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BackgroundFacioscapulohumeral dystrophy (FSHD) is an inherited muscular dystrophy clinically characterised by muscle weakness starting with the facial and upper extremity muscles. A disease model has been developed that postulates that failure in somatic repression of the transcription factor DUX4 embedded in the D4Z4 repeat on chromosome 4q causes FSHD. However, due to the position of the D4Z4 repeat close to the telomere and the complex genetic and epigenetic aetiology of FSHD, there is ongoing debate about the transcriptional deregulation of closely linked genes and their involvement in FSHD.MethodDetailed genetic characterisation and gene expression analysis of patients with clinically confirmed FSHD and control individuals.ResultsIdentification of two FSHD families in which the disease is caused by repeat contraction and DUX4 expression from chromosome 10 due to a de novo D4Z4 repeat exchange between chromosomes 4 and 10. We show that the genetic lesion causal to FSHD in these families is physically separated from other candidate genes on chromosome 4. We demonstrate that muscle cell cultures from affected family members exhibit the characteristic molecular features of FSHD, including DUX4 and DUX4 target gene expression, without showing evidence for transcriptional deregulation of other chromosome 4-specific candidate genes.ConclusionThis study shows that in rare situations, FSHD can occur on chromosome 10 due to an interchromosomal rearrangement with the FSHD locus on chromosome 4q. These findings provide further evidence that DUX4 derepression is the dominant disease pathway for FSHD. Hence, therapeutic strategies should focus on DUX4 as the primary target.

ObjectiveTo evaluate facial weakness in patients with FSHD to better define clinical signs, and pilot a facial weakness severity score.Methods87 FSHD patients and 55 controls were video recorded while performing seven facial tasks. The videos were assessed by three independent examiners to compile an overview of signs of facial weakness. Next, videos were semi-quantitatively assessed using a newly developed 4-point facial weakness score (FWS). This score was evaluated and correlated to other FSHD disease characteristics.ResultsPatients had lower scores on the total FWS than controls (mean score 43 ± 28, range 4–118, vs 14 ± 9, range 0–35,p p ConclusionThis study provides an overview of the clinical spectrum of facial weakness and its relation to other disease characteristics. The 4-point scale we introduced to grade the severity of facial weakness enables correlation of facial weakness to disease characteristics, but is not suited as clinical outcome measure for longitudinal studies.

Contains fulltext : 207092.pdf (Publisher’s version ) (Closed access) In the era of patient-centered medicine, shared decision-making (SDM) - in which healthcare professionals and patients exchange information and preferences and jointly reach a decision - has emerged as the gold standard model for the provision of formal healthcare. Indeed, in many geographical settings, patients are frequently invited to participate in choices concerning the design and delivery of their medical management. From a clinical perspective, benefits of this type of patient involvement encompass, for example, enhanced treatment satisfaction, improved medical compliance, better health outcomes, and maintained or promoted quality of life. Yet, although the theory and enactment of SDM in healthcare are well-described in the literature [1-3], comparatively less attention has been devoted to contextualizing questions relating to if, when, and how to include patients in decisions within medical research. In this context, patient involvement would be expected to be potentially relevant for and applicable to a wide range of activities and processes, from the identification of research priorities and development of grant applications, to the design of patient information and consent procedures, formulation of interventions, identification and recruitment of study sample populations, feasibility of a clinical trial, identification, selection, and specification of endpoints and outcomes in clinical trials and observational studies, data collection and analysis, and dissemination of results. To this end, 45 clinicians, healthcare professionals, researchers, patients, caregivers, and representatives from regulatory authorities and pharmaceutical companies from 15 different countries met to discuss the level of involvement of patients with neuromuscular diseases, specifically in the following settings of medical research for neuromuscular diseases: i) registries and biobanks; ii) clinical trials; and iii) regulatory processes. In this report, we present summaries of the talks that were given during the workshop, as well as discussion outcomes from the three topic areas listed above.

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.

To determine how much of the clinical variability in facioscapulohumeral muscular dystrophy type 1 (FSHD1) can be explained by the D4Z4 repeat array size, D4Z4 methylation and familial factors, we included 152 carriers of an FSHD1 allele (23 single cases, 129 familial cases from 37 families) and performed state-of-the-art genetic testing, extensive clinical evaluation and quantitative muscle MRI. Familial factors accounted for 50% of the variance in disease severity (FSHD clinical score). The explained variance by the D4Z4 repeat array size for disease severity was limited (approximately 10%), and varied per body region (facial muscles, upper and lower extremities approximately 30%, 15% and 3%, respectively). Unaffected gene carriers had longer repeat array sizes compared to symptomatic individuals (7.3 vs 6.0 units, P = 0.000) and slightly higher Delta1 methylation levels (D4Z4 methylation corrected for repeat size, 0.96 vs -2.46, P = 0.048). The D4Z4 repeat array size and D4Z4 methylation contribute to variability in disease severity and penetrance, but other disease modifying factors must be involved as well. The larger effect of the D4Z4 repeat array on facial muscle involvement suggests that these muscles are more sensitive to the influence of the FSHD1 locus itself, whereas leg muscle involvement seems highly dependent on modifying factors.

Ophthalmological abnormalities in facioscapulohumeral dystrophy may lead to treatable vision loss, facilitate diagnostics, could help unravelling the pathophysiology and serve as biomarkers. In this study, we provide a detailed description of the ophthalmological findings in a well-defined cohort of patients with facioscapulohumeral dystrophy using state of the art retina imaging techniques. Thirty-three genetically confirmed patients (aged 7–80 years) and 24 unrelated healthy controls (aged 6–68 years) underwent clinical ophthalmological examination, fundus photography, optical coherence tomography/angiography, genotyping and neurological examination. All patients had normal corrected visual acuity and normal intraocular pressure. In 27 of the 33 patients, weakness of the orbicularis oculi was observed. Central retinal pathology, only seen in patients and not in healthy controls, included twisting (tortuosity) of the retinal arteries in 25 of the 33 patients and retinal pigment epithelium defects in 4 of the 33 patients. Asymmetrical foveal hypoplasia was present in three patients, and exudative abnormalities were observed in one patient. There was a correlation between the severity of retinal tortuosity and the D4Z4 repeat array size (R2 = 0.44, P, Ophthalmological abnormalities are an important aspect of facioscapulohumeral dystrophy. We show that retinal abnormalities such as arterial tortuosity are frequent and mostly subclinical in facioscapulohumeral dystrophy. The severity of retinal tortuosity correlated with the genetic defect, thereby providing clinical evidence for an underlying genetic linkage between the retina and facioscapulohumeral dystrophy., Graphical Abstract Graphical Abstract

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Aim: To assess the long-term natural course of early-onset facioscapulohumeral dystrophy (FSHD), which is important for patient management and trial-readiness, and is currently lacking.Methods: We had the unique opportunity to evaluate 10 patients with early-onset FSHD after 22 years follow-up. Patients underwent a semi-structured interview, physical examination and additional genotyping.Results: Nine initial study participants (median age 37 years) were included, one patient died shortly after first publication. At first examination, one patient was wheelchair dependent, one patient walked aided, and eight patients walked unaided. After 22 years, four patients were wheelchair dependent, three walked aided, and two walked unaided. Systemic features, including hearing loss (56%), intellectual disability (44%), and a decreased respiratory function (56%), were frequent. Patients participated socially and economically with most patients living in a regular house (n = 6) and/or having a paid job (n = 4).Discussion: Patients with early-onset FSHD generally had a severe phenotype compared to classical onset FSHD. However, after 22 years of follow up they showed a wide variation in severity and, despite these physical limitations, participated socially and economically. These observations are important for patient management and should be taken into account in clinical trials. (C) 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Objective:To add quantitative muscle MRI to the clinical trial toolbox for facioscapulohumeral muscular dystrophy (FSHD) by correlating it to clinical outcome measures in a large cohort of genetically and clinically well-characterized patients with FSHD comprising the entire clinical spectrum.Methods:Quantitative MRI scans of leg muscles of 140 patients with FSHD1 and FSHD2 were assessed for fatty infiltration and TIRM hyperintensities and were correlated to multiple clinical outcome measures.Results:The mean fat fraction of the total leg musculature correlated highly with the motor function measure, FSHD clinical score, Ricci score, and 6-minute walking test (correlation coefficients −0.845, 0.835, 0.791, −0.701, respectively). Fat fraction per muscle group correlated well with corresponding muscle strength (correlation coefficients up to −0.82). The hamstring muscles, adductor muscles, rectus femoris, and gastrocnemius medialis were affected most frequently, also in early stage disease and in patients without leg muscle weakness. Muscle involvement was asymmetric in 20% of all muscle pairs and fatty infiltration within muscles showed a decrease from distal to proximal of 3.9%. TIRM hyperintense areas, suggesting inflammation, were found in 3.5% of all muscles, with and without fatty infiltration.Conclusions:We show a strong correlation between quantitative muscle MRI and clinical outcome measures. Muscle MRI is able to detect muscle pathology before clinical involvement of the leg muscles. This indicates that quantitative leg muscle MRI is a promising biomarker that captures disease severity and motor functioning and can thus be included in the FSHD trial toolbox.

BACKGROUND: Patient and public involvement for co-creation is increasingly recognized as a valuable strategy to develop healthcare research targeting patients' real needs. However, its practical implementation is not as advanced and unanimously accepted as it could be, due to cultural differences and complexities of managing healthcare programs and clinical studies, especially in the rare disease field. MAIN BODY: The European Neuromuscular Centre, a European foundation of patient organizations, involved its key stakeholders in a special workshop to investigate the position of the neuromuscular patient community with respect to healthcare and medical research to identify and address gaps and bottlenecks. The workshop took place in Milan (Italy) on January 19-20, 2018, involving 45 participants who were mainly representatives of the patient community, but also included experts from clinical centers, industry and regulatory bodies. In order to provide practical examples and constructive suggestions, specific topics were identified upfront. The first set of issues concerned the quality of life at specific phases of a patient's life, such as at the time of diagnosis or during pediatric to adult transition, and patient involvement in medical research on activities in daily living including patient reported outcome measures. The second set of issues concerned the involvement of patients in the management of clinical research tools, such as registries and biobanks, and their participation in study design or marketing authorization processes. Introductory presentations were followed by parallel working group sessions, to gain constructive contributions from all participants. The concept of shared decision making was used to ensure, in discussions, a partnership-based identification of the wishes and needs of all stakeholders involved, and the "ladder of participation" tool served as a model to evaluate the actual and the desired level of patients' involvement in all topics addressed. A general consensus on the outcome of the meeting was collected during the final plenary session. This paper reports the outcome of the workshop and the specific suggestions derived from the analysis of the first set of topics, related to quality of life. The outcomes of the second set of topics are reported elsewhere and are only briefly summarized herein for the sake of completeness. CONCLUSIONS: The neuromuscular community proved to be very active and engaged at different levels in the healthcare initiatives of interest. The workshop participants critically discussed several topics, providing practical examples where different stakeholders could play a role in making a change and bridging gaps. Overall, they indicated the need for education of all stakeholders for better communication, where everyone should become an ambassador to promote real change. Support should also come from institutions and healthcare bodies both at structural and economic level. ispartof: ORPHANET JOURNAL OF RARE DISEASES vol:14 issue:1 ispartof: location:England status: published

Purpose To characterize new molecular factors implicated in a hereditary congenital facial paresis (HCFP) family and otosclerosis. Methods We performed exome sequencing in a four-generation family presenting nonprogressive HCFP and mixed hearing loss (HL). MEPE was analyzed using either Sanger sequencing or molecular inversion probes combined with massive parallel sequencing in 89 otosclerosis families, 1604 unrelated affected subjects, and 1538 unscreened controls. Results Exome sequencing in the HCFP family led to the identification of a rare segregating heterozygous frameshift variant p.(Gln425Lysfs*38) in MEPE. As the HL phenotype in this family resembled otosclerosis, we performed variant burden and variance components analyses in a large otosclerosis cohort and demonstrated that nonsense and frameshift MEPE variants were significantly enriched in affected subjects (p = 0.0006–0.0060). Conclusion MEPE exerts its function in bone homeostasis by two domains, an RGD and an acidic serine aspartate-rich MEPE-associated (ASARM) motif inhibiting respectively bone resorption and mineralization. All variants associated with otosclerosis are predicted to result in nonsense mediated decay or an ASARM-and-RGD-truncated MEPE. The HCFP variant is predicted to produce an ASARM-truncated MEPE with an intact RGD motif. This difference in effect on the protein corresponds with the presumed pathophysiology of both diseases, and provides a plausible molecular explanation for the distinct phenotypic outcome.

Since 1992, the European Neuromuscular Centre facilitated workshops to bring experts in the field of neuromuscular disorders together. After organising more than 235 workshops, it is time to evaluate what impact these 25 years of ENMC workshops have had on the neuromuscular research field and on people affected by a neuromuscular condition. To measure this, workshop topics were retrospectively evaluated and bibliometric analyses on the citation scores of ENMC-derived publications were performed. In addition, a personalized survey was used to investigate the actual achievement and implementation of workshop deliverables. The evaluation of 25 years' workshop topics revealed a strong representation of muscular dystrophies, congenital and mitochondrial myopathies. The publications derived from ENMC workshops scored "high impact" as illustrated by the Mean Normalized Citation Score of 1.24. Also 16% of the ENMC papers belong to the top 10% best cited articles in the neuromuscular field. The main outcome of the personalised survey was that 90% of all workshop deliverables were started and either ongoing or completed. Of these deliverables, 78% were implemented in the field; bringing state-of-the-art knowledge and new collaborations to researchers and clinicians, improving designs of clinical trials and innovating tools to make accurate diagnoses.

Overweight and obesity are common in patients with facioscapulohumeral dystrophy (FSHD) and myotonic dystrophy type 1 (DM1). Lifestyle change is often challenging for patients with neuromuscular diseases, especially to increase physical activity. When lifestyle changes have not been effective, bariatric surgery is a treatment option. However, very little is known about the benefits and risks in patients with neuromuscular disorders. This study therefore aims to obtain insight into the patients' perspectives and experiences, the outcome, effects and risks of bariatric surgery in these disorders. We performed a qualitative study, consisting of 14 in-depth interviews with six patients (three FSHD and three DM1; five women, one man; aged range 31-47 years), four relatives, three bariatric surgeons and one general practitioner. The study used a qualitative descriptive method. Four themes were formulated: (1) overweight as burden; (2) bariatric surgery as last option; (3) not your standard patient; and (4) a different life, a different me. This study shows that bariatric surgery has beneficial physical and mental effects for most patients with FSHD and DM1, and does not influence the muscular disease course. Bariatric surgery is feasible in patients with FSHD and DM1, but specific precautions and a suitable follow-up including tailored dietary and training advices are required. (C) 2018 Elsevier B.V. All rights reserved.

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.

Item does not contain fulltext To better understand postural and movement disabilities, the pattern of total body muscle fat infiltration was analyzed in a large group of patients with facioscapulohumeral muscular dystrophy. Additionally, we studied whether residual D4Z4 repeat array length adjusted for age and gender could predict the degree of muscle involvement. Total body computed tomography scans of 70 patients were used to assess the degree of fat infiltration of 42 muscles from neck to ankle level on a semi-quantitative scale. Groups of muscles that highly correlated regarding fat infiltration were identified using factor analysis. Linear regression analysis was performed using muscle fat infiltration as the dependent variable and D4Z4 repeat length and age as independent variables. A pattern of muscle fat infiltration in facioscapulohumeral muscular dystrophy could be constructed. Trunk muscles were most frequently affected. Of these, back extensors were more frequently affected than previously reported. Asymmetry in muscle involvement was seen in 45% of the muscles that were infiltrated with fat. The right-sided upper extremity showed significantly higher scores for fat infiltration compared to the left side, which could not be explained by handedness. It was possible to explain 29% of the fat infiltration based on D4Z4 repeat length, corrected for age and gender. Based on our results we conclude that frequent involvement of fat infiltration in back extensors, in addition to the abdominal muscles, emphasizes the extent of trunk involvement, which may have a profound impact on postural control even in otherwise mildly affected patients.

Item does not contain fulltext To test the hypothesis that wheelchair dependency and (kypho-)scoliosis are risk factors for developing respiratory insufficiency in facioscapulohumeral muscular dystrophy, we examined 81 patients with facioscapulohumeral muscular dystrophy 1 of varying degrees of severity ranging from ambulatory patients to wheelchair-bound patients. We examined the patients neurologically and by conducting pulmonary function tests: Forced Vital Capacity, Forced Expiratory Volume in 1 second, and static maximal inspiratory and expiratory mouth pressures. We did not find pulmonary function test abnormalities in ambulant facioscapulohumeral muscular dystrophy patients. Even though none of the patients complained of respiratory dysfunction, mild to severe respiratory insufficiency was found in more than one third of the wheelchair-dependent patients. Maximal inspiratory pressures and maximal expiratory pressures were decreased in most patients, with a trend that maximal expiratory pressures were more affected than maximal inspiratory pressures. Wheelchair-dependent patients with (kypho-)scoliosis showed the most restricted lung function. Wheelchair-dependent patients with (kypho-)scoliosis are at risk for developing respiratory function impairment. We advise examining this group of facioscapulohumeral muscular dystrophy patients periodically, even in the absence of symptoms of respiratory insufficiency, given its frequency and impact on daily life and the therapeutic consequences.

Contains fulltext : 182475.pdf (Publisher’s version ) (Closed access) Infantile or early onset is estimated to occur in around 10% of all facioscapulohumeral dystrophy (FSHD) patients. Although small series of early onset FSHD patients have been reported, comprehensive data on the clinical phenotype is missing. We performed a systematic literature search on the clinical features of early onset FSHD comprising a total of 43 articles with individual data on 227 patients. Additional data from four cohorts was provided by the authors. Mean age at reporting was 18.8 years, and 40% of patients were wheelchair-dependent at that age. Half of the patients had systemic features, including hearing loss (40%), retinal abnormalities (37%) and developmental delay (8%). We found an inverse correlation between repeat size and disease severity, similar to adult-onset FSHD. De novo FSHD1 mutations were more prevalent than in adult-onset FSHD. Compared to adult FSHD, our findings indicate that early onset FSHD is overall characterized by a more severe muscle phenotype and a higher prevalence of systemic features. However, similar as in adults, a significant clinical heterogeneity was observed. Based on this, we consider early onset FSHD to be on the severe end of the FSHD disease spectrum. We found natural history studies and treatment studies to be very scarce in early onset FSHD, therefore longitudinal studies are needed to improve prognostication, clinical management and trial-readiness.

Item does not contain fulltext Facioscapulohumeral muscular dystrophy (FSHD: MIM#158900) is a common myopathy with marked but largely unexplained clinical inter- and intra-familial variability. It is caused by contractions of the D4Z4 repeat array on chromosome 4 to 1-10 units (FSHD1), or by mutations in the D4Z4-binding chromatin modifier SMCHD1 (FSHD2). Both situations lead to a partial opening of the D4Z4 chromatin structure and transcription of D4Z4-encoded polyadenylated DUX4 mRNA in muscle. We measured D4Z4 CpG methylation in control, FSHD1 and FSHD2 individuals and found a significant correlation with the D4Z4 repeat array size. After correction for repeat array size, we show that the variability in clinical severity in FSHD1 and FSHD2 individuals is dependent on individual differences in susceptibility to D4Z4 hypomethylation. In FSHD1, for individuals with D4Z4 repeat arrays of 1-6 units, the clinical severity mainly depends on the size of the D4Z4 repeat. However, in individuals with arrays of 7-10 units, the clinical severity also depends on other factors that regulate D4Z4 methylation because affected individuals, but not non-penetrant mutation carriers, have a greater reduction of D4Z4 CpG methylation than can be expected based on the size of the pathogenic D4Z4 repeat array. In FSHD2, this epigenetic susceptibility depends on the nature of the SMCHD1 mutation in combination with D4Z4 repeat array size with dominant negative mutations being more deleterious than haploinsufficiency mutations. Our study thus identifies an epigenetic basis for the striking variability in onset and disease progression that is considered a clinical hallmark of FSHD.

Item does not contain fulltext OBJECTIVE: To investigate the effect of aerobic exercise training (AET) and cognitive-behavioral therapy (CBT) on chronic fatigue in patients with facioscapulohumeral muscular dystrophy (FSHD). METHODS: We performed a multicenter, assessor-blinded, randomized clinical trial (RCT). Fifty-seven patients with FSHD type 1 with severe chronic fatigue were randomly allocated to AET, CBT, or usual care (UC). Outcomes were assessed before treatment, following 16 weeks of intervention, and after a 12-week follow-up. A linear mixed model for repeated measurements was used to study the estimated group differences. RESULTS: Following treatment, both the AET (28 participants) and CBT (25 participants) intervention groups had less fatigue relative to the UC group (24 participants), with a difference of -9.1 for AET (95% confidence interval [CI] -12.4 to -5.8) and -13.3 for CBT (95% CI -16.5 to -10.2). These beneficial effects lasted through follow-up, with a difference of -8.2 for AET (95% CI -12.4 to -5.8) and -10.2 for CBT (95% CI -14.0 to -6.3). The patients who received CBT had an increase in registered and experienced physical activity, sleep quality, and social participation. The patients who received AET had an increase in registered physical activity only. The increase in registered physical activity in both groups and the improvement in social participation following CBT were still present at follow-up. CONCLUSIONS: This RCT shows that AET and CBT can ameliorate chronic fatigue in patients with FSHD. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, in patients with FSHD type 1 and severe chronic fatigue, AET or CBT reduces the severity of chronic fatigue.

Objective: To investigate whether sarcomeric dysfunction contributes to muscle weakness in facioscapulohumeral muscular dystrophy (FSHD). Methods: Sarcomeric function was evaluated by contractile studies on demembranated single muscle fibers obtained from quadriceps muscle biopsies of 4 patients with FSHD and 4 healthy controls. The sarcomere length dependency of force was determined together with measurements of thin filament length using immunofluorescence confocal scanning laser microscopy. X-ray diffraction techniques were used to study myofilament lattice spacing. Results: FSHD muscle fibers produced only 70% of active force compared to healthy controls, a reduction which was exclusive to type II muscle fibers. Changes in force were not due to changes in thin filament length or sarcomere length. Passive force was increased 5- to 12-fold in both fiber types, with increased calcium sensitivity of force generation and decreased myofilament lattice spacing, indicating compensation by the sarcomeric protein titin. Conclusions: We have demonstrated a reduction in sarcomeric force in type II FSHD muscle fibers, and suggest compensatory mechanisms through titin stiffening. Based on these findings, we propose that sarcomeric dysfunction plays a critical role in the development of muscle weakness in FSHD. © 2013 American Academy of Neurology.

Item does not contain fulltext Facioscapulohumeral muscular dystrophy (FSHD) is an inherited and progressive muscle disorder. Although its name suggests otherwise, it comprises weakness of the facial, shoulder and upper arm muscles, and also of the trunk and leg muscles. Its severity and disease course vary greatly and mild or early FSHD can be difficult to recognise. Knowledge of its subtle signs and symptoms can lead directly to the correct diagnosis without diagnostic delay and without needing multiple diagnostic procedures. We give an overview of the signs and symptoms of FSHD in severe as well as in mild cases, to facilitate correct and instant recognition of this relatively common muscle disorder.

An ENMC workshop on standards of care and management of facioscapulohumeral muscular dystrophy (FSHD) patients was held on January 15–17, 2010 in Naarden, The Netherlands. Twenty-four participants from eight countries participated. The primary objective was to develop standards of care in the diagnosis and management of patients with FSHD. Recommendations were formulated based on evidence, when available, or on the consensus of expert opinion. The workshop also identified areas where further studies are needed. Additionally, given the recent progress in understanding the underlying pathophysiology of FSHD, the workshop also examined issues of trial readiness in FSHD including the availability of appropriate outcome measures and access to patients through registries.

Contains fulltext : 88054_2.pdf (Publisher’s version ) (Closed access) Contains fulltext : 88054.pdf (author's version ) (Open Access) Spinal muscular atrophies (SMA, also known as hereditary motor neuropathies) and hereditary motor and sensory neuropathies (HMSN) are clinically and genetically heterogeneous disorders of the peripheral nervous system. Here we report that mutations in the TRPV4 gene cause congenital distal SMA, scapuloperoneal SMA, HMSN 2C. We identified three missense substitutions (R269H, R315W and R316C) affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel in five families. Expression of mutant TRPV4 constructs in cells from the HeLa line revealed diminished surface localization of mutant proteins. In addition, TRPV4-regulated Ca(2+) influx was substantially reduced even after stimulation with 4alphaPDD, a TRPV4 channel-specific agonist, and with hypo-osmotic solution. In summary, we describe a new hereditary channelopathy caused by mutations in TRPV4 and present evidence that the resulting substitutions in the N-terminal ankyrin domain affect channel maturation, leading to reduced surface expression of functional TRPV4 channels. 01 februari 2010

Addition by Contraction Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common hereditary neuromuscular disorders in Western populations, affecting about 1 in 20,000 people. In most patients, the disorder is associated with contraction of a D4Z4 microsatellite repeat array on chromosome 4q, but this contraction can also occur in the absence of disease, so the underlying genetic mechanisms have remained elusive. Lemmers et al. (p. 1650 , published online 19 August; see the Perspective by Mahadevan ) now show that FSHD patients carry sequence variants that create a canonical polyadenylation signal for transcripts derived from DUX4 , a homeobox gene straddling the last D4Z4 repeat unit and the adjacent sequence. Addition of poly(A) stabilizes the DUX4 transcript, which is likely to be a contributing factor in the disease.

Contains fulltext : 80775.pdf (Publisher’s version ) (Closed access) BACKGROUND AND AIMS: Muscle weakness is a potentially important, yet poorly studied, risk factor for falls. Detailed studies of patients with specific myopathies may shed new light on the relation between muscle weakness and falls. Here falls in patients with facioscapulohumeral disease (FSHD) who suffered from lower limb muscle weakness were examined. This study provides insights into the prevalence, relevance and pathophysiology of falls in FSHD. METHODS: A validated questionnaire was used as well as a prospective 3 month follow-up to examine the prevalence, circumstances and consequences of falls in 73 patients with FSHD and 49 matched healthy controls. In a subgroup of 28 subjects, muscle strength was also examined and balance was assessed electrophysiologically using body worn gyroscopes. RESULTS: In the questionnaire, 30% of the patients reported falling at least once a month whereas none of the controls did. Injuries occurred in almost 70% of the patients. The prospective study showed that patients fell mostly at home, mainly due to intrinsic (patient related) causes, and usually in a forward direction. Fallers were unstable while climbing stairs, rising from a chair and standing with eyes closed whereas non-fallers had normal balance control. Frequent fallers had greater muscle weakness than infrequent fallers. CONCLUSION: These findings demonstrate the high prevalence and clinical relevance of falls in FSHD. The relation between muscle weakness and instability among fallers is also highlighted. Because patients fell mainly at home, fall prevention strategies should focus on home adaptations. As mainly intrinsic causes underlie falls, the impact of adopting balance strategies or balance training should be explored in this patient group.

Contains fulltext : 80718.pdf (Publisher’s version ) (Closed access) PURPOSE OF REVIEW: Knowledge of the pathogenetic mechanisms in facioscapulohumeral muscular dystrophy is still scattered, but has recently been advanced through novel developments on the genetic scientific front. RECENT FINDINGS: The present brief review highlights some recent studies on the pathogenesis of facioscapulohumeral muscular dystrophy pointing to major involvement of muscle development pathways and possibly vascular development pathways as well, which feeds into ideas about homeobox-related transcriptional dysregulation, which was originally suggested, based on the apparent descending order of muscle weakness. SUMMARY: The present findings and observations set a broad agenda for further research and possible therapeutic targets.

Contains fulltext : 52246.pdf (Publisher’s version ) (Closed access) BACKGROUND: Patients with facioscapulohumeral muscular dystrophy (FSHD) show a contraction of the D4Z4 repeat array in the subtelomere of chromosome 4q. This D4Z4 contraction is associated with significant allele-specific hypomethylation of the repeat. Hypomethylation of D4Z4 is also observed in patients with phenotypic FSHD without contraction of D4Z4 and in patients with the immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, an unrelated disease that does not present with muscular dystrophy and is in part caused by DNMT3B mutations. METHODS: In order to identify the gene defect and to find the pathogenetic epigenetic pathway in phenotypic FSHD, we have aimed to identify the differences and commonalities in phenotypic FSHD and ICF by 1) investigation of DNA methylation of non-D4Z4 repeat arrays, 2) analysis of mitogen-stimulated lymphocytes to detect pericentromeric abnormalities involving chromosomes 1, 9, and 16, 3) determination of IgA, IgG, and IgM levels, and 4) mutational analysis of candidate genes to identify a second disease locus involved in the pathogenesis of phenotypic FSHD. RESULTS: Our results do not show epigenetic or phenotypic commonalities between phenotypic FSHD and ICF other than the earlier observed D4Z4 hypomethylation. We could not identify any mutations in the candidate genes tested for. CONCLUSION: Our data suggest that in phenotypic FSHD hypomethylation is restricted to D4Z4 and that phenotypic FSHD and ICF do not share a defect in the same molecular pathway.

Contains fulltext : 51802.pdf (Publisher’s version ) (Closed access) BACKGROUND : We recently reported a randomised controlled trial on the efficacy of strength training and the beta2-adrenergic agonist albuterol in patients with facioscapulohumeral muscular dystrophy (FSHD). Strength training and albuterol appeared safe interventions with limited positive effect on muscle strength and volume. We concurrently explored the prevalence and the characteristics of pain and fatigue in the participating FSHD patients, because these are probably underreported but clinically relevant symptoms in this disorder. Next, we studied the effects of albuterol and strength training on pain, experienced fatigue, health-related functional status and psychological distress. METHODS : Sixty-five patients were randomised to strength training of elbow flexors and ankle dorsiflexors or non-training. After 26 weeks, albuterol (sustained-release, 8 mg bid) was added in a randomised, double-blind, placebo-controlled design. Outcomes comprised self-reported pain, experienced fatigue, functional status and psychological distress obtained with validated questionnaires at 52 weeks. RESULTS : Eighty percent of patients reported chronic persistent or periodic, multifocal pains. Thirty-four percent of the participants were severely fatigued. Strength training and albuterol failed to have a significant effect on all outcomes. CONCLUSIONS : Pain and fatigue are important features in FSHD. Strength training and albuterol do not have a positive or negative effect on pain, experienced fatigue, functional status and psychological distress.

Mobius syndrome (MBS) is a neurological disorder that is characterized by paralysis of the facial nerves and variable other congenital anomalies. The aetiology of this syndrome has been enigmatic since the initial descriptions by von Graefe in 1880 and by Mobius in 1888, and it has been debated for decades whether MBS has a genetic or a non-genetic aetiology. Here, we report de novo mutations affecting two genes, PLXND1 and REV3L in MBS patients. PLXND1 and REV3L represent totally unrelated pathways involved in hindbrain development: neural migration and DNA translesion synthesis, essential for the replication of endogenously damaged DNA, respectively. Interestingly, analysis of Plxnd1 and Rev3l mutant mice shows that disruption of these separate pathways converge at the facial branchiomotor nucleus, affecting either motoneuron migration or proliferation. The finding that PLXND1 and REV3L mutations are responsible for a proportion of MBS patients suggests that de novo mutations in other genes might account for other MBS patients., Fundacion Seneca fellowship; EMBO short-term fellowship; IBRO Project InEurope grants programme; Fundacion Cultural Privada Esteban-Romero; European Union FP7 Large-Scale Integrating Project Genetic and Epigenetic Networks in Cognitive Dysfunction; Scientific and Technological Research Council of Turkey (TÜBİTAK); CRANIRARE consortia of the European Research Area Network (E-RARE); Italian Association of Mobius Syndrome (AISMO); Dutch Cancer Society; Netherlands Organization for Health Research and Development

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Contains fulltext : 49602.pdf (Publisher’s version ) (Closed access) Facioscapulohumeral muscular dystrophy (FSHD) is associated with a contraction of the D4Z4 allele on chromosome 4qter. There is also marked DNA hypomethylation of the D4Z4 allele. The DNA hypomethylation may have a central role in the pathogenesis of FSHD. Supplemental folic acid can boost DNA methylation. We evaluated the effect of oral folic acid and methionine supplementation on the methylation level of 4qter D4Z4 alleles in peripheral-blood lymphocytes of nine patients affected with FSHD and six healthy controls. Methylation levels did not change, while recommended serum-folate concentrations were reached.

Contains fulltext : 50478.pdf (Publisher’s version ) (Closed access) Hereditary congenital facial palsy (HCFP) is an autosomal-dominant disorder consisting of paresis or paralysis of the VIIth (facial) cranial nerve. Genetic heterogeneity for this disorder has been suggested based on linkage analysis in two large Dutch families. Two loci have been identified, one on chromosome 3q21.2-q22.1 (HCFP1) and another on chromosome 10q21.3-q22.1 (HCFP2). Here, we report linkage analysis in a large Pakistani family with dominant congenital facial palsy. A region cosegregating with the disorder was identified on the long arm of chromosome 3, which overlaps with the previously identified HCFP1 locus on chromosome 3q21-q22, thus confirming the involvement of this locus in HCFP. The critical region could be reduced from 5.7 to 3.0 cM between the markers D3S3607 and GDB ID:11524500. In addition, mutation analysis on seven candidate genes: KLF15, FLJ40083, PODXL2, TMCC1, PLEXIN-A1, PLEXIN-D1, and GATA-2, was performed. All genes are located within the critical interval of the Dutch HCFP1 family. The genes PODXL2, PLEXIN-D1, GATA-2, and TMCC1 are also located within the smaller critical interval of the Pakistani HCFP family. Based on the results obtained, all seven genes could be excluded as causative genes in HCFP.

Contains fulltext : 48457.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To assess the prevalence of severe fatigue and its relation to functional impairment in daily life in patients with relatively common types of neuromuscular disorders. METHODS: 598 patients with a neuromuscular disease were studied (139 with facioscapulohumeral dystrophy, 322 with adult onset myotonic dystrophy, and 137 with hereditary motor and sensory neuropathy type I). Fatigue severity was assessed with Checklist Individual Strength (CIS-fatigue). Functional impairments in daily life were measured with the short form 36 item health questionnaire (SF-36). RESULTS: The three different neuromuscular patient groups were of similar age and sex. Severe experienced fatigue was reported by 61-74% of the patients. Severely fatigued patients had more problems with physical functioning, social functioning, mental health, bodily pain, and general health perception. There were some differences between the three disorders in the effects of fatigue. CONCLUSIONS: Severe fatigue is reported by the majority of patients with relatively common types of neuromuscular disorders. Because experienced fatigue severity is associated with the severity of various functional impairments in daily life, it is a clinically and socially relevant problem in this group of patients.

Contains fulltext : 32585.pdf (Publisher’s version ) (Closed access) Myositis specific autoantibodies (MSAs) are proven to be specific for myositis compared with other inflammatory connective tissue diseases. Their specificity compared, however, with other neuromuscular disorders, which are included in the differential diagnosis of patients in whom the diagnosis myositis is under consideration, is unknown. We prospectively screened sera from 107 patients with various neuromuscular disorders for the most common MSAs and compared the results with the findings in a group of 97 myositis patients, published previously. Special attention was paid to patients with facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant muscle disease with marked inflammation in skeletal muscle tissue.Only one patient in the neuromuscular disorders group tested positive for an MSA, compared with 41 in the myositis group, resulting in a specificity of 99%. None of the FSHD patients tested positive. We conclude that the tested MSAs are highly specific for myositis and that they are not merely associated with muscle inflammation.

Item does not contain fulltext Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of the D4Z4 repeat on 4q35. We describe a FSHD family of unusual genetic complexity presenting with two independent mitotic contractions of D4Z4 in two successive generations. In addition, a non-pathogenic FSHD-sized allele of approximately the same size is interfering with the DNA diagnosis in this family. Interestingly, this allele is not recognized by the probes 4qA and 4qB representing two distal variants of 4qter, suggesting the presence of yet another, infrequent variant of 4qter.

Contains fulltext : 58455.pdf (Publisher’s version ) (Closed access) BACKGROUND: Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is associated with partial deletion of the subtelomeric D4Z4 repeat array on chromosome 4qter. This chromosomal rearrangement may result in regional chromatin relaxation and transcriptional deregulation of genes nearby. METHODS AND RESULTS: Here we describe the isolation and characterisation of FRG2, a member of a chromosomally dispersed gene family, mapping only 37 kb proximal to the D4Z4 repeat array. Homology and motif searches yielded no clues to the function of the predicted protein. FRG2 expression is undetectable in all tissues tested except for differentiating myoblasts of FSHD patients, which display low, yet distinct levels of FRG2 expression, partly from chromosome 4 but predominantly originating from its homologue on chromosome 10. However, in non-FSHD myopathy patients only distantly related FRG2 homologues are transcribed, while differentiating myoblasts from healthy controls fail to express any member of this gene family. Moreover, fibroblasts of FSHD patients and control individuals undergoing forced Ad5-MyoD mediated myogenesis show expression of FRG2 mainly originating from chromosome 10. Luciferase reporter assays show that the FRG2 promoter region can direct high levels of expression but is inhibited by increasing numbers of D4Z4 repeat units. Transient transfection experiments with FRG2 fusion-protein constructs reveal nuclear localisation and apparently FRG2 overexpression causes a wide range of morphological changes. CONCLUSION: The localisation of FRG2 genes close to the D4Z4 repeats on chromosome 4 and 10, their transcriptional upregulation specifically in FSHD myoblast cultures, potential involvement in myogenesis, and promoter properties qualify FRG2 as an attractive candidate for FSHD pathogenesis.

Item does not contain fulltext This first description of the oculopharyngeal muscular dystrophy (OPMD) phenotype in Dutch patients shows that limb girdle weakness can occur early in the course of disease and can give the first and major complaint in OPMD patients. The aim of this study was to examine clinically, histologically and genetically all Dutch OPMD patients known at the Neuromuscular Centre Nijmegen, to measure the limb girdle weakness (MRC scale) and to quantify the consequences of the limb girdle weakness on daily activities (Rankin scale). Remarkable in this population was the early onset and the severity of the limb girdle weakness. We found a higher percentage of patients with limb girdle weakness than reported before in non-Dutch OPMD populations. This limb girdle weakness caused limitations in daily activities more than the other symptoms of OPMD. It was difficult to compare the severity of the limb girdle weakness of Dutch patients with other patients because of the lack of data related to quantification of limb girdle weakness in non-Dutch OPMD patients. Because of the influence of the limb girdle weakness on the daily activities of the patients, we recommend that more attention is paid to the proximal limb muscles in OPMD patients early in the course of the disease.

Item does not contain fulltext OBJECTIVE: To investigate the variable clinical picture of Mobius syndrome (MIM no. 157900) and to further understand the pathogenesis of the disorder. METHODS: A standardized questionnaire was submitted to 37 Dutch patients with Mobius syndrome. All underwent standardized neurologic examination with special attention to cranial nerve functions, motor skills, and facial and limb anomalies. RESULTS: Of 37 patients with facial paresis, 97% had bilateral and 3% had unilateral ocular abduction weakness. Further analysis showed isolated abducens nerve palsy in 9%, a conjugated horizontal gaze paresis in 48%, features of Duane retraction syndrome in 34%, and congenital fibrosis of the extraocular muscles in 9%. Other signs included lingual involvement (77%), dysfunction of palate and pharynx (56%), general motor disability (88%), poor coordination (83%), and respiratory abnormalities (19%). CONCLUSION: Mobius syndrome is more than a cranial nerve or nuclear developmental disorder. It is a syndrome of rhombencephalic maldevelopment involving predominantly motor nuclei and axons, as well as traversing long tracts. The authors also noted gaze palsies, Duane retraction syndrome, feeding and respiratory problems, and poor motor development, suggesting a regional developmental disorder.

Item does not contain fulltext OBJECTIVE: Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is associated with a contraction of the D4Z4 repeat array on chromosome 4. So far, homozygosity or compound heterozygosity for FSHD alleles has not been described, and it has been debated whether the absence of such subjects is because of the rarity or the lethality of the disorder. METHODS: Two unrelated families in which the probands are compound heterozygous for two FSHD-sized alleles were studied. Clinical examination, pulsed-field gel electrophoresis (PFGE) studies of DNA with probes proximal and distal to D4Z4, and cytogenetic analysis of metaphase chromosomes by FISH were performed. RESULTS: Complementary molecular and cytogenetic approaches confirmed the chromosome 4qA origin of all FSHD-sized repeat arrays that segregate in the families. CONCLUSIONS: Heterozygosity for FSHD-sized alleles is compatible with life in men and women. A possible dosage effect was observed in both probands in whom each 4qA allele contributed to the FSHD phenotype. Because at least one of the FSHD alleles in both families showed an unusual low penetrance, the authors propose that susceptibility for FSHD is partly determined by intrinsic properties of the disease allele other than the residual D4Z4 repeat size alone.

Contains fulltext : 137803.pdf (Publisher’s version ) (Open Access) Facioscapulohumeral muscular dystrophy (FSHD) is an untreatable disease, characterized by asymmetric progressive weakness of skeletal muscle with fatty infiltration. Although the main genetic defect has been uncovered, the downstream mechanisms causing FSHD are not understood. The objective of this study was to determine natural disease state and progression in muscles of FSHD patients and to establish diagnostic biomarkers by quantitative MRI of fat infiltration and phosphorylated metabolites. MRI was performed at 3T with dedicated coils on legs of 41 patients (28 men/13 women, age 34-76 years), of which eleven were re-examined after four months of usual care. Muscular fat fraction was determined with multi spin-echo and T1 weighted MRI, edema by TIRM and phosphorylated metabolites by 3D (31)P MR spectroscopic imaging. Fat fractions were compared to clinical severity, muscle force, age, edema and phosphocreatine (PCr)/ATP. Longitudinal intramuscular fat fraction variation was analyzed by linear regression. Increased intramuscular fat correlated with age (p

Item does not contain fulltext OBJECTIVE: To determine the incidence and prevalence of facioscapulohumeral muscular dystrophy (FSHD) in the Netherlands. METHODS: Using 3-source capture-recapture methodology, we estimated the total yearly number of newly found symptomatic individuals with FSHD, including those not registered in any of the 3 sources. To this end, symptomatic individuals with FSHD were available from 3 large population-based registries in the Netherlands if diagnosed within a 10-year period (January 1, 2001 to December 31, 2010). Multiplication of the incidence and disease duration delivered the prevalence estimate. RESULTS: On average, 52 people are newly diagnosed with FSHD every year. This results in an incidence rate of 0.3/100,000 person-years in the Netherlands. The prevalence rate was 12/100,000, equivalent to 2,000 affected individuals. CONCLUSIONS: We present population-based incidence and prevalence estimates regarding symptomatic individuals with FSHD, including an estimation of the number of symptomatic individuals not present in any of the 3 used registries. This study shows that the total number of symptomatic persons with FSHD in the population may well be underestimated and a considerable number of affected individuals remain undiagnosed. This suggests that FSHD is one of the most prevalent neuromuscular disorders.

Facioscapulohumeral muscular dystrophy is caused by partial deletion of the D4Z4 repeat array on chromosome 4q35. Genetic diagnosis is based on sizing of this repeat array, which is complicated by cross-hybridization of a homologous polymorphic repeat array on chromosome 10 and by the frequent exchanges between these chromosomal regions. The restriction enzyme XapI optimizes the diagnosis of facioscapulohumeral muscular dystrophy by uniquely digesting 4-derived repeat units and leaving 10-derived repeat units undigested, thus complementing BlnI, which uniquely digests 10-derived repeat units. A triple analysis with EcoRI, EcoRI/BlnI, and XapI unequivocally allows characterization of each of the four alleles, whether homogeneous or hybrid. This is particularly useful in the case of identical sized 4-derived and 10-derived arrays, in situations of suspected facioscapulohumeral muscular dystrophy with nonstandard allele configurations, and for assignment of hybrid fragments to their original alleles.

Objectives To characterize clinically and molecularly a large, non-chromosome 4-linked facioscapulohumeral muscular dystrophy (FSHMD) family. Methods Neurological evaluations of affected (N = 55) and at-risk (N = 48) individuals were performed along with selected laboratory analyses, including creatine kinase testing, muscle biopsy, p13E-11 fragment analysis, and cytogenetic studies. Genetic analyses of the scapuloperoneal muscular dystrophy and scapuloperoneal muscular atrophy regions on chromosome 12 were performed using genetic markers flanking the intervals of interest and parametric LOD score analyses. Results Clinically, the FSHMD in individuals in this family is indistinguishable from that observed in chromosome 4-linked FSHMD. Fragment analysis with p13E-11 showed no small fragment segregating with the family and no evidence for 4:10 translocation or deletion of the p13E-11 binding site. Linkage analysis excluded the loci for autosomal-dominant scapuloperoneal muscular dystrophy and scapuloperoneal muscular atrophy. Conclusions This family is clinically similar to patients with the chromosome 4-linked FSHMD. These data support our previous hypothesis of genetic heterogeneity within FSHMD.

Chromosomal rearrangements occur more frequently in subtelomeric domains than in other regions of the genome and are often associated with human pathology. To further elucidate the plasticity of subtelomeric domains, we examined the 3.3 kb D4Z4 repeat array on chromosome 4 and its homologue on chromosome 10 in 208 Dutch blood donors by pulsed field gel electrophoresis. These subtelomeric repeats are known to rearrange and partial deletions of this polymorphic array on chromosome 4 are associated with facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant myopathy. Our results show that mitotic rearrangements occur frequently as 3% of individuals display somatic mosaicism for a repeat expansion or contraction explaining the high variability of subtelomeric repeat array sizes. Translocated 4-type repeat arrays on chromosome 10 and the reverse configuration of 10-type repeat arrays on chromosome 4 are observed in 21% of individuals. The translocated repeat arrays on chromosome 4 tend to be more heterogeneous than 4-type repeats on chromosome 10. The repeat length on chromosome 4 is on average larger than on chromosome 10. But on both chromosomes we observe a multi-modal repeat length distribution with equidistant peaks at intervals of 65 kb, possibly reflecting a higher-order chromatin structure. Interestingly, in as many as six random blood donors (3%) we identified FSHD-sized 4-type repeat arrays. Assuming that these individuals are clinically unaffected, these results imply an incomplete penetrance in the upper range of FSHD alleles. Overall, the observed dynamic characteristics of these homologous domains may serve as a model for subtelomeric plasticity.