Search

Facioscapulohumeral muscular dystrophy 2 (FSHD2) is a genetic muscular disorder characterized by DNA hypomethylation on the 4q-subtelomeric macrosatellite repeat array, D4Z4. FSHD2 is caused by heterozygous mutations in the gene encoding structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1). Because there has been no study on FSHD2 in Asian populations, it is not known whether this disease mechanism is widely seen. To identify FSHD2 patients with SMCHD1 mutations in the Japanese population, bisulfite pyrosequencing was used to measure DNA methylation on the D4Z4 repeat array, and in patients with DNA hypomethylation, the SMCHD1 gene was sequenced by the Sanger method. Twenty patients with D4Z4 hypomethylation were identified. Of these, 13 patients from 11 unrelated families had ten novel and one reported SMCHD1 mutations: four splice-site, two nonsense, two in-frame deletion, two out-of-frame deletion, and one missense mutations. One of the splice-site mutations was homozygous in the single patient identified with this. In summary, we identified novel SMCHD1 mutations in a Japanese cohort of FSHD2 patients, confirming the presence of this disease in a wider population than previously known., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Unlabelled: The purpose of the study was to determine muscle metabolism adaptation to exercise in facioscapulohumeral muscular dystrophy patients (FSHD) and to study the correlation with clinical functional status (6-min walk test). 8 FSHD patients and 15 age-matched healthy controls (Controls) performed two isokinetic constant-load knee extension exercises: (1) at 20% of their maximal extensors' peak torque (i.e., the same relative workload) and (2) at (20N⋅m) (the same absolute workload) for up to 4 min. All exercises consisted of rhythmic, voluntary, isokinetic, concentric contractions of the quadriceps femoris at 90°/s, whereas the flexion was performed passively at the same speed. Muscle oxygenation in the vastus lateralis was evaluated using near-infrared spectroscopy (NIRS). The FSHD patients displayed a lower maximal peak torque than controls (-41%, p < 0.05). During the two-exercise modalities, deoxygenated haemoglobin (HHb) and total haemoglobin volume (tHb) were lower in the FSHD patients (p < 0.05). The initial muscle deoxygenation time delay was shorter in the control group (FSHD: 15.1 ± 4.1 s vs., Controls: 10.4 ± 2.1 s, p < 0.05). Mean response time and maximal peak torque were both correlated with functional impairment (walking endurance). The results suggest that FSHD patients present an impairment in their capacity to deliver or to use oxygen., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The objective of this study was to investigate the clinical and genetic features of Korean patients with facioscapulohumeral muscular dystrophy type 1 (FSHD), and assessed the impact of molecular defects on phenotypic expression. We enrolled 104 FSHD patients from 87 unrelated Korean families with D4Z4 repeat array of less than 11 copies on 4q35. Sixty-one men and forty-three women were enrolled. Median D4Z4 copy number was 4 units and 99 (95%) Korean patients with FSHD carried 1-6 units. The median age at symptom onset was 13 [interquartile range: 8-17] years old. In 100 symptomatic patients, muscle weakness began in facial muscles in 58 patients, shoulder-girdle muscles in 37, and pelvic-girdle muscles in 5. Disease severity was significantly correlated with D4Z4 copy number. In addition, women were more severely affected than men even though there were no differences in age at examination or in D4Z4 copy number between the two genders. This gender difference among Korean patients was the opposite of analysis on individuals of European ancestry. In conclusion, the present study demonstrated the new diagnostic threshold for FSHD in Koreans based on the D4Z4 repeat array size distribution from 1 to 6 units and expanded the clinical spectrum., (Copyright © 2015 Elsevier B.V. All rights reserved.)

We report the first case of a heterozygous T78M mutation in the caveolin-3 gene (CAV3) associated with rippling muscle disease and proximal myopathy. The patient displayed also bilateral winged scapula with limited abduction of upper arms and marked asymmetric atrophy of leg muscles shown by magnetic resonance imaging. Immunohistochemistry on the patient's muscle biopsy demonstrated a reduction of caveolin-3 staining, compatible with the diagnosis of caveolinopathy. Interestingly, consistent with the possible diagnosis of FSHD, the patient carried a 35 kb D4Z4 allele on chromosome 4q35. We discuss the hypothesis that the two genetic mutations may exert a synergistic effect in determining the phenotype observed in this patient., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The peripheral retinal vascular abnormality which accompanies FSHD belongs morphologically and clinically to a class of developmental 'retinal hypovasculopathies' caused by abnormalities of 'Wnt' signalling, which controls retinal angiogenesis. Wnt signalling is also fundamental to myogenesis. This paper integrates modern concepts of myogenic cell signalling and of transcription factor expression and control with data from the classic early ophthalmic and myology embryology literature. Together, they support an hypothesis that abnormalities of Wnt signalling, which activates myogenic programs and transcription factors in myoblasts and satellite cells, leads to defective muscle regeneration in FSHD. The selective vulnerability of different FSHD muscles (notably facial muscle, from the second branchial arch) might reflect patterns of transcription factor redundancies. This hypothesis has implications for FSHD research through study of transcription factors patterning in normal human muscles, and for autologous cell transplantation., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Cardiac disease is a common clinical manifestation of neuromuscular disorders, particularly of muscular dystrophies. Heart muscle cells as well as specialized conducting myocardial fibres may be affected by the dystrophic process. The incidence and nature of cardiac involvement vary with different types of muscular dystrophies. Some mainly lead to myocardial disease, resulting in cardiomyopathy and heart failure, while others particularly affect the conduction system, leading to arrhythmias and sudden death. As prognosis of muscular dystrophy patients may be directly related to cardiac status, surveillance and timely management of cardiac complications are important. However, recognition of cardiac involvement requires active investigation and remains challenging since typical signs and symptoms of cardiac dysfunction may not be present and progression is unpredictable. In this review, we present a comprehensive overview of hereditary muscular dystrophies associated with cardiac disease to provide an efficient strategy for the expertise and management of these diseases., (2010 Elsevier B.V. All rights reserved.)

The purpose of this study was to implement a quantitative MR imaging method for the determination of muscular and fat content in individual skeletal muscles of patients with facioscapulohumeral muscular dystrophy (FSHD). Turbo Inversion Recovery Magnitude (TIRM) and multiecho MR images were acquired from seven FSHD patients and healthy volunteers. Signal decay in the multiecho MR images was fitted to a biexponential function with fixed relaxation rates for muscle and fat tissue and used to calculate the degree of fatty infiltration in eight muscles in the lower leg. Considerable differences in fatty infiltration between different muscles were observed in FSHD patients, suggesting that this could be used as a biomarker for disease progression. TIRM imaging indicated an inflammatory component of the disease previously only observed in muscle biopsies. Typically, muscle involvement was non-uniform even within one muscle, indicating that MRI can be used as a valuable tool to study pathophysiology and therapy evaluation in FSHD.

Only three facioscapulohumeral muscular dystrophy (FSHD) patients have been reported to have cardiomyopathy. An asymptomatic 38-year-old man was incidentally found to have electrocardiographic abnormalities. His echocardiogram demonstrated mild dilatation of the left ventricle and poor contractility. Cardiac histopathology indicated hypertrophic cardiomyopathy. Later he developed muscle weakness in the right arm. Scapular winging and asymmetrical facial weakness were evident. Muscle biopsy at the age of 44 years showed myopathic changes consistent with FSHD. His daughter had symptoms of infantile FSHD, which was genetically confirmed. This is the first report of an FSHD patient with biopsy-proven cardiomyopathy.

This case report describes a young boy with concomitant genetically-confirmed Duchenne muscular dystrophy and facioscapulohumeral muscular dystrophy with a novel dystrophin mutation in exon 6 and a D4Z4 fragment of 31 kb. This child presented with a more severe phenotype than expected for either individual disease process and underscores the role for thorough diagnostic investigation in identifying atypical clinical presentations.

Point mutations in mtDNA-encoded tRNA genes frequently cause isolated myopathies but rarely cause the facioscapulohumeral phenotype. We report on a patient affected with chronic progressive weakness of facioscapulohumeral/peroneal muscles whose muscle biopsy showed a mitochondrial myopathy. mtDNA direct sequencing and RFLP analysis revealed a heteroplasmic transition T12313C which disrupts a conserved site in the T Psi C stem of the tRNA(Leu(CUN)) gene and fulfills the accepted criteria of pathogenicity. A partial deletion of the nuclear DNA D4Z4 region with residual repeat sizes of 25 kb was also found in the patient and in her mother. This is the first reported case of mitochondrial myopathy/facioscapulohumeral muscular dystrophy (FSHD) "double trouble".

Facioscapulohumeral muscular dystrophy (FSHD) patients carry contractions of the D4Z4-tandem repeat array on chromosome 4q35. Decrease in D4Z4 copy number is thought to alter a chromatin structure and activate expression of neighboring genes. D4Z4 contains a putative double-homeobox gene called DUX4. We identified DUX4 mRNAs in cells transfected with genomic fragments containing the DUX4 gene. Using RT-PCR we also recognized expressed DUX4 mRNAs in primary FSHD myoblasts. Polyclonal antibodies raised against specific DUX4 peptides detected the DUX4 protein in cells transfected with D4Z4 elements. DUX4 localizes in the nucleus of cells transfected with CMV-DUX4 expression vectors. A DUX4-related protein is endogenously expressed in nuclei of adult and fetal human rhabdomyosarcoma cell lines. Overexpression of DUX4 induces cell death, induces caspase 3/7 activity and alters emerin distribution at the nuclear envelope. We propose that DUX4-mediated cell death contributes to the pathogenic pathway in FSHD.

Facioscapulohumeral muscular dystrophy has a distinctive regional distribution but variable clinical expression and may be markedly asymmetrical. We report two patients presenting weakness and wasting confined to a single lower limb. Creatine kinase was slightly increased, electromyogram and muscle biopsy were myopathic. Muscle computed tomography showed normal shoulder, mid-arm, pelvic and mid-thigh scans but involvement of calf muscles. In both cases, weakness of facial and periscapular muscles was found in other family members unaware of the disease. Molecular analysis showed 4q35 deletion in one family. These cases broaden the presentation of facioscapulohumeral muscular dystrophy to include isolated monomelic atrophy of lower limb with calf muscle involvement.