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Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study.

ABSTRACT: OBJECTIVE:Facioscapulohumeral 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. METHODS:We performed a nationwide, single-investigator, natural history study on FSHD in childhood. RESULTS:Multiple-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. INTERPRETATION:FSHD 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.

SUBMITTER: Goselink RJM

PROVIDER: S-EPMC6282793 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study.

Goselink Rianne J M RJM Schreuder Tim H A THA van Alfen Nens N de Groot Imelda J M IJM Jansen Merel M Lemmers Richard J L F RJLF van der Vliet Patrick J PJ van der Stoep Nienke N Theelen Thomas T Voermans Nicol C NC van der Maarel Silvère M SM van Engelen Baziel G M BGM Erasmus Corrie E CE

Annals of neurology 20181016 5

<h4>Objective</h4>Facioscapulohumeral 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.<h4>Methods</h4>We performed a nationwide, single-investigator, natural history study on FSHD in childhood.<h4>Results</h4>Multiple-source recruitme ...[more]

PMID: 30179273

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Project description:BackgroundFacioscapulohumeral muscular dystrophy (FSHD; OMIM 158900 & 158901) is a progressive skeletal muscle dystrophy, characterized by an autosomal dominant inheritance pattern. One of the major unsolved questions in FSHD is the marked clinical heterogeneity, ranging from asymptomatic individuals to severely affected patients with an early onset. An estimated 10% of FSHD patients have an early onset (onset before 10 years of age) and are traditionally classified as infantile FSHD. This subgroup is regarded as severely affected and extra-muscular symptoms, such as hearing loss and retinopathy, are frequently described. However, information on the prevalence, natural history and clinical management of early onset FSHD is currently lacking, thereby hampering adequate patient counselling and management. Therefore, a population-based prospective cohort study on FSHD in children is highly needed.Methods/designThis explorative study aims to recruit all children (aged 0-17 years) with a genetically confirmed diagnosis of FSHD in The Netherlands. The children will be assessed at baseline and at 2-year follow-up. The general aim of the study is the description of the clinical features and genetic characteristics of this paediatric cohort. The primary outcome is the motor function as measured by the Motor Function Measure. Secondary outcomes include quantitative and qualitative description of the clinical phenotype, muscle imaging, genotyping and prevalence estimations. The ultimate objective will be a thorough description of the natural history, predictors of disease severity and quality of life in children with FSHD.DiscussionThe results of this population-based study are vital for adequate patient management and clinical trial-readiness. Furthermore, this study is expected to provide additional insight in the epigenetic and environmental disease modifying factors. In addition to improve counselling, this could contribute to unravelling the aetiology of FSHD.Trial registrationclinicaltrials.gov NCT02625662.

Project description:BACKGROUND:Infantile neuroaxonal dystrophy (INAD) is a rapidly progressive neurodegenerative disorder of early onset causing premature death. It results from biallelic pathogenic variants in PLA2G6, which encodes a calcium-independent phospholipase A2. OBJECTIVE:We aim to outline the natural history of INAD and provide a comprehensive description of its clinical, radiological, laboratory, and molecular findings. MATERIALS AND METHODS:We comprehensively analyzed the charts of 28 patients: 16 patients from Riyadh, Saudi Arabia, 8 patients from North and South America and 4 patients from Europe with a molecularly confirmed diagnosis of PLA2G6-associated neurodegeneration (PLAN) and a clinical history consistent with INAD. RESULTS:In our cohort, speech impairment and loss of gross motor milestones were the earliest signs of the disease. As the disease progressed, loss of fine motor milestones and bulbar dysfunction were observed. Temporo-frontal function was among the last of the milestones to be lost. Appendicular spastic hypertonia, axial hypotonia, and hyperreflexia were common neurological findings. Other common clinical findings include nystagmus (60.7%), seizures (42.9%), gastrointestinal disease (42.9%), skeletal deformities (35.7%), and strabismus (28.6%). Cerebellar atrophy and elevations in serum AST and LDH levels were consistent features of INAD. There was a statistically significant difference when comparing patients with non-sense/truncating variants compared with missense/in-frame deletions in the time of initial concern (p?=?0.04), initial loss of language (p?=?0.001), initial loss of fine motor skills (p?=?0.009), and initial loss of bulbar skills (p?=?0.007). CONCLUSION:INAD is an ultra-rare neurodegenerative disorder that presents in early childhood, with a relentlessly progressive clinical course. Knowledge of the natural history of INAD may serve as a resource for healthcare providers to develop a targeted care plan and may facilitate the design of clinical trials to treat this disease.

Project description:Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9 years, range: 0.0-2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8-4.0) and age of ambulation loss (median: 7 years, range: 1.2-38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype-phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopaedic, cardiac and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations.

Dataset Information

Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study.

Publications

Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study.

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