Analysis of intercellular communication patterns in facioscapulohumeral muscular dystrophy based on single-cell nuclear transcriptome sequencing / 国际生物医学工程杂志

Objective:To analyze the patterns of intercellular communication in facioscapulohumeral muscular dystrophy (FSHD) by single-cell nuclear transcriptome sequencing.Methods:Bilateral asymmetrical lesions mouth orbicular muscle of two patients with FSHD and mouth orbicular muscle of two healthy patients were selected. Six samples were obtained, and were divided into control group, mild group and severe group. The normal orbicularis muscle sample was collected from 2 healthy individuals (the control group). The muscle samples in the mild group were from two patients with relatively normal muscle sides, and the samples in the severe group were from two patients with more severe muscle damage sides. Single-cell nuclear transcriptome sequencing was performed on all cells of the three groups. Reduced dimension clustering and cell definition were performed to identify differentially expressed genes and enrichment pathways. Intercellular communication patterns among major cell types and key signaling pathways were explored by cellular communication analysis.Results:Differential gene expression analysis of FSHD bilateral muscle samples identified 46 functionally differentially expressed genes associated with the disease in different cell types, related to apoptosis, oxidative stress, immune inflammation, and muscle function. Intercellular communication was generally increased in the severe group. Fibro-adipogenic progenitors (FAPs) and macrophages are important signaling sources in the abnormal muscle microenvironment of FSHD and are closely associated with disease progression. There are six unique signaling pathways in the mild group, including bone morphogenetic proteins (BMP), transforming growth factor-β (TGF-β), CXC motif chemokine ligand (CXCL), adhesion G protein-coupled receptor E5 (ADGRE5), interleukin-16 (IL-16), and wingless-type MMTV integration site family (WNT) signaling pathways. These signaling pathways are mainly involved in the interaction between macrophages, FAPs, and adipocytes and may be involved in the regulation of fat deposition and fibrosis changes in the diseased muscle.Conclusions:Single-cell nuclear transcriptome sequencing provides a relatively comprehensive pattern of intercellular communication between key cell types in FSHD, providing an appropriate reference for understanding the intercellular regulatory mechanisms of the FSHD muscle microenvironment.

A "Triple Trouble" Case of Facioscapulohumeral Muscular Dystrophy Accompanied by Peripheral Neuropathy and Myoclonic Epilepsy / 中华医学杂志(英文版)

<p><b>Background</b>Facioscapulohumeral 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.</p><p><b>Methods</b>Standard 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.</p><p><b>Results</b>The 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.</p><p><b>Conclusions</b>The 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.</p>

Bilateral Cochlear Implantation in Facioscapulohumeral Muscular Dystrophy Presenting Sensorineural Hearing Loss / 대한이비인후과학회지

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.

Beevor’s Sign: A Review.

Beevor’s sign named after Charles Edward Beevor is one of the eponymous medical signs in the dictionary of neurologists. The present article reviews the history and the pathophysiology of Beevor’s sign. This sign is famous in Facioscapulohumeral muscular dystrophy and in the spinal cord injuries of T10. There are very few researches done regarding Beevor’s sign and a little can be found in the history. On eliciting the sign, one can observe caudal movement of navel on cervical flexion. In normal individuals the position of umbilicus does not change but in patients of Facioscapulohumeral muscular dystrophy, spinal crod lesion T10 or myopathy, the umbilicus is seen to move towards the head. Very few studies have been done regarding other diseases where Beevor’s sign is seen but a lot of studies have been done on fasiculohumeral dystrophy and Beevor’s sign. Research is needed in other diseases showing positive Beevor’s sign and its management.

Clinical Features and Genetic Analysis of Fascioscapulohumeral Muscular Dystrophy

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.

Avaliação dos resultados da artrodese da articulação escapulotorácica no tratamento da escápula alada na distrofia fascioescapulumeral / Evaluation of scapulothoracic arthrodesis results in the treatment of winged scapula in facioscapulohumeral dystrophy

OBJETIVO: Avaliar a técnica cirúrgica da artrodese escapulotorácica na distrofia fascioescapulumeral (DFEU), analisando os resultados e as complicações pós-operatórias. MÉTODOS: No período de fevereiro de 1992 a fevereiro de 2006 foram realizadas oito artrodeses escapulotorácicas em cinco pacientes no Departamento de Ortopedia e Traumatologia da Faculdade de Ciências Médicas da Santa Casa de São Paulo (DOT-FCM-SCSP). Os critérios para indicação cirúrgica foram: dor, déficit funcional do membro acometido, fadiga muscular e deformidade estética. Na técnica cirúrgica empregada para a artrodese foi realizada a fixação da escápula à parede torácica por meio de amarrilho com fios de poliéster n° 5, uma placa metálica estreita e fina, além de colocação de enxerto esponjoso autólogo. RESULTADOS: O seguimento médio dos pacientes foi de 124 meses. Na comparação da amplitude de movimentos pré e pós-operatórios, notou-se melhora na elevação, mantida a rotação lateral, com o UCLA no período pré-operatório variando de 7 a 11 e pós-operatório de 29 a 33. Dentre as complicações, encontraram-se dois casos de pneumotórax, um caso de soltura do material de síntese e um caso de ausência de consolidação óssea. COMENTÁRIO: Obtida consolidação da artrodese em seis casos, além da melhora da dor e elevação. Dois casos foram reoperados, sendo um devido à quebra do material e o outro, à não consolidação. Todos evoluíram para consolidação.

OBJECTIVE: To evaluate the surgical scapulothoracic arthrodesis technique in facioscapulohumeral dystrophy (FSHD) by analyzing post-op results and complications. METHODS: from February 1992 to February 2006, eight scapulothoracic arthrodesis procedures were performed in five patients at the Orthopedics and Traumatology Department of the Medical Sciences School at the Santa Casa Hospital of São Paulo (DOT-FCM-SCSP). The criteria for surgical indication were pain, functional deficit of the limb involved, muscular fatigue, and esthetic deformity. The surgical technique used for the arthrodesis fixated the scapula to the thoracic wall by tying a narrow, slim plate with No. 5 polyester threads and placing an autologous cancellous bone graft. RESULTS: Mean follow-up of the patients was of 124 months. Comparing the range of movement before and after surgery, the authors observed an improvement in raising, lateral rotation being kept, with the pre-op UCLA ranging from 7 to 11, and the post-op UCLA ranging from 29 to 33. Complications included two cases of pneumothorax; one case of the detachment of synthesis material, and one case of lack of bone fusion. COMMENT: Arthrodesis fusion was achieved in six cases, besides improvement in pain and raising. Two cases were reoperated on, one of them due to breakage of the material and another one due to lack of fusion. All cases evolved on to fusion.

Facioscapulohumeral Muscular Dystrophy Confirmedby D4Z4 Analysis

No abstract available.

Clinical and Genetic Analysis of Korean Patients with Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominantly inherited muscular disorder, which is characterized by weakness of facial, shoulder and hip girdle, humeral, and anterior distal leg muscles. The FSHD gene has been mapped to 4q35 and a deletion of integral copies of a 3.3-kb DNA repeat motif named D4Z4 was known to be the genetic background of the disorder. Although FSHD is the second most common muscular dystrophy in adulthood, there were few reports on the genetically confirmed patients in Korea. Recently, we experienced four Korean patients with clinical features resembling FSHD. In order to confirm the diagnosis, conventional Southern blot (SB) analysis by using double digestion with EcoRI and BlnI and hybridization with p13E-11 probe was performed in three patients and newly developed long polymerase chain reaction (PCR) method was used for one patient because genomic DNA was not enough for conventional SB for this patient. All patients were demonstrated to have shortened D4Z4 repeats that were consistent with FSHD. Therefore, we could confirm the diagnosis of FSHD in four Korean patients and appropriate genetic counseling was done for the patients and their families. It is of note that long-PCR method could be a good alternative for conventional SB when D4Z4 repeats were less than 5.

Early-Onset Facioscapulohumeral Muscular Dystrophy: Significance of Pelvic Extensor in Sagittal Spinal Imbalance / 대한정형외과학회잡지

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.

Prenatal Diagnosis by Direct DNA Analysis in Facioscapulohumeral Muscular Dystrophy (FSHD) Families

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder which has been clinically shown to cause progressive weakness and result in atrophy of the facial muscles, shoulder girdle and upper arm muscles. The responsible gene for the FSHD has been located on chromosome 4q35-qter. The probes p13E-11 and pFR-1 detect DNA rearrangements associated with FSHD as under 28 kb DNA fragment in genomic southern analysis digested with EcoR I and the fragment contains 3.3 kb Kpn I tandem repeats. In this study, 4 fetuses with a family history of FSHD were analysed by genomic southern hybridization analysis with probes to determine whether they carried the deleted region. Of the 4 fetuses, three of them had mothers who were FSHD patients and the other one had a father affected with FSHD. After 10-11 weeks of gestation, we performed chorionic villi sampling and extracted DNA from uncultured and cultured tissue cells for the direct DNA analysis. The result of the southern analysis showed two fetuses having received about 15-18 kb of deleted genes from the father and the mother respectively, and found to be FSHD patients. The other two fetuses were shown to have two normal alleles from the parents and found to be normal. Two pregnancies which were determined to be normal were carried to term delivering two healthy babies.