Early-onset Facioscapulohumeral Muscular Dystrophy Research Articles

FSHD: EP.167 Longitudinal clinical course of early-onset facioscapulohumeral muscular dystrophy

FSHD: EP.167 Longitudinal clinical course of early-onset facioscapulohumeral muscular dystrophy

Clinical phenotype and genotype of early-onset facioscapulohumeral muscular dystrophy type 1

Objective: To explore the clinical, pathological and genetic characteristics of early-onset facioscapulohumeral muscular dystrophy type 1 (FSHD1), in order to increase awareness of the disease. Methods: In this retrospective study, the history of 3 patients, who were diagnosed with early-onset FSHD1 by molecular genetic test in Pediatric Outpatient Department of Peking University First Hospital from 4(th) June 2012 to 4(th) June 2018, were collected. Their clinical data, genotypes, phenotypes and pathological features of muscle biopsy were analyzed. Results: All the three patients were males at the age of 14 years, 11 years and 9 years 11 months, respectively, whose onset age was between infancy and early childhood and they got confirmed diagnosis within 4 to 10 years after the onset of illness. Their molecular genetic testing indicated that the number of D4Z4 repeat arrays located in 4qA were 2, 3 and 4, which was consistent with the characteristics of early-onset FSHD1. Their common clinical manifestations were facial, scapular and proximal lower limb muscle progressively and asymmetrically weakness. All patients had different severity of spine deformity and high-frequency dominant sensorineural hearing loss, however, the phenotype of the third patient with 4 D4Z4 repeats was significantly the most severe. Conclusions: Early-onset FSHD1 usually concealed onset and is difficult to diagnose. Its precise diagnosis depends on molecular genetic techniques, but the genotypes of 3 patients here are not corresponding to phenotypes strictly and it is necessary to accumulate more cases for further analysis in order to provide a more reliable basis for the relationship of genotype-phenotype and prognosis evaluation of the disease.

Early onset as a marker for disease severity in facioscapulohumeral muscular dystrophy.

To assess the relation between age at onset and disease severity in facioscapulohumeral muscular dystrophy (FSHD). In 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. Twenty-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%). Patients 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.

A multinational study on motor function in early-onset FSHD.

To investigate motor function associations with age, sex, and D4Z4 repeats among participants with early-onset facioscapulohumeral muscular dystrophy (FSHD) type 1 as defined by weakness onset before 10 years of age. We collected standardized motor assessments, including manual muscle testing (MMT), quantitative muscle testing, functional motor evaluations, and clinical severity scores (CSSs), at 12 Cooperative International Neuromuscular Research Group centers. To measure associations, we used linear regression models adjusted for sex, evaluation age, age at onset of weakness, and D4Z4 repeats. Among 52 participants (60% female, mean age 22.9 ± 14.7 years), weakness was most pronounced in the shoulder and abdominal musculature. Older enrollment age was associated with greater CSSs (p = 0.003). When adjusted for enrollment age, sex, and D4Z4 repeats, younger age at onset of facial weakness was associated with greater CSSs, slower velocities in timed function tests, and lower MMT scores (p < 0.05). Significant clinical variability was observed in early-onset FSHD. Earlier age at onset of facial weakness was associated with greater disease severity. Longitudinal assessments are needed to determine the rate of disease progression in this population.

P.341 - Results of a Phase 1b/2 Study of ATYR1940 in adolescents and young adults with early onset facioscapulohumeral muscular dystrophy (FSHD) (ATYR1940-C-003)

P.341 - Results of a Phase 1b/2 Study of ATYR1940 in adolescents and young adults with early onset facioscapulohumeral muscular dystrophy (FSHD) (ATYR1940-C-003)

A Pediatric Review of Facioscapulohumeral Muscular Dystrophy.

Facioscapulohumeral dystrophy is one of the most common forms of muscular dystrophies worldwide. It is a complex and heterogeneous disease secondary to insufficient epigenetic repression of D4Z4 repeats and aberrant expression of DUX4 in skeletal muscles. Type 1 facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of D4Z4 repeats on 4q35, whereas type 2 FSHD is associated with mutations of the SMCHD1 or DNMT3B gene in the presence of a disease-permissive 4qA haplotype. Classical FSHD is a slowly progressive disorder with gradual-onset of muscle atrophy and a descending pattern of muscle weakness. In contrast, early-onset FSHD is associated with a large deletion of D4Z4 repeats and a more severe disease phenotype, including early loss of independent ambulation as well as extramuscular manifestations, such as retinal vasculopathy, hearing loss, and central nervous system (CNS) involvement. However, the correlation between D4Z4 repeats and disease severity remains imprecise. The current standard of care guidelines offers comprehensive assessment and symptomatic management of secondary complications. Several clinical trials are currently underway for FSHD. New and emerging treatments focus on correcting the transcriptional misregulation of D4Z4 and reversing the cytotoxic effects of DUX4. Other potential therapeutic targets include reduction of inflammation, improving muscle mass, and activating compensatory molecular pathways. The utility of disease-modifying treatments will depend on selection of sensitive clinical endpoints as well as validation of muscle magnetic resonance imaging (MRI) and other biomarkers to detect meaningful changes in disease progression. Correction of the epigenetic defects using new gene editing as well as other DUX4 silencing technologies offers potential treatment options for many individuals with FSHD.

Early-Onset Facioscapulohumeral Muscular Dystrophy Type 1 With Some Atypical Features

Facioscapulohumeral muscular dystrophy cases with facial weakness before the age of 5 and signs of shoulder weakness by the age of 10 are defined as early onset. Contraction of the D4Z4 repeat on chromosome 4q35 is causally related to facioscapulohumeral muscular dystrophy type 1, and the residual size of the D4Z4 repeat shows a roughly inverse correlation with the severity of the disease. Contraction of the D4Z4 repeat on chromosome 4q35 is believed to induce a local change in chromatin structure and consequent transcriptional deregulation of 4qter genes. We present early-onset cases in the Polish population that amounted to 21% of our total population with facioscapulohumeral muscular dystrophy. More than 27% of them presented with severe phenotypes (wheelchair dependency). The residual D4Z4 repeat sizes ranged from 1 to 4 units. In addition, even within early-onset facioscapulohumeral muscular dystrophy type 1 phenotypes, some cases had uncommon features (head drop, early disabling contractures, progressive ptosis, and respiratory insufficiency and cardiomyopathy).

Early-onset facioscapulohumeral muscular dystrophy – significance of pelvic extensors in sagittal spinal imbalance

Although facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited myopathy, cases of infantile or early-childhood onset have rarely been reported. The purpose of this study was to describe a case of early-onset FSHD with lumbar hyperlordosis, which shows the significance of the dynamic component of sagittal spinal imbalance. An 11-year-old girl 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. 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 because it could have eliminated the compensatory lumbar hyperextension, thus making the spine of the patient stoop forward through her hip joint during walking by the weakness of her pelvic extensor muscles. This FSHD case is an impressive example of a patient showing the concept that weak pelvic extensor muscles cannot keep the spine upright and balanced.

Changes in motor cortex excitability in facioscapulohumeral muscular dystrophy

Previous studies found that some patients with severe, early onset facioscapulohumeral muscular dystrophy (FSHD) present epilepsy and mental retardation. This suggests a functional involvement of central nervous system in severe FSHD. It is unknown whether minor functional changes of central nervous system are also present in less severe forms of FSHD. To investigate this, we examined the excitability of neuronal networks of the motor cortex with a range of transcranial magnetic stimulation paradigms in 20 FSHD patients with heterogeneous clinical severity and compared the data with that from 20 age-matched healthy individuals and from 6 age-matched patients with other muscle diseases. There was significantly less intracortical inhibition in FSHD patients (mean responses ± SD reduced to 58.1±43.5% of the test size) than in controls (mean responses ± SD reduced to 29.3±13.5% of the test size; P=0.025) and in patients with other muscle diseases (mean responses ±SD, reduced to 30.6±11.7% of the test size; P=0.046). No significant difference was found between the control group and patients with other muscle diseases ( P=0.970).

Tongue atrophy in facioscapulohumeral muscular dystrophy.

Involvement of the lingual muscle is considered one of the exclusion criteria of facioscapulohumeral muscular dystrophy (FSHD). In a series of 151 Japanese patients with 4q35-FSHD, seven patients (4.6%) had tongue atrophy with abnormal MRI findings and typical myogenic patterns of electromyography. All seven patients belong to a group of early-onset FSHD with large gene deletions on chromosome 4q35. Our result suggests that the patients with 4q35-FSHD could have myopathic tongue atrophy.

Facioscapulohumeral muscular dystrophy: clinical diversity and genetic abnormalities in Japanese patients.

We studied 71 Japanese individuals, 42 patients (30 familial and 12 sporadic) suspected to have facioscapulohumeral muscular dystrophy (FSHD) and 29 family members, clinically and genetically using the chromosome 4qter DNA marker p13E-11. Early onset FSHD was detected in 7 patients, tortuosity of retinal arterioles and hearing impairment in 3 patients, progressive respiratory failure in 3 patients and limb-girdle type muscular weakness in 6 patients. Thirty-six (85.7%) FSHD patients, 3 asymptomatic family members and 1 of 35 healthy volunteers showed EcoRI digestion fragments shorter than 28kb. New mutations were detected in 25% of the patients with shorter EcoRI fragment. The age of disease onset appeared younger with successive generations in 6 parent-child pairs in FSHD families. We confirmed the existence of phenotypic and genetic diversities in Japanese patients with FSHD. It is still difficult to explain the phenotypic diversity merely by the size of the abnormal EcoRI fragment detected with the p13E-11 probe.

Early onset facioscapulohumeral muscular dystrophy

We report 10 patients (5 familial, 5 sporadic) with facioscapulohumeral muscular dystrophy (FSHD) with onset of facial and shoulder girdle weakness in early infancy. They showed the same broad range of clinical signs and symptoms as can be seen normally in FSHD. In 7 patients Southern blotting with p13E-11 was performed which showed an abnormal EcoRI fragment (13-22 kb) in 6 of them. We conclude that early onset FSHD does not differ from regular FSHD clinically or genetically. However, the precise mechanisms involved in the extensive clinical variability of the disease are still unknown.