scholarly journals Early-Onset Infantile Facioscapulohumeral Muscular Dystrophy: A Timely Review

2020 ◽  
Vol 21 (20) ◽  
pp. 7783
Author(s):  
Tai-Heng Chen ◽  
Yan-Zhang Wu ◽  
Yung-Hao Tseng
Keyword(s):  
Muscular Dystrophy ◽  
Early Onset ◽  
Case Reports ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Clinical Severity ◽  
Genetic Diagnostics ◽  
Rapid Decline ◽  
Novel Treatments ◽  
D4z4 Repeat ◽  
History Of

Facioscapulohumeral muscular dystrophy (FSHD)—the worldwide third most common inherited muscular dystrophy caused by the heterozygous contraction of a 3.3 kb tandem repeat (D4Z4) on a chromosome with a 4q35 haplotype—is a progressive genetic myopathy with variable onset of symptoms, distribution of muscle weakness, and clinical severity. While much is known about the clinical course of adult FSHD, data on the early-onset infantile phenotype, especially on the progression of the disease, are relatively scarce. Contrary to the classical form, patients with infantile FSHD more often have a rapid decline in muscle wasting and systemic features with multiple extramuscular involvements. A rough correlation between the phenotypic severity of FSHD and the D4Z4 repeat size has been reported, and the majority of patients with infantile FSHD obtain a very short D4Z4 repeat length (one to three copies, EcoRI size 10–14 kb), in contrast to the classical, slowly progressive, form of FSHD (15–38 kb). With the increasing identifications of case reports and the advance in genetic diagnostics, recent studies have suggested that the infantile variant of FSHD is not a genetically separate entity but a part of the FSHD spectrum. Nevertheless, many questions about the clinical phenotype and natural history of infantile FSHD remain unanswered, limiting evidence-based clinical management. In this review, we summarize the updated research to gain insight into the clinical spectrum of infantile FSHD and raise views to improve recognition and understanding of its underlying pathomechanism, and further, to advance novel treatments and standard care methods.

Early-onset facioscapulohumeral muscular dystrophy: two case reports

1997 ◽  
Vol 19 (8) ◽  
pp. 563-567 ◽  
Author(s):  
Akiko Okinaga ◽  
Taro Matsuoka ◽  
Jiro Umeda ◽  
Itaru Yanagihara ◽  
Koji Inui ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Early Onset ◽  
Case Reports ◽  
Facioscapulohumeral Muscular Dystrophy

scholarly journals Early onset as a marker for disease severity in facioscapulohumeral muscular dystrophy

Neurology ◽  
2018 ◽  
Vol 92 (4) ◽  
pp. e378-e385 ◽  
Author(s):  
Rianne J.M. Goselink ◽  
Karlien Mul ◽  
Caroline R. van Kernebeek ◽  
Richard J.L.F. Lemmers ◽  
Silvère M. van der Maarel ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Muscular Dystrophy ◽  
Disease Severity ◽  
Muscle Weakness ◽  
Early Onset ◽  
Disease Duration ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Work Status ◽  
Control Groups ◽  
Genetic Characteristics

ObjectiveTo assess the relation between age at onset and disease severity in facioscapulohumeral muscular dystrophy (FSHD).MethodsIn this prospective cross-sectional study, we matched adult patients with FSHD with an early disease onset with 2 sex-matched FSHD control groups with a classic onset; the first group was age matched, and the second group was disease duration matched. Genetic characteristics, muscle performance, respiratory functioning, hearing loss, vision loss, epilepsy, educational level, and work status were compared with the 2 control groups.ResultsTwenty-eight patients with early-onset FSHD were age (n = 28) or duration (n = 27) matched with classic-onset patients. Patients with early-onset FSHD had more severe muscle weakness (mean FSHD clinical score 11 vs 5 in the age-matched and 9 in the duration-matched group, p < 0.05) and a higher frequency of wheelchair dependency (57%, 0%, and 30%, respectively, p < 0.05). In addition, systemic features were more frequent in early-onset FSHD, most important, hearing loss, decreased respiratory function and spinal deformities. There was no difference in work status. Genetically, the shortest D4Z4 repeat arrays (2–3 units) were found exclusively in the early-onset group, and the largest repeat arrays (8–9 units) were found only in the classic-onset groups. De novo mutations were more frequent in early-onset patients (46% vs 4%).ConclusionsPatients with early-onset FSHD more often have severe muscle weakness and systemic features. The disease severity is greater than in patients with classic-onset FSHD who are matched for disease duration, suggesting that the progression is faster in early-onset patients.

scholarly journals Cardiac Involvement in Facioscapulohumeral Muscular Dystrophy (FSHD)

2021 ◽  
Vol 12 ◽  
Author(s):  
Allison Ducharme-Smith ◽  
Stefan Nicolau ◽  
C. Anwar A. Chahal ◽  
Kirstie Ducharme-Smith ◽  
Shujah Rehman ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Atrioventricular Block ◽  
Cardiac Involvement ◽  
Case Reports ◽  
Shoulder Girdle ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Reduced Ejection Fraction ◽  
Cardiac Abnormalities ◽  
Conduction Abnormality ◽  
Conduction Abnormalities

Background: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies and predominantly affects facial and shoulder girdle muscles. Previous case reports and cohort studies identified minor cardiac abnormalities in FSHD patients, but their nature and frequency remain incompletely characterized.Methods: We reviewed cardiac, neurological and genetic findings of 104 patients with genetically confirmed FSHD.Results: The most common conduction abnormality was complete (7%) or incomplete (5%) right bundle branch block (RBBB). Bifascicular block, left anterior fascicular block, complete atrioventricular block, and 2:1 atrioventricular block each occurred in 1% of patients. Atrial fibrillation or flutter were seen in 5% of patients. Eight percent of patients had heart failure with reduced ejection fraction and 25% had valvular disease. The latter included aortic stenosis in 6% (severe in 4% and moderate in 2%) and moderate aortic regurgitation in 8%. Mitral valve prolapse (MVP) was present in 9% of patients without significant mitral regurgitation. There were no significant associations between structural or conduction abnormalities and age, degree of muscle weakness, or size of the 4q deletion.Conclusions: Both structural and conduction abnormalities can occur in FSHD. The most common abnormalities are benign (RBBB and MVP), but more significant cardiac involvement was also observed. The presence of cardiac abnormalities cannot be predicted from the severity of the neurological phenotype, nor from the genotype.

Early-Onset Facioscapulohumeral Muscular Dystrophy Type 1 With Some Atypical Features

2014 ◽  
Vol 30 (5) ◽  
pp. 580-587 ◽  
Author(s):  
Małgorzata Dorobek ◽  
Silvère M. van der Maarel ◽  
Richard J. L. F. Lemmers ◽  
Barbara Ryniewicz ◽  
Dagmara Kabzińska ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Early Onset ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Atypical Features

scholarly journals A multinational study on motor function in early-onset FSHD

Neurology ◽  
2018 ◽  
Vol 90 (15) ◽  
pp. e1333-e1338 ◽  
Author(s):  
Jean K. Mah ◽  
Jia Feng ◽  
Marni B. Jacobs ◽  
Tina Duong ◽  
Kate Carroll ◽  
...  
Keyword(s):  
Motor Function ◽  
Early Onset ◽  
Age At Onset ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Clinical Severity ◽  
Manual Muscle Testing ◽  
Linear Regression Models ◽  
Facial Weakness ◽  
Muscle Testing ◽  
Severity Scores

ObjectivesTo investigate motor function associations with age, sex, and D4Z4 repeats among participants with early-onset facioscapulohumeral muscular dystrophy (FSHD) type 1 as defined by weakness onset before 10 years of age.MethodsWe collected standardized motor assessments, including manual muscle testing (MMT), quantitative muscle testing, functional motor evaluations, and clinical severity scores (CSSs), at 12 Cooperative International Neuromuscular Research Group centers. To measure associations, we used linear regression models adjusted for sex, evaluation age, age at onset of weakness, and D4Z4 repeats.ResultsAmong 52 participants (60% female, mean age 22.9 ± 14.7 years), weakness was most pronounced in the shoulder and abdominal musculature. Older enrollment age was associated with greater CSSs (p = 0.003). When adjusted for enrollment age, sex, and D4Z4 repeats, younger age at onset of facial weakness was associated with greater CSSs, slower velocities in timed function tests, and lower MMT scores (p < 0.05).ConclusionSignificant clinical variability was observed in early-onset FSHD. Earlier age at onset of facial weakness was associated with greater disease severity. Longitudinal assessments are needed to determine the rate of disease progression in this population.

scholarly journals Type 1 FSHD with 6–10 Repeated Units: Factors Underlying Severity in Index Cases and Disease Penetrance in Their Relatives Attention

2020 ◽  
Vol 21 (6) ◽  
pp. 2221
Author(s):  
Emmanuelle Salort-Campana ◽  
Farzad Fatehi ◽  
Sadia Beloribi-Djefaflia ◽  
Stéphane Roche ◽  
Karine Nguyen ◽  
...  
Keyword(s):  
Disease Severity ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Clinical Severity ◽  
Cross Sectional ◽  
Repeat Array ◽  
D4z4 Repeat ◽  
Severity Scores ◽  
Group 2 ◽  
Group 1

Molecular defects in type 1 facioscapulohumeral muscular dystrophy (FSHD) are caused by a heterozygous contraction of the D4Z4 repeat array from 1 to 10 repeat units (RUs) on 4q35. This study compared (1) the phenotype and severity of FSHD1 between patients carrying 6–8 vs. 9–10 RUs, (2) the amount of methylation in different D4Z4 regions between patients with FSHD1 with different clinical severity scores (CSS). This cross-sectional multicenter study was conducted to measure functional scales and for genetic analysis. Patients were classified into two categories according to RUs: Group 1, 6–8; Group 2, 9–10. Methylation analysis was performed in 27 patients. A total of 99 carriers of a contracted D4Z4 array were examined. No significant correlations between RUs and CSS (r = 0.04, p = 0.73) and any of the clinical outcome scales were observed between the two groups. Hypomethylation was significantly more pronounced in patients with high CSS (>3.5) than those with low CSS (<1.5) (in DR1 and 5P), indicating that the extent of hypomethylation might modulate disease severity. In Group 1, the disease severity is not strongly correlated with the allele size and is mostly correlated with the methylation of D4Z4 regions.

EP.26Phenotype may predict the clinical severity of facioscapulohumeral muscular dystrophy

2019 ◽  
Vol 29 ◽  
pp. S77
Author(s):  
Y. Liu ◽  
D. Yue ◽  
W. Zhu ◽  
J. Li ◽  
S. Cai ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Clinical Severity

scholarly journals Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy

Neurology ◽  
2020 ◽  
Vol 94 (23) ◽  
pp. e2441-e2447 ◽  
Author(s):  
Kohei Hamanaka ◽  
Darina Šikrová ◽  
Satomi Mitsuhashi ◽  
Hiroki Masuda ◽  
Yukari Sekiguchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Target Gene ◽  
Disease Gene ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Target Gene Expression ◽  
D4z4 Repeat ◽  
Biopsy Examination ◽  
Chromatin Relaxation

ObjectiveFacioscapulohumeral muscular dystrophy (FSHD) is a heterogenetic disorder predominantly characterized by progressive facial and scapular muscle weakness. Patients with FSHD either have a contraction of the D4Z4 repeat on chromosome 4q35 or mutations in D4Z4 chromatin modifiers SMCHD1 and DNMT3B, both causing D4Z4 chromatin relaxation and inappropriate expression of the D4Z4-encoded DUX4 gene in skeletal muscle. In this study, we tested the hypothesis whether LRIF1, a known SMCHD1 protein interactor, is a disease gene for idiopathic FSHD2.MethodsClinical examination of a patient with idiopathic FSHD2 was combined with pathologic muscle biopsy examination and with genetic, epigenetic, and molecular studies.ResultsA homozygous LRIF1 mutation was identified in a patient with a clinical phenotype consistent with FSHD. This mutation resulted in the absence of the long isoform of LRIF1 protein, D4Z4 chromatin relaxation, and DUX4 and DUX4 target gene expression in myonuclei, all molecular and epigenetic hallmarks of FSHD. In concordance, LRIF1 was shown to bind to the D4Z4 repeat, and knockdown of the LRIF1 long isoform in muscle cells results in DUX4 and DUX4 target gene expression.ConclusionLRIF1 is a bona fide disease gene for FSHD2. This study further reinforces the unifying genetic mechanism, which postulates that FSHD is caused by D4Z4 chromatin relaxation, resulting in inappropriate DUX4 expression in skeletal muscle.

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