correspondence in the majority of muscles in the thigh and leg (Video 1 ). Evidence that STIR‐positive signal precedes the muscle degeneration has previously been reported in both acquired and genetic myopathies, such as idiopathic inflammatory myopathies and facioscapulohumeral muscular dystrophy [ 47 , 48 , 49 ] where STIR positivity corresponded to muscle edema and, more specifically, to inflammation [ 14 ]. To date, there is no evidence of an inflammatory process behind muscle degeneration in DM1 muscle biopsies.…”

Section: Discussionmentioning

confidence: 96%

Muscle magnetic resonance imaging in myotonic dystrophy type 1 (DM1): Refining muscle involvement and implications for clinical trials

Garibaldi

Nicoletti

Bucci

et al. 2021

Euro J of Neurology

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Background Only a few studies have reported muscle imaging data on small cohorts of patients with myotonic dystrophy type 1 (DM1). We aimed to investigate the muscle involvement in a large cohort of patients in order to refine the pattern of muscle involvement, to better understand the pathophysiological mechanisms of muscle weakness, and to identify potential imaging biomarkers for disease activity and severity. Methods One hundred and thirty‐four DM1 patients underwent a cross‐sectional muscle magnetic resonance imaging (MRI) study. Short tau inversion recovery (STIR) and T1 sequences in the lower and upper body were analyzed. Fat replacement, muscle atrophy and STIR positivity were evaluated using three different scales. Correlations between MRI scores, clinical features and genetic background were investigated. Results The most frequent pattern of muscle involvement in T1 consisted of fat replacement of the tongue, sternocleidomastoideus, paraspinalis, gluteus minimus, distal quadriceps and gastrocnemius medialis. Degree of fat replacement at MRI correlated with clinical severity and disease duration, but not with CTG expansion. Fat replacement was also detected in milder/asymptomatic patients. More than 80% of patients had STIR‐positive signals in muscles. Most DM1 patients also showed a variable degree of muscle atrophy regardless of MRI signs of fat replacement. A subset of patients (20%) showed a ‘marbled’ muscle appearance. Conclusions Muscle MRI is a sensitive biomarker of disease severity alsofor the milder spectrum of disease. STIR hyperintensity seems to precede fat replacement in T1. Beyond fat replacement, STIR positivity, muscle atrophy and a ‘marbled’ appearance suggest further mechanisms of muscle wasting and weakness in DM1, representing additional outcome measures and therapeutic targets for forthcoming clinical trials.

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Section: Discussionmentioning

confidence: 96%

Muscle magnetic resonance imaging in myotonic dystrophy type 1 (DM1): Refining muscle involvement and implications for clinical trials

Garibaldi

Nicoletti

Bucci

et al. 2021

Euro J of Neurology

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“…D4Z4 repeat on the permissive 4q allele, with patients with FSHD2 homozygous for disease-permissive alleles being more frequently symptomatic, 23 and with the observation that patients carrying an 18p deletion that includes SMCHD1 can develop FSHD only when carrying a permissive 4qA allele with a D4Z4 repeat <20 RU. 24,42,43 Larger patient cohorts are required to determine the upper limit of D4Z4 repeat size in which SMCHD1 disease-causing variants can still cause FSHD and to determine the penetrance.…”

Section: Discussionmentioning

confidence: 99%

FSHD1 and FSHD2 form a disease continuum

et al. 2019

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ObjectiveTo compare the clinical features of patients showing a classical phenotype of facioscapulohumeral muscular dystrophy (FSHD) with genetic and epigenetic characteristics of the FSHD1 and FSHD2 loci D4Z4 and SMCHD1.MethodsThis is a national multicenter cohort study. We measured motor strength, motor function, and disease severity by manual muscle testing sumscore, Brooke and Vignos scores, clinical severity score (CSS), and age-corrected CSS, respectively. We correlated these scores with genetic (D4Z4 repeat size and haplotype; SMCHD1 variant status) and epigenetic (D4Z4 methylation) parameters.ResultsWe included 103 patients: 54 men and 49 women. Among them, we identified 64 patients with FSHD1 and 20 patients with FSHD2. Seven patients had genetic and epigenetic characteristics of FSHD1 and FSHD2, all carrying repeats of 9–10 D4Z4 repeat units (RU) and a pathogenic SMCHD1 variant. In the remaining patients, FSHD was genetically excluded or remained unconfirmed. All clinically affected SMCHD1 mutation carriers had a D4Z4 repeat of 9–16 RU on a disease permissive 4qA haplotype. These patients are significantly more severely affected by all clinical scales when compared to patients with FSHD1 with upper-sized FSHD1 alleles (8–10 RU).ConclusionThe overlap between FSHD1 and FSHD2 patients in the 9–10 D4Z4 RU range suggests that FSHD1 and FSHD2 form a disease continuum. The previously established repeat size threshold for FSHD1 (1–10 RU) and FSHD2 (11–20 RU) needs to be reconsidered.Clinicaltrials.gov identifierNCT01970735.

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“…These 18p− patients with SMCHD1 among the deleted genes were found to have reduced D4Z4 repressive chromatin marks and express DUX4 in myonuclei when a permissive 4qA allele is present . Although these patients present a wide range of unrelated symptoms, FSHD clinical features were also detected in a few cases, demonstrating that the loss of one copy of SMCHD1 can cause FSHD2 . Furthermore, when FSHD2 patients have more than one permissive 4qA allele of appropriate size (ie, 1‐8 units in FSHD1, <20 in FSHD2), biallelic expression of DUX4 can occur, which can result in a higher susceptibility to disease presentation and could potentially cause a more severe FSHD phenotype …”

Section: D4z4 Chromatin Structure and The Role Of Smchd1mentioning

confidence: 99%

Consequences of epigenetic derepression in facioscapulohumeral muscular dystrophy

et al. 2020

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Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is caused either by the contraction of the D4Z4 macrosatellite repeat at the distal end of chromosome 4q to a size of 1 to 10 repeat units (FSHD1) or by mutations in D4Z4 chromatin modifiers such as Structural Maintenance of Chromosomes Hinge Domain Containing 1 (FSHD2). These two genotypes share a phenotype characterized by progressive and often asymmetric muscle weakening and atrophy, and common epigenetic alterations of the D4Z4 repeat. All together, these epigenetic changes converge the two genetic forms into one disease and explain the derepression of the DUX4 gene, which is otherwise kept epigenetically silent in skeletal muscle. DUX4 is consistently transcriptionally upregulated in FSHD1 and FSHD2 skeletal muscle cells where it is believed to exercise a toxic effect. Here we provide a review of the recent literature describing the progress in understanding the complex genetic and epigenetic architecture of FSHD, with a focus on one of the consequences that these epigenetic changes inflict, the DUX4-induced immune deregulation cascade. Moreover, we review the latest therapeutic strategies, with particular attention to the potential of epigenetic correction of the FSHD locus. K E Y W O R D S

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Inflammatory facioscapulohumeral muscular dystrophy type 2 in 18p deletion syndrome

Cited by 7 publications

References 12 publications

Muscle magnetic resonance imaging in myotonic dystrophy type 1 (DM1): Refining muscle involvement and implications for clinical trials

Muscle magnetic resonance imaging in myotonic dystrophy type 1 (DM1): Refining muscle involvement and implications for clinical trials

FSHD1 and FSHD2 form a disease continuum

Consequences of epigenetic derepression in facioscapulohumeral muscular dystrophy

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