scholarly journals FSHD1 and FSHD2 form a disease continuum

Neurology ◽  
2019 ◽  
Vol 92 (19) ◽  
pp. e2273-e2285 ◽  
Author(s):  
Sabrina Sacconi ◽  
Audrey Briand-Suleau ◽  
Marilyn Gros ◽  
Christian Baudoin ◽  
Richard J.L.F. Lemmers ◽  
...  
Keyword(s):  
Facioscapulohumeral Muscular Dystrophy ◽  
Clinical Severity ◽  
Manual Muscle Testing ◽  
Multicenter Cohort Study ◽  
Clinical Scales ◽  
D4z4 Repeat ◽  
Repeat Units ◽  
Muscle Testing ◽  
Repeat Size ◽  
Size Threshold

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.

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.

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.

scholarly journals P.007 Onset of facial weakness correlated with muscle strength in infantile facioscapulohumeral dystrophy (FSHD)

2016 ◽  
Vol 43 (S2) ◽  
pp. S23-S23
Author(s):  
JK Mah ◽  
J Feng ◽  
C Carty ◽  
Y Chen ◽  
T Duong ◽  
...  
Keyword(s):  
Muscle Strength ◽  
Disease Severity ◽  
Age At Onset ◽  
Clinical Severity ◽  
Manual Muscle Testing ◽  
Shoulder Abduction ◽  
Facial Weakness ◽  
Muscle Involvement ◽  
Muscle Testing ◽  
Severity Scores

Background: We investigated motor function associations with age, gender, and D4Z4 fragment size among participants with infantile FSHD. Methods: We collected standardized motor assessments including goniometry, manual muscle testing (MMT), quantitative muscle testing (QMT), and FSHD clinical severity scores (CSS) at 12 CINRG sites. To measure associations, we used linear regression models adjusted for age at enrollment, onset of weakness, gender, and D4Z4 repeats. Results: 53 participants (59% female, mean age 23.1±14.6 years) were enrolled. Weakness was most pronounced at the shoulder girdle and rectus abdominis (median MMT 30-38% of normal). Older enrollment age was associated with greater CSS (p=0.005) and reduced range of motion in shoulder abduction, shoulder flexion, elbow flexion, and ankle dorsiflexion (all p<0.01). Females and participants with larger D4Z4 repeats had milder shoulder/arm weakness and lesser disease severity (all p<0.05). Increased age at onset of facial weakness was significantly associated with greater total muscle strength, as measured by QMT and MMT (both p=0.002). Conclusions: We confirm the descending pattern of muscle involvement and milder disease severity in females or those with larger D4Z4 repeats. Furthermore, earlier age at onset of facial weakness was associated with greater muscle weakness. Future longitudinal assessments will describe rates of disease progression in this population.

scholarly journals A family-based study into penetrance in facioscapulohumeral muscular dystrophy type 1

Neurology ◽  
2018 ◽  
Vol 91 (5) ◽  
pp. e444-e454 ◽  
Author(s):  
Mariëlle Wohlgemuth ◽  
Richard J. Lemmers ◽  
Marianne Jonker ◽  
Elly van der Kooi ◽  
Corinne G. Horlings ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Weakness ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Clinical Severity ◽  
Maximum Likelihood Estimates ◽  
Careful Examination ◽  
Mutation Carriers ◽  
Repeat Size ◽  
Asymptomatic Patients ◽  
Family Based

ObjectiveAn observational cross-sectional study was conducted in a national facioscapulohumeral muscular dystrophy (FSHD) expertise center to estimate the penetrance of FSHD1 and to evaluate phenotype–genotype correlations.MethodsTen FSHD1 probands carrying 4–9 D4Z4 unit alleles and 140 relatives were examined. All 150 participants were genetically characterized, including D4Z4 methylation levels in the mutation carriers. Mutation carriers were classified as (1) symptomatic: with symptoms of muscle weakness on history and muscle FSHD signs on examination; (2) asymptomatic: without symptoms of muscle weakness but with muscle FSHD signs on examination; and (3) nonpenetrant: without symptoms of muscle weakness on history and without muscle FSHD signs on examination. We assessed the relationship between age-corrected clinical severity score and repeat size, sex, and D4Z4 methylation levels.ResultsThe maximum likelihood estimates of symptomatic and those of symptomatic plus asymptomatic FSHD showed that penetrance depends on repeat size and increases until late adulthood. We observed many asymptomatic carriers with subtle facial weakness with or without mild shoulder girdle weakness (25% [17/69]). Nonpenetrance was observed less frequently than in recent population studies (17% [12/69]), and most asymptomatic patients reported some shoulder pain. D4Z4 methylation tended to be lower in moderately to severely affected mutation carriers with 7 or 9 repeats.DiscussionThis family-based study detected a lower overall nonpenetrance than previously observed, probably due to many asymptomatic mutation carriers identified by careful examination of facial and shoulder muscles. The recognition of asymptomatic mutation carriers is essential for selection of participants for future trials, and the likelihood estimates are helpful in counseling.

scholarly journals Identification of Serum Interleukin 6 Levels as a Disease Severity Biomarker in Facioscapulohumeral Muscular Dystrophy

2021 ◽  
pp. 1-11
Author(s):  
Marilyn Gros ◽  
Andreia M. Nunes ◽  
Douglas Daoudlarian ◽  
Jonathan Pini ◽  
Emanuela Martinuzzi ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Model ◽  
Disease Severity ◽  
Interleukin 6 ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Large Cohort ◽  
Adult Patients ◽  
Clinical Severity ◽  
Muscle Testing ◽  
Functional Scores

Background: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies in adults, displaying a progressive, frequently asymmetric involvement of a typical muscles’ pattern. FSHD is associated with epigenetic derepression of the polymorphic D4Z4 repeat on chromosome 4q, leading to DUX4 retrogene toxic expression in skeletal muscles. Identifying biomarkers that correlate with disease severity would facilitate clinical management and assess potential FSHD therapeutics’ efficacy. Objectives: This study purpose was to analyze serum cytokines to identify potential biomarkers in a large cohort of adult patients with FSHD. Methods: We retrospectively measured the levels of 20 pro-inflammatory and regulatory cytokines in sera from 100 genetically confirmed adult FSHD1 patients. Associations between cytokine concentrations and various clinical scores were investigated. We then measured serum and muscle interleukin 6 (IL-6) levels in a validated FSHD-like mouse model, ranging in severity and DUX4 expression. Results: IL-6 was identified as the only cytokine with a concentration correlating with several clinical severity and functional scores, including Clinical Severity Score, Manual Muscle Testing sum score, Brooke and Vignos scores. Further, FSHD patients displayed overall IL-6 levels more than twice high as control, and patients with milder phenotypes exhibited lower IL-6 serum concentration than those with severe muscular weakness. Lastly, an FSHD-like mouse model analysis confirmed that IL-6 levels positively correlate with disease severity and DUX4 expression. Conclusions: Serum IL-6, therefore, shows promise as a serum biomarker of FSHD severity in a large cohort of FSHD1 adult patients.

Quick Reference: Chapter 3: The Musculoskeletal System and Chapter 4: The Nervous System

2000 ◽  
Vol 5 (3) ◽  
pp. 4-4
Keyword(s):  
Nervous System ◽  
Lower Extremity ◽  
Musculoskeletal System ◽  
Multistep Method ◽  
Manual Muscle Testing ◽  
Motor Deficits ◽  
Lower Extremity Weakness ◽  
Residual Symptoms ◽  
Muscle Testing ◽  
Almost All

Abstract Lesions of the peripheral nervous system (PNS), whether due to injury or illness, commonly result in residual symptoms and signs and, hence, permanent impairment. The AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), Fourth Edition, divides PNS deficits into sensory and motor and includes pain in the former. This article, which regards rating sensory and motor deficits of the lower extremities, is continued from the March/April 2000 issue of The Guides Newsletter. Procedures for rating extremity neural deficits are described in Chapter 3, The Musculoskeletal System, section 3.1k for the upper extremity and sections 3.2k and 3.2l for the lower limb. Sensory deficits and dysesthesia are both disorders of sensation, but the former can be interpreted to mean diminished or absent sensation (hypesthesia or anesthesia) Dysesthesia implies abnormal sensation in the absence of a stimulus or unpleasant sensation elicited by normal touch. Sections 3.2k and 3.2d indicate that almost all partial motor loss in the lower extremity can be rated using Table 39. In addition, Section 4.4b and Table 21 indicate the multistep method used for spinal and some additional nerves and be used alternatively to rate lower extremity weakness in general. Partial motor loss in the lower extremity is rated by manual muscle testing, which is described in the AMA Guides in Section 3.2d.

scholarly journals Impact of structured physical therapy intervention on functional recovery in a patient with CAPOS syndrome: a case report

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Shailesh Gardas ◽  
Aishwarya Mahajan
Keyword(s):  
Functional Performance ◽  
Functional Independence Measure ◽  
Functional Independence ◽  
Measurement Scale ◽  
Manual Muscle Testing ◽  
Trunk Control ◽  
Control Measurement ◽  
Muscle Testing ◽  
Post Test ◽  
Capos Syndrome

Abstract Background CAPOS syndrome (cerebellar ataxia, areflexia, pescavus, optic atrophy, and sensorineural hearing loss) is a rare congenital autosomal dominant disorder. The resulting neurological sequelae of impairments are progressive in nature and may interfere with functional independence, performing activities of daily living (ADL’s), and subsequently, affecting the quality of life (QOL). Since it is an extremely rare disorder, there is a severe dearth in the literature about how specific physiotherapy interventions may affect their functional status. Therefore, our objective was to investigate the effects of proprioceptive neuromuscular facilitation (PNF) and Frenkel’s coordination exercises on functional recovery in a patient with CAPOS syndrome. Case presentation We herein present a case of a 25-year-old Indian male with complaints of generalized body weakness, difficulty visualizing distant objects, nystagmus, progressive sensorineural deafness, and ataxia. He was rehabilitated with a structured/customized physiotherapy protocol consisting of PNF approach and coordination exercises for 4 weeks, 6 days/week, 60 min daily. An improvement in overall functional performance of patient as per post-intervention scores of manual muscle testing, trunk control measurement scale, functional independence measure (components of self-care, transfers, and locomotion), and decline in severity of ataxia on scale for assessment and rating of ataxia scale was observed. Conclusion PNF and Frenkel’s exercises resulted in an improvement in overall functional performance of the patient. Improvement was observed in post-test scores of Manual Muscle Testing (MMT), Trunk Control Measurement Scale (TCMS), and Functional Independence Measure (FIM) for the components of self-care, transfers, and locomotion. Additionally, results also showed a decline in severity of ataxia on post-test scores of scale for the assessment and rating of ataxia (SARA) scale (i.e., from severe to moderate).

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