Natural History of Facioscapulohumeral Dystrophy in Children
Jildou N. DijkstraRianne J.M. GoselinkNens van AlfenImelda J. M. de GrootMaaike PelsmaNienke van der StoepThomas TheelenBaziel G.M. van EngelenNicol C. VoermansCorrie E. Erasmus
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Abstract:
Data on the natural history of facioscapulohumeral dystrophy (FSHD) in childhood are limited and critical for improved patient care and clinical trial readiness. Our objective was to describe the disease course of FSHD in children.We performed a nationwide, single-center, prospective cohort study of FSHD in childhood assessing muscle functioning, imaging, and quality of life over 2 years of follow-up.We included 20 children with genetically confirmed FSHD who were 2 to 17 years of age. Overall, symptoms were slowly progressive, and the mean FSHD clinical score increased from 2.1 to 2.8 (p = 0.003). The rate of progression was highly variable. At baseline, 16 of 20 symptomatic children had facial weakness; after 2 years, facial weakness was observed in 19 of 20 children. Muscle strength did not change between baseline and follow-up. The most frequently and most severely affected muscles were the trapezius and deltoid. The functional exercise capacity, measured with the 6-minute walk test, improved. Systemic features were infrequent and nonprogressive. Weakness-associated complications such as lumbar hyperlordosis and dysarthria were common, and their prevalence increased during follow-up. Pain and fatigue were frequent complaints in children, and their prevalence also increased during follow-up. Muscle ultrasonography revealed a progressive increase in echogenicity.FSHD in childhood has a slowly progressive but variable course over 2 years of follow-up. The most promising outcome measures to detect progression were the FSHD clinical score and muscle ultrasonography. Despite this disease progression, an improvement on functional capacity may still occur as the child grows up. Pain, fatigue, and a decreased quality of life were common symptoms and need to be addressed in the management of childhood FSHD. Our data can be used to counsel patients and as baseline measures for treatment trials in childhood FSHD.Keywords:
Facioscapulohumeral muscular dystrophy
Muscle weakness
Natural history study
Muscular dystrophies are a group of disorders that cause progressive muscle weakness. There is an increasing interest for the development of biomarkers for these disorders and specifically for Duchene Muscular Dystrophy. Limited research however, has been performed on the biomarkers' development for the most rare muscular dystrophies, like the Facioscapulohumeral Muscular Dystrophy, Limb-Girdle Muscular Dystrophy and Myotonic Dystrophy type 2. Here, we aimed to identify novel serum-based miRNA biomarkers for these rare muscular dystrophies, through high-throughput next-generation RNA sequencing. We identified many miRNAs that associate with muscular dystrophy patients compared to controls. Based on a series of selection criteria, the two best candidate miRNAs for each of these disorders were chosen and validated in a larger number of patients. Our results showed that miR-223-3p and miR-206 are promising serum-based biomarkers for Facioscapulohumeral Muscular Dystrophy type 1, miR-143-3p and miR-486-3p for Limb-Girdle Muscular Dystrophy type 2A whereas miR-363-3p and miR-25-3p associate with Myotonic Dystrophy type 2. Some of the identified miRNAs were significantly elevated in the serum of the patients compared to controls, whereas some others were lower. In conclusion, we provide new evidence that certain circulating miRNAs may be used as biomarkers for three types of rare muscular dystrophies.
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Muscular dystrophies are a clinically and genetically heterogeneous group of inherited myogenic disorders. In clinical tests for these diseases, creatine kinase (CK) is generally used as diagnostic blood-based biomarker. However, because CK levels can be altered by various other factors, such as vigorous exercise, etc., false positive is observed. Therefore, three microRNAs (miRNAs), miR-1, miR-133a, and miR-206, were previously reported as alternative biomarkers for duchenne muscular dystrophy (DMD). However, no alternative biomarkers have been established for the other muscular dystrophies.We, therefore, evaluated whether these miR-1, miR-133a, and miR-206 can be used as powerful biomarkers using the serum from muscular dystrophy patients including DMD, myotonic dystrophy 1 (DM1), limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy (FSHD), becker muscular dystrophy (BMD), and distal myopathy with rimmed vacuoles (DMRV) by qualitative polymerase chain reaction (PCR) amplification assay.Statistical analysis indicated that all these miRNA levels in serum represented no significant differences between all muscle disorders examined in this study and controls by Bonferroni correction. However, some of these indicated significant differences without correction for testing multiple diseases (P < 0.05). The median values of miR-1 levels in the serum of patients with LGMD, FSHD, and BMD were approximately 5.5, 3.3 and 1.7 compared to that in controls, 0.68, respectively. Similarly, those of miR-133a and miR-206 levels in the serum of BMD patients were about 2.5 and 2.1 compared to those in controls, 1.03 and 1.32, respectively.Taken together, our data demonstrate that levels of miR-1, miR-133a, and miR-206 in serum of BMD and miR-1 in sera of LGMD and FSHD patients showed no significant differences compared with those of controls by Bonferroni correction. However, the results might need increase in sample sizes to evaluate these three miRNAs as variable biomarkers.
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Creatine kinase
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A new study supported in part by the NIAMS has found that two separate genetic arrangements – both on chromosome 4 – are needed to start the disease process in facioscapulohumeral muscular dystrophy (FSHD), one of the most common forms of muscular dystrophy.
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ABSTRACT BACKGROUND: Muscle weakness is a debilitating condition that can lead to frailty, falls, and functional decline. Muscle weakness is found across many diseases; therefore, understanding what constitutes this condition is paramount. The National Library of Medicine provides 2 definitions of muscle weakness, both from a disease perspective. These definitions are narrow and do not account for overlapping causes of muscle weakness. Nurses are holistic practitioners, so they need to understand the clinical characteristics of muscle weakness, regardless of underlying disease processes. METHODS: Secondary analysis of data from an earlier qualitative study. Using content analysis of transcripts of semistructured interviews with a multidisciplinary group of 12 experts in the management of muscle disorders, we identified characteristics of muscle weakness from the clinicians' perspectives. RESULTS: Muscle weakness has characteristics of debility, loss of function, and asymmetry. The characteristics of debility include lack of strength, atrophy, and fatigue. Muscle weakness does coexist with muscle tightness. CONCLUSIONS: The characteristics of muscle weakness identified in our study are markedly different from those included in National Library of Medicine definitions. As a condition, muscle weakness has both subjective and objective traits. Therefore, clinician assessment and patient input combined capture the comprehensive nature of muscle weakness. Nurses' awareness of what constitutes muscle weakness, regardless of diagnosis, is the first step in optimal management of this condition.
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BETWEEN the middle and the end of the 19th century, muscular dystrophies were established as clinical and pathological entities distinct from neurogenic muscular atrophies. However, keen eyes of excellent clinicians have never overlooked unusual signs occasionally observed in muscular dystrophy patients. Landouzy and Déjèrine1observed fasciculations in one of their patients with facioscapulohumeral (FSH) dystrophy and stated, "Fibrillary contractions of muscle favor myelopathy." Some cases of atypical muscular dystrophies with fasciculations have been described. As early as 1886 Penzoldt2recognized such a disease and considered it a transitional form between muscular dystrophy and spinal muscular atrophy. Erb3in 1910 emphasized the difficulty in diagnosing muscular dystrophy because of the presence of such a transitional form. However, little attention was paid such atypical muscular dystrophies. Recently, biochemical, electron microscopic, and electrophysiological studies have shown the presence of several new diseases, some of which are clinically difficult to differentiate
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BETWEEN the middle and the end of the 19th century, muscular dystrophies were established as clinical and pathological entities distinct from neurogenic muscular atrophies. However, keen eyes of excellent clinicians have never overlooked unusual signs occasionally observed in muscular dystrophy patients. Landouzy and Déjèrine1observed fasciculations in one of their patients with facioscapulohumeral (FSH) dystrophy and stated, "Fibrillary contractions of muscle favor myelopathy." Some cases of atypical muscular dystrophies with fasciculations have been described. As early as 1886 Penzoldt2recognized such a disease and considered it a transitional form between muscular dystrophy and spinal muscular atrophy. Erb3in 1910 emphasized the difficulty in diagnosing muscular dystrophy because of the presence of such a transitional form. However, little attention was paid such atypical muscular dystrophies. Recently, biochemical, electron microscopic, and electrophysiological studies have shown the presence of several new diseases, some of which are clinically difficult to differentiate
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To increase the knowledge about pregnancy and delivery in women with certain muscle diseases, which is important for obstetric management and family planning of affected women.The obstetric histories of patients with facioscapulohumeral (FSH) muscular dystrophy, limb-girdle (LG) muscular dystrophy, and congenital myopathies (CM) were retrospectively evaluated using questionnaires and medical reports.The condition of 27 patients with different myopathies (FSH muscular dystrophy, n = 11; LG muscular dystrophy, n = 9; and CM, n = 7 [subdivided into 5 patients with central core disease, 1 patient with cytoplasmic bodies, and 1 patient with unspecified myopathy]) were ascertained from January 1, 1992, to December 31, 1994, through departments of neurology and human genetics, and the German self-support group for muscle diseases. Fifty-eight gestations resulting in 52 live births were reviewed.Miscarriages were reported in 3 of 26 gestations in 11 patients with FSH dystrophy, whereas 3 of 15 pregnancies in patients with LG dystrophy were terminated. Preterm births occurred in 2 patients with FSH dystrophy and in 3 patients with CM. Operative deliveries (vaginal operation or cesarean section) were performed in 6 of 23 gestations in patients with FSH dystrophy (1 emergency section), in 5 of 12 patients with LG dystrophy (2 emergency sections), and in 3 of 17 deliveries in patients with CM. Patients with FSH dystrophy generally coped well with their muscle disease in pregnancy and after delivery; however, 4 women were stated to have difficulties in caring for their families. The situation differed in LG dystrophy, where most women (5 of 9) experienced worsening of weakness in pregnancy and required assistance after delivery. In the patients with CM, 3 women experienced a deterioration during pregnancy, and 4 patients reported difficulties after delivery.No deleterious outcome of pregnancy and labor was observed in this series of patients with muscular dystrophy or CM, although operative deliveries were more frequent. A significant aggravation of symptoms in gestation is more likely to occur in patients with early-onset and progressive myopathy than in those with stable disease courses.
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