scholarly journals Orofacial Muscle Weakening in Facioscapulohumeral Muscular Dystrophy (FSHD) Patients

Children ◽  
2022 ◽  
Vol 9 (1) ◽  
pp. 96
Author(s):  
Dimitrios Konstantonis ◽  
Kyriaki Kekou ◽  
Petros Papaefthymiou ◽  
Heleni Vastardis ◽  
Nikoleta Konstantoni ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Weakness ◽  
Fragment Size ◽  
Molecular Genetic ◽  
Muscular Activity ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Molecular Genetic Analysis ◽  
Family Status ◽  
Facial Growth ◽  
Repeat Array

Background: Facioscapulohumeral muscular dystrophy is the third most commonly found type of muscular dystrophy. The aim of this study was to correlate the D4Z4 repeat array fragment size to the orofacial muscle weakening exhibited in a group of patients with a genetically supported diagnosis of FSHD. Methods: Molecular genetic analysis was performed for 52 patients (27 female and 25 male) from a group that consisted of 36 patients with autosomal dominant pedigrees and 16 patients with either sporadic or unknown family status. The patients were tested with the southern blotting technique, using EcoRI/Avrll double digestion, and fragments were detected by a p13E-11 telomeric probe. Spearman’s correlation was used to compare the fragment size with the degree of muscle weakening found in the forehead, periocular and perioral muscles. Results: A positive non-significant correlation between the DNA fragment size and severity of muscle weakness was found for the forehead (r = 0.27; p = 0187), the periocular (r = 0.24; p = 0.232) and the left and right perioral (r = 0.29; p = 0.122), (r = 0.32; p = 0.085) muscles. Conclusions: Although FSHD patients exhibited a decrease in muscular activity related to the forehead, perioral, and periocular muscles the genotype–phenotype associations confirmed a weak to moderate non-significant correlation between repeat size and the severity of muscle weakness. Orofacial muscle weakening and its association with a D4Z4 contraction alone may not have the significance to serve as a prognostic biomarker, due to the weak to moderate association. Further studies with larger sample sizes are needed to determine the degree of genetic involvement in the facial growth in FSHD patients.

scholarly journals OP0079 LIMB GIRDLE MUSCULAR DYSTROPHY TYPE 2B - A RARE MYOSITIS MIMIC

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 43.1-43
Author(s):  
A. Merriman ◽  
S. Boyle
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Weakness ◽  
Molecular Genetic ◽  
Inflammatory Myopathy ◽  
Molecular Genetic Analysis ◽  
Limb Girdle Muscular Dystrophy ◽  
Proximal Muscle Weakness ◽  
Proximal Muscle ◽  
Clin Neurol ◽  
Genetics Services

Background:Proximal muscle weakness with associated raised creatine kinase (CK) commonly leads to referral to Rheumatology for the investigation of Idiopathic Inflammatory Myopathy (IIM). Some genetic myopathies can have a similar presentation with investigations that suggest inflammatory disease, leading to difficulty with accurate diagnosis (Amato & Brown, 2011; Harlan & Mammen, 2019).Objectives:To describe the case of a patient with Limb Girdle Muscular Dystrophy Type 2B (LGMD2B), whose initial presentation mimicked an inflammatory myopathy.Methods:Case report.Results:A 43-year-old patient was reviewed by Rheumatology due to proximal muscle weakness with a raised CK. Muscle biopsy was suggestive of inflammatory myopathy. Therefore, he was started on treatment with corticosteroids. Corticosteroid treatment resulted in no improvement in his weakness or CK. His diagnosis was reviewed, and he was referred to the Neurology and Genetics services. Following molecular genetic analysis, a diagnosis of Limb Girdle Muscular Dystrophy Type 2B was made.Conclusion:Muscle biopsies can suggest an inflammatory aetiology in some genetic myopathies (Amato & Brown, 2011; Harlan & Mammen, 2019). If a patient with suspected IIM presents with atypical features, or they do not respond as expected to treatment, then consider a genetic myopathy such as LGMD2B as a cause and involve the Neurology and Genetics services in the case.References:[1]Amato, A. A., & Brown, R. H., Jr. (2011). Dysferlinopathies. Handb Clin Neurol, 101, 111-118. https://doi.org/10.1016/b978-0-08-045031-5.00007-4[2]Harlan, M & Mammen A. L (2019). Myositis Mimics: The Differential Diagnosis of Myositis. In: R. Aggarwal and C. V. Oddis (Eds.) Managing Myositis (pp. 209-223). Springer, Cham.Disclosure of Interests:None declared

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.

Clinical and molecular genetic analysis of a family with late-onset LAMA2-related muscular dystrophy

2016 ◽  
Vol 38 (2) ◽  
pp. 242-249 ◽  
Author(s):  
Juan Ding ◽  
Dandan Zhao ◽  
Renqian Du ◽  
Yuehua Zhang ◽  
Haipo Yang ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Genetic Analysis ◽  
Late Onset ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis

G.P.108 Sarcomeric dysfunction contributes to muscle weakness in facioscapulohumeral muscular dystrophy

2012 ◽  
Vol 22 (9-10) ◽  
pp. 900-901
Author(s):  
S. Lassche ◽  
G.J.M. Stienen ◽  
T.C. Irving ◽  
S.M. van der Maarel ◽  
G.W. Padberg ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Weakness ◽  
Facioscapulohumeral Muscular Dystrophy

scholarly journals New approach for diagnostic of Facioscapulohumeral muscular dystrophy based on PCR

2019 ◽  
pp. 3-9
Author(s):  
Н.В. Зернов ◽  
А.А. Гуськова ◽  
М.Ю. Скоблов
Keyword(s):  
Muscular Dystrophy ◽  
Molecular Genetic ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Diagnostic Methods ◽  
Pulse Field ◽  
Agarose Gel ◽  
New Approach ◽  
Pulse Field Gel Electrophoresis ◽  
Pcr Products ◽  
The Moment

Актуальность. Миодистрофия Ландузи-Дежерина (МЛД) является одной из наиболее часто встречающихся мышечных дистрофий. В 95% случаев заболевание связано с частичной делецией массива повторов D4Z4 на одном из аллелей 4-й хромосомы. Существующие диагностические методики гибридизации по Саузерну и молекулярного комбинга являются ресурсо- и времязатратными. В настоящее время в Российской Федерации молекулярно-генетическая диагностика МЛД не проводится. Цель. Поиск новых подходов к диагностике МЛД для использования в молекулярно-генетических лабораториях. Методы. ДНК выделялась в агарозных блоках и подвергалась обработке эндонуклеазой EcoRI. Полученные фрагменты ДНК разделялись методом пульс-электрофореза в агарозном геле, после этого агарозный гель фрагментировался согласно маркеру молекулярного веса и использовался в качестве матрицы для полимеразной цепной реакции (ПЦР). Принадлежность полученных ПЦР-продуктов к последовательностям повторов D4Z4 4-й хромосомы подтверждалась секвенированием по Сэнгеру. Результаты. Протокол пульс-электрофореза оптимизирован таким образом, что после всех этапов ДНК в агарозном геле пригодна для использования в качестве матрицы для ПЦР. Разработана ПЦР-система специфичной амплификации контрольных ДНК-матриц 4-й хромосомы и подтверждена секвенированием принадлежность получаемых ПЦР-продуктов к последовательности повторов D4Z4 4-й хромосомы. Выводы. Показана возможность использования ДНК в агарозном геле после пульс-электрофореза в качестве матрицы для детекции повторов D4Z4 методом ПЦР. Представленная ПЦР-система специфично амплифицирует последовательности D4Z4 4-й хромосомы. Используя данную ПЦР-систему и геномную ДНК пациента с известной длиной массива повторов D4Z4 проведена успешная диагностика МЛД. Таким образом разработан новый подход к диагностике МЛД для использования в молекулярно-генетических лабораториях. Relevance. Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies. In 95% of cases, the disease is associated with partial deletion of the array of the D4Z4 repeats on one of the alleles of the 4th chromosome. The existing diagnostic methods of Southern blotting and molecular combing are quite resource-and time-consuming. At the moment, molecular genetic diagnostic of FSHD is not provided on the territory of the Russian Federation. Aim: to find new approaches for molecular genetic diagnostic of FSHD acceptable for use in standard molecular genetic laboratories Materials and methods: DNA isolated in agarose plugs and treated by the EcoRI restriction enzyme. DNA fragments then were separated by pulse field gel electrophoresis (PFGE) in agarose gel. After PFGE, the agarose gel was fragmented and used as a matrix for PCR. The identity of the obtained PCR products to the sequence of the D4Z4 repeats of the 4th chromosome was confirmed by sequencing by Sanger. Results. The PFGE protocol is optimized in such a way that, after all stages, DNA in agarose gel is suitable for use as a matrix for PCR. We achieve a specific amplification of the control DNA matrices of the 4th chromosome and confirm belonging of the PCR products to the sequence of D4Z4 repeats of the 4th chromosome by the Senger sequencing. Conclusions. This paper shows the possibility of using DNA in agarose gel after PFGE as a matrix for detection of D4Z4 repeats by PCR. The presented PCR system specifically amplify sequence of the 4th chromosome D4Z4 repeats. Using this PCR system and genomic DNA of a patient with a known length of the D4Z4 repeats array, a successful diagnosis of FSHD was performed. Thus, we propose a new approach for FSHD diagnostic, acceptable for use in standard molecular genetic laboratories.

Molecular genetic analysis of 67 patients with duchenne/becker muscular dystrophy

1992 ◽  
Vol 90 (1-2) ◽  
Author(s):  
Susanne Niemann-Seyde ◽  
Ryszard Slomski ◽  
Frauke Rininsland ◽  
Ute Ellermeyer ◽  
Jolanta Kwiatkowska ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Genetic Analysis ◽  
Molecular Genetic ◽  
Becker Muscular Dystrophy ◽  
Molecular Genetic Analysis

scholarly journals Role of associated alleles and hypomethylation status in the clinical expression of facioscapulohumeral muscular dystrophy

2011 ◽  
Vol 152 (39) ◽  
pp. 1576-1585 ◽  
Author(s):  
Henriett Pikó ◽  
Mária Judit Molnár ◽  
Ágnes Herczegfalvi ◽  
Péter Mayer ◽  
Veronika Karcagi
Keyword(s):  
Muscular Dystrophy ◽  
Fragment Size ◽  
Restriction Analysis ◽  
Methylation Status ◽  
Prenatal Testing ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
D4z4 Repeat ◽  
Modifying Factors ◽  
Diagnostic Panel ◽  
Total Dna

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of the D4Z4 repeat region on 4q35. In addition, epigenetic modifying factors play a role in the complex pathomechanism of the disease. Aims: Introduction of a new diagnostic panel in Hungary for the extended molecular analysis of the disease which also provides new insights into the pathomechanism. Methods: In total, DNA samples of 185 clinically diagnosed FSHD patients and 71 asymptomatic relatives were analyzed by EcoRI and BlnI restriction digestion and Southern blot technique with probe p13-E11. Further investigations of the 4q35 alleles associated with the FSHD phenotype utilized qA and qB probes and a restriction analysis of the proximal D4Z4 unit by detecting a G/C SNP and the methylation status. Results: From the patients analyzed 115 had the D4Z4 repeat contraction, whereas from 71 asymptomatic family members five harbored the pathogenic fragment size. In eight families, prenatal testing had to be offered with an outcome of four affected fetuses. Methylation test was performed in 31 genetically confirmed FSHD patients and hypomethylation status was detected in all cases. All the 115 confirmed patients had 4qA alleles with the G polymorphism. Translocation events between 4q35 and the homologous 10q26 regions were also detected. Conclusion: Molecular diagnosis of FSHD became a routine approach in Hungary thus supporting the work of the clinicians, improving quality of life and genetic counseling of the affected families. The provided results from this research suggest that FSHD is associated with complex epigenetic disease mechanisms. Orv. Hetil., 2011, 152, 1576–1585.

scholarly journals Cellular and animal models for facioscapulohumeral muscular dystrophy

2020 ◽  
Vol 13 (10) ◽  
pp. dmm046904
Author(s):  
Alec M. DeSimone ◽  
Justin Cohen ◽  
Monkol Lek ◽  
Angela Lek
Keyword(s):  
Muscular Dystrophy ◽  
Myogenic Differentiation ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Lower Limbs ◽  
Repeat Array ◽  
Drug Candidates ◽  
Cellular Models ◽  
Wide Range

ABSTRACTFacioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy and presents with weakness of the facial, scapular and humeral muscles, which frequently progresses to the lower limbs and truncal areas, causing profound disability. Myopathy results from epigenetic de-repression of the D4Z4 microsatellite repeat array on chromosome 4, which allows misexpression of the developmentally regulated DUX4 gene. DUX4 is toxic when misexpressed in skeletal muscle and disrupts several cellular pathways, including myogenic differentiation and fusion, which likely underpins pathology. DUX4 and the D4Z4 array are strongly conserved only in primates, making FSHD modeling in non-primate animals difficult. Additionally, its cytotoxicity and unusual mosaic expression pattern further complicate the generation of in vitro and in vivo models of FSHD. However, the pressing need to develop systems to test therapeutic approaches has led to the creation of multiple engineered FSHD models. Owing to the complex genetic, epigenetic and molecular factors underlying FSHD, it is difficult to engineer a system that accurately recapitulates every aspect of the human disease. Nevertheless, the past several years have seen the development of many new disease models, each with their own associated strengths that emphasize different aspects of the disease. Here, we review the wide range of FSHD models, including several in vitro cellular models, and an array of transgenic and xenograft in vivo models, with particular attention to newly developed systems and how they are being used to deepen our understanding of FSHD pathology and to test the efficacy of drug candidates.

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