Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly inherited disorder with an initially restricted pattern of weakness. Early involvement of the facial and scapular stabilizer muscles results in a distinctive clinical presentation. Progression is descending, with subsequent involvement of either the distal anterior leg or hip-girdle muscles. There is wide variability in age at onset, disease severity, and side-to-side symmetry, which is evident even within affected members of the same family. Although FSHD is considered a relatively benign dystrophy by some, as many as 20% of patients eventually become wheelchair-bound. Associated nonskeletal muscle manifestations include high-frequency hearing loss as well as retinal telangiectasias, both of which are rarely symptomatic. The causal genetic lesion in FSHD was described over a decade ago, raising hope that knowledge about its molecular and cellular pathophysiology was soon to follow. In the vast majority of cases, FSHD results from a heterozygous partial deletion of a critical number of repetitive elements (D4Z4) on chromosome 4q35; yet, to date, no causal gene has been identified. The accumulating evidence points to a complex, perhaps unique, molecular genetic mechanism. The absence of detectable expressed sequences from D4Z4, the association of FSHD-causing 4q35 deletions with a specific distal genomic sequence (4qA allele), altered DNA methylation patterns on 4q35, as well as other direct and indirect evidence point to epigenetic mechanisms. As a consequence, partial deletion of D4Z4 results in a (local) chromatin change and ultimately results in the loss of appropriate control of gene expression. There is at present no effective treatment for FSHD. A better understanding of the underlying pathophysiology is needed to design targeted interventions. Despite these limitations, however, two randomized controlled clinical trials have been conducted on FSHD. These trials, along with a previous natural history study, have helped to better define outcome measures for future trials in FSHD as well as other dystrophies.

Facioscapulohumeral muscular dystrophy

Genotype analysis by using the p13E-11 probe and other 4q35 polymorphic markers was performed in 122 Italian facioscapulohumeral muscular dystrophy families and 230 normal controls. EcoRI-BlnI double digestion was routinely used to avoid the interference of small EcoRI fragments of 10qter origin that were found in 15% of the controls. An EcoRI fragment ranging between 10 and 28 kb that was resistant to BlnI digestion was detected in 114 of 122 families (93%) comprising 76 familial and 38 isolated cases. Among the unaffected individuals, 3 were somatic mosaics and 7, carrying an EcoRI fragment larger than 20 kb, could be rated as nonpenetrant gene carriers. In a cohort of 165 patients with facioscapulohumeral muscular dystrophy we found an inverse correlation between fragment size and clinical severity. A severe lower limb involvement was observed in 100% of patients with an EcoRI fragment size of 10 to 13 kb (1-2 KpnI repeats left), in 53% of patients with a fragment size of 16 to 20 kb (3-4 KpnI repeats left), and in 19% of patients with a fragment size larger than 21 kb (>4 KpnI repeats left). Our results confirm that the size of the fragment is a major factor in determining the facioscapulohumeral muscular dystrophy phenotype and that it has an impact on clinical prognosis and genetic counseling of the disease.

Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype.

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.

https://jnnp.bmj.com/content/jnnp/76/10/1406.full.pdf

Experienced fatigue in facioscapulohumeral dystrophy, myotonic dystrophy, and HMSN-I

The objective of this study is to characterize clinical features of joint and skeletal deformities in Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). Clinical information including age, gender, presence of deformity, initial symptom side, neuropsychological and motor features, family history, and treatment with levodopa/dopamine agonists was collected on consecutive patients with PD, MSA, and PSP evaluated at the Movement Disorders Clinic at Baylor College of Medicine. In this series of 202 patients, 36.1% had deformities of the limbs, neck, or trunk, including 33.5% of PD, 68.4% of MSA, and 26.3% of PSP patients. "Striatal" hand and foot deformities were present in 13.4%, involuntary trunk flexion in 12.9%, anterocollis in 9.4%, and scoliosis in 8.4% of all patients. Patients with these joint and skeletal deformities had higher mean Unified Parkinson's Disease Rating Scale scores (57.4 vs. 46.6; P < 0.01) and were more often treated with levodopa (69.9% vs. 50.4%; P < 0.01) than patients without deformity, independent of disease duration. Patients with striatal deformity were younger than patients without deformity (mean 60.4 vs. 68.6 years; P < 0.01), and they tended to have an earlier age of onset of initial parkinsonian symptoms (mean 54.7 vs. 62.5 years; P < 0.01). Furthermore, the side of striatal deformity correlated with the side of initial parkinsonian symptoms in all patients (100%) with striatal hand and in 83.3% of patients with striatal foot. Joint and skeletal deformities are common and frequently under-recognized features of PD, MSA, and PSP that often cause marked functional disability independent of other motor symptoms.

Joint and skeletal deformities in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy

Skeletal muscles are composed of fibres of different types, each type being identified by the isoform of myosin heavy chain which is expressed as slow 1, fast 2A, fast 2X, and fast 2B. Slow fibres are resistant to fatigue due to their highly oxidative metabolism whereas 2X and 2B fibres are easily fatiguable and fast 2A fibres exhibit intermediate fatigue resistance. Slow fibres and fast fibres are present in equal proportions in the adult human diaphragm while intercostal muscles contain a higher proportion of fast fibres. A small fibre size, abundance of capillaries, and a high aerobic oxidative enzyme activity are typical features of diaphragm fibres and give them the resistance to fatigue required by their continuous activity. Because of their fibre composition, intercostal muscles are less resistant to fatigue. The structural and functional characteristics of respiratory muscle fibres are not fixed, however, and can be modified in response to several physiological and pathological conditions such as training (adaptation to changes in respiratory load), adaptation to hypoxia, age related changes, and changes associated with respiratory diseases. The properties of respiratory muscle fibres can also be modified by pharmacological agents such as β 2 agonists and corticosteroids used for the treatment of respiratory diseases.

https://thorax.bmj.com/content/thoraxjnl/59/9/808.full.pdf

G.W. Padberg

Papers

Diagnostic criteria for facioscapulohumeral muscular dystrophy