Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array. Recent studies revealed that the FAT1 expression is associated with disease activity of FSHD, and the FAT1 alterations result in myopathy with a FSHD-like phenotype. We describe a 59-year-old woman with both contracted D4Z4 repeat units and a FAT1 mutation. Shoulder girdle muscle weakness developed at the age of 56 years, and was followed by proximal leg weakness. When we examined her at 59 years of age, she displayed asymmetric and predominant weakness of facial and proximal muscles. Muscle biopsy showed increased variation in fiber size and multifocal degenerating fibers with lymphocytic infiltration. Southern blot analysis revealed 8 D4Z4 repeat units, and targeted sequencing of modifier genes demonstrated the c.10331 A>G variant in the FAT1 gene. This FAT1 variant has previously been reported as pathogenic variant in a patient with FSHD-like phenotype. Our study is the first report of a FAT1 mutation in a FSHD1 patient, and suggests that FAT1 alterations might work as a genetic modifier.
Cadherins/*genetics ; Female ; Humans ; Magnetic Resonance Imaging ; Middle Aged ; Muscles/pathology ; Muscular Dystrophy, Facioscapulohumeral/diagnostic imaging/*genetics/pathology ; Mutation/*genetics ; Phenotype

BackgroundFacioscapulohumeral muscular dystrophy (FSHD) is characterized by asymmetric muscular deficit of facial, shoulder-girdle muscles, and descending to lower limb muscles, but it exists in several extramuscular manifestations or overlapping syndromes. Herein, we report a "complex disease plus" patient with FSHD1, accompanied by peripheral neuropathy and myoclonic epilepsy.

MethodsStandard clinical assessments, particular auxiliary examination, histological analysis, and molecular analysis were performed through the new Comprehensive Clinical Evaluation Form, pulsed-field gel electrophoresis-based Southern blot, Multiplex Ligation-dependent Probe Amplification (MLPA), whole exome sequencing (WES), and targeted methylation sequencing.

ResultsThe patient presented with mild facial weakness, humeral poly-hill sign, scapular winging, peroneal weakness, drop foot, pes cavus, and myoclonic epilepsy. Furthermore, electrophysiology revealed severely demyelinated and axonal injury. The muscle and nerve biopsy revealed broadly fiber Type II grouping atrophy and myelinated nerve fibers that significantly decreased with thin myelinated fibers and onion bulbs changes. Generalized sharp and sharp-slow wave complexes on electroencephalography support the diagnosis toward myoclonic epilepsy. In addition, molecular testing demonstrated a co-segregated 20-kb 4q35-EcoRI fragment and permissive allele A, which corresponded with D4Z4 hypomethylation status in the family. Both the patient's mother and brother only presented the typical FSHD but lacked overlapping syndromes. However, no mutations for hereditary peripheral neuropathy and myoclonic epilepsy were discovered by MLPA and WES.

ConclusionsThe present study described a "tripe trouble" with FSHD, peripheral neuropathy, and myoclonic epilepsy, adding the spectrum of overlapping syndromes and contributing to the credible diagnosis of atypical phenotype. It would provide a direct clue on medical care and genetic counseling.

Adult ; Child ; Epilepsies, Myoclonic ; complications ; Evoked Potentials, Visual ; Humans ; Male ; Muscle, Skeletal ; Muscular Dystrophy, Facioscapulohumeral ; complications ; Peripheral Nervous System Diseases ; complications

Facioscapulohumeral muscular dystrophy (FSHD) presents a muscular weakness in the face, shoulder girdle, and legs. In addition, bilateral, progressive, high-frequency sensorineural hearing loss (SNHL) can be expressed. A 3-year-old boy visited with bilateral facial paralysis and bilateral hearing loss. Audiological evaluations revealed bilateral, progressive, sloping SNHL and bilateral hearing aids was used for more than 3 years. Cochlear implantation was carried out on left side when he was 6 years old and on right side when he was 7 years old. Seven months after cochlear implantation on left side, his shoulder muscle weakness was found and the genetic analysis showed decreased D4Z4 repeat size in 4qA allele confirming a diagnosis of FSHD. After auditory rehabilitation using electroacoustic stimulation, his hearing and speech perception were much improved. This case suggests that cochlear implantation can be beneficial in patients with SNHL associated with FSHD.
Alleles ; Child, Preschool ; Cochlear Implantation* ; Cochlear Implants* ; Diagnosis ; Facial Paralysis ; Hearing ; Hearing Aids ; Hearing Loss ; Hearing Loss, Bilateral ; Hearing Loss, Sensorineural* ; Humans ; Leg ; Male ; Muscle Weakness ; Muscular Dystrophy, Facioscapulohumeral* ; Rehabilitation ; Shoulder ; Speech Perception

Adolescent ; Adult ; Asian Continental Ancestry Group ; genetics ; China ; DNA Methylation ; Female ; Humans ; Male ; Muscular Dystrophy, Facioscapulohumeral ; genetics ; Pedigree ; Young Adult

BACKGROUNDFacioscapulohumeral muscular dystrophy (FSHD), a common autosomal dominant muscular disorder, is caused by contraction of the D4Z4 repeats on 4q35. The complicated genotype-phenotype correlation among different ethnic population remains a controversial subject. We aimed to refine this correlation in order to provide new information for genetic counseling.

METHODSHere, a cohort of 136 Chinese families including 178 affected individuals and 137 unaffected members were investigated. Genetic analyses were performed using the p13E-11, 4qA and 4qB probes after pulsed field gel electrophoresis separation and southern blotting. A 10-grade FSHD clinical severity scale was adopted for clinical assessment. The genotype-phenotype correlation was established by linear regression analyses.

RESULTSWe observed a roughly inversed correlation between the short EcoRI fragment size and age-corrected clinical severity score in 154 symptomatic patients (P < 0.05). Compared to male patients, a significant higher proportion of females in both asymptomatic carriers and severe patients showed larger variation in the size of short EcoRI fragment. A high incidence (19/42, 45.2%) of asymptomatic (or minimally affected) carriers was found in familial members.

CONCLUSIONSAlthough the number of D4Z4 repeats is known as one of the critical influences on genotype-phenotype correlation, a majority of phenotypic spectrum was still incompatible with their heterozygous contraction of the D4Z4 repeat, especial in female cases. Our results suggest that there are multi-factors synergistically modulating the phenotypic expression.

Adolescent ; Adult ; Asian Continental Ancestry Group ; genetics ; Child ; Child, Preschool ; Female ; Genetic Association Studies ; Humans ; Male ; Middle Aged ; Muscular Dystrophy, Facioscapulohumeral ; genetics ; pathology ; Phenotype ; Retrospective Studies ; Young Adult

Humans ; Muscular Dystrophy, Facioscapulohumeral ; Neurodegenerative Diseases ; Neurology ; Research ; Spinocerebellar Ataxias

Adolescent ; Adult ; Female ; Humans ; Male ; Middle Aged ; Muscular Dystrophy, Facioscapulohumeral ; diagnosis ; genetics ; Pedigree ; Young Adult

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is associated with contractions of the polymorphic D4Z4-repeat array in 4q35 and has the distinctive clinical presentation of an initial involvement of the facial, shoulder-girdle, and upper-arm muscles. The aim of the present study was to determine clinical characteristics in Korean patients with FSHD and potential relationships between contracted D4Z4-repeat size and the FSHD phenotype. METHODS: We studied 34 genetically confirmed patients who had repeat sizes less than 38 kb, and analyzed their clinical manifestations with a structured protocol. The expressed phenotypes were scored according to the Clinical Severity Score formulated by Ricci and van Overveld. RESULTS: The clinical spectrum ranged widely, from asymptomatic individuals with minimal signs to wheelchair- bound patients. The initial affects were mainly in the facial muscles (68.8%), followed by the shoulder-girdle muscle (28.1%). Asymmetric features of the face and shoulder girdle were also important findings (71.9% and 90.0%, respectively). Winging scapular (87.5%), transverse smile (84.4%), Beevor's sign (68.8%), and sleeping with eyes opened (59.4%) were clinically important signs. There was a significant negative correlation between repeat size and clinical severity (r=-0.38, p=0.03). CONCLUSIONS: Distinctive clinical characteristics of FSHD are descending progression and asymmetric distribution of the muscle weakness. Our results also confirmed that the severity of FSHD increases with decreasing D4Z4-repeat size.
Contracts ; Eye ; Facial Muscles ; Genotype ; Humans ; Muscle Weakness ; Muscles ; Muscular Dystrophies ; Muscular Dystrophy, Facioscapulohumeral ; Phenotype ; Shoulder

OBJECTIVES: Sporadic inclusion body myositis (s-IBM) is characterized by progressive muscle weakness and inclusion bodies on muscle biopsy and is the most common type of myopathy in patients over 50 years old. However, it is not only under-diagnosed but also frequently misdiagnosed as polymyositis hence treated with steroids. In the evaluation of progressive weakness in older males, S-IBM should be investigated. This case report and literature review is presented to explore these issues. A discussion on the clinical and laboratory manifestations and histopathological findings are also included.

REPORT OF THE CASE: A 42-year-old male presented with six-year history of a slowly progressive weakness seen as difficulty brushing his teeth, buttoning his shirt, tying his shoelaces, associated with progressive dysphagia. He undergone EMGNCV of all extremities and was given a provisional diagnosis of facioscapulohumeral dystrophy. He was treated with Prednisone 5 mg/tab, 2 tablets twice a week, which he took for 2 years but afforded no relief. The weakness progressed, and he eventually required assistance to walk. Pertinent on general physical examination was severe, diffuse, symmetric muscle atrophy. Neurologic examination was consistent with proximal muscle weakness. Diagnostics showed normal CPK and ESR. Muscle biopsy revealed rimmed vacuoles, mononuclear inflammatory infiltrates, tubulofilaments which suggests a diagnosis of sporadic inclusion body myositis.

CONCLUSION: Though s-IBM is the most common myopathy in patients over 50 years of age, its symptoms can start up to 20 years earlier. Hence in the evaluation of progressive weakness in adult males, s-IBM should be an important diagnostic consideration.

Human ; Male ; Myositis, Inclusion Body ; Muscle Weakness ; Prednisone ; Vacuoles ; Deglutition Disorders ; Polymyositis ; Muscular Dystrophy, Facioscapulohumeral ; Neurologic Examination ; Muscular Atrophy ; Inclusion Bodies ; Biopsy ; Tablets

An 11-year-old girl with early-onset facioscapulohumeral muscular dystrophy (FSHD) presented with progressive gait disturbance and lumbar hyperlordosis. The motor power of her pelvic extensor muscles was grade 3. Pelvic tilt and hip flexion were markedly increased as determined by gait analysis. This FSHD case is an impressive example of a patient demonstrating the concept that weak pelvic extensor muscles cannot keep the spine upright and balanced. The most important factor in the development of hyperlordosis is the weakness of the pelvic extensor muscles, and the results of gait analysis exquisitely explain the pathophysiology. The patient stands with her spine hyperextended to maintain upright posture by a compensatory mechanism of relatively strong back extensor muscles. Corrective surgery for lumbar hyperlordosis was not considered as it could eliminate the compensatory lumbar hyperextension, thus making the spine of the patient stoop forward through the hip joint during walking, being caused by the weakness of her pelvic extensor muscles.
Child ; Gait ; Hip ; Hip Joint ; Humans ; Muscles ; Muscular Dystrophy, Facioscapulohumeral ; Posture ; Spine ; Walking