A standardized clinical evaluation of patients affected by facioscapulohumeral muscular dystrophy: The FSHD clinical score

Lamperti, Costanza; Fabbri, Giampietro; Vercelli, Liliana; D'Amico, Roberto; Frusciante, Roberto; Bonifazi, E.; Fiorillo, Chiara; Borsato, C.; Cao, Michelangelo; Servida, Maura; Greco, Francesca; Leo, Rita Di; Volpi, L.; Manzoli, Claudia; Cudia, Paola; Pastorello, Ebe; Ricciardi, L; Siciliano, Gabriele; Galluzzi, G.; Rodolico, Carmelo; Santoro, Lucio; Tomelleri, Giuliano; Angelini, C.; Ricci, Enzo; Palmucci, L.; Moggio, Maurizio; Tupler, Rossella

doi:10.1002/mus.21671

Cited by 128 publications

(136 citation statements)

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“…Patients were graded by the FSHD clinical score26 and the age‐adjusted clinical severity scale 27, 28. Both parents were assessed clinically, and the clinical severity scale27 was determined.…”

Section: Methodsmentioning

confidence: 99%

Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study

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Schreuder

Alfen

et al. 2018

Annals of Neurology

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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

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Section: Methodsmentioning

confidence: 99%

Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study

Goselink

Schreuder

Alfen

et al. 2018

Annals of Neurology

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“…Clinical severity of the disease was numerically defined according to the standardized protocol developed by Lamperti et al (21). All recruited subjects R126 ALTERED TROPONIN T SPLICING IN FSHD underwent DNA testing.…”

Section: Methodsmentioning

confidence: 99%

“…10, muscle samples were obtained from two FSHD family groups and eight unrelated subjects; the D4Z4 repeat size at 4q35 was molecularly defined in all subjects. Individuals carrying the FSHD molecular defect, as well as normal controls, were clinically examined, using a standardized protocol, which generates the FSHD clinical score (21). The total score can range from 0, when no signs of muscle weakness are present, to 15, when all muscle groups tested are severely impaired (21).…”

Section: R131 Altered Troponin T Splicing In Fshdmentioning

confidence: 99%

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

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Germinario

Esposito

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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cioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is characterized by atrophy and weakness of selective muscle groups. FSHD is considered an autosomal dominant disease with incomplete penetrance and unpredictable variability of clinical expression within families. Mice overexpressing FRG1 (FSHD region gene 1), a candidate gene for this disease, develop a progressive myopathy with features of the human disorder. Here, we show that in FRG1-overexpressing mice, fast muscles, which are the most affected by the dystrophic process, display anomalous fast skeletal troponin T (fTnT) isoform, resulting from the aberrant splicing of the Tnnt3 mRNA that precedes the appearance of dystrophic signs. We determine that muscles of FRG1 mice develop less strength due to impaired contractile properties of fast-twitch fibers associated with an anomalous MyHC-actin ratio and a reduced sensitivity to Ca 2ϩ . We demonstrate that the decrease of Ca 2ϩ sensitivity of fast-twitch fibers depends on the anomalous troponin complex and can be rescued by the substitution with the wild-type proteins. Finally, we find that the presence of aberrant splicing isoforms of TNNT3 characterizes dystrophic muscles in FSHD patients. Collectively, our results suggest that anomalous TNNT3 profile correlates with the muscle impairment in both humans and mice. On the basis of these results, we propose that aberrant fTnT represents a biological marker of muscle phenotype severity and disease progression. muscular dystrophy; aberrant splicing; muscle weakness; FRG1; troponin T FACIOSCAPULOHUMERAL MUSCULAR dystrophy (FSHD), one of the three most common hereditary myopathies, presents progressive atrophy and weakness of a highly specific set of muscle groups (10,11,31). FSHD is characterized by insidious onset and unpredictable progression with high variability of clinical expression, even within the same family (36,37,42). At present, no molecular mechanisms have been implicated in the development of these disease phenotypes, and no biological markers are available to define and monitor disease expression.More than 50 genes have been associated with muscular dystrophies (MD), whose genetic defects have been molecularly defined, and numerous animal models have been developed (30). In many cases, invaluable insights into disease mechanisms, structure and function of gene products, and approaches for therapeutic interventions have benefited from the study of animal models of the different MDs (1). In this context, FSHD is unique because no mutations have been found in any protein-coding gene. Instead, FSHD has been associated with reduction of the number of tandemly repeated 3.3-kb DNA segments (named D4Z4 repeats) located at the subtelomeric region of chromosome 4q (2, 44, 48). The number of D4Z4 repeats varies from 11 to 150 in the general population, whereas less than 11 repeats are present in sporadic and familial FSHD patients (48). The current model to explain FSHD is that the reduction of D4Z4 repeats in FSHD subjects initiates in...

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“…The clinical protocol examines muscle groups specifically affected in FSHD. The test uses functional criteria, which allow expression of clinical severity in quantitative terms (Lamperti et al, 2010). The clinical examination results in an evaluation scale, which is divided into six independent sections that assess the strength and the functionality of (I) facial muscles (scored from 0 to 2); (II) scapular girdle muscles (scored from 0 to 3); (III) upper limb muscles (scored from 0 to 2); (IV) distal leg muscles (scored from 0 to 2); (V) pelvic girdle muscles (scored from 0 to 5); and (VI) abdominal muscles (scored from 0 to 1).…”

Section: A Standardized Clinical Evaluation Tool: Fshd Scorementioning

confidence: 99%

“…The protocol represents a robust evaluation procedure for FSHD patients that can be performed easily in the medical office and is not influenced by the tester. The robustness of the clinical evaluation protocol provides a tool that can therefore be used by different neurologists in large cooperative clinical studies and allows translating what is called clinical impression of the progressive involvement of specific muscle groups into a number (Lamperti et al, 2010) (The FSHD clinical form and the FSHD evaluation scale form, as well as a visual guide to clinical assessment, are available online at www.fshd.it).…”

Section: A Standardized Clinical Evaluation Tool: Fshd Scorementioning

confidence: 99%