Carey-Fineman-Ziter Syndrome: A MYMK-Related Myopathy Mimicking Brainstem Dysgenesis

Camacho, Ana; Martínez, Beatriz; Álvarez, Sara; Gil-Fournier, Belén; Ramiro, Soraya; Hernández-Laín, Aurelio; Núñez, Noemí; Simón, Rogelio

doi:10.3233/jnd-200477

Cited by 8 publications

(5 citation statements)

References 15 publications

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“…Facial weakness and respiratory distress, likely due to weak diaphragm, are often present [ 99 ] and resemble MYOSCO, EMARDD ( Table 1 ) and MYODRIF. Muscle biopsies from quadriceps display limited myopathic features but marked myofibre hypertrophy, likely arising from dysregulated, rather than a lack of, myoblast fusion, and generalised fibre-type disproportion that resembles SELENON-deficiency [ [99] , [100] , [101] ] ( Fig. 3 E).…”

Section: Gene Mutations That Cause Primary Satellite Cell-opathiesmentioning

confidence: 99%

Defining and identifying satellite cell-opathies within muscular dystrophies and myopathies

Ganassi

Muntoni

Zammit

2022

Experimental Cell Research

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Muscular dystrophies and congenital myopathies arise from specific genetic mutations causing skeletal muscle weakness that reduces quality of life. Muscle health relies on resident muscle stem cells called satellite cells, which enable life-course muscle growth, maintenance, repair and regeneration. Such tuned plasticity gradually diminishes in muscle diseases, suggesting compromised satellite cell function. A central issue however, is whether the pathogenic mutation perturbs satellite cell function directly and/or indirectly via an increasingly hostile microenvironment as disease progresses. Here, we explore the effects on satellite cell function of pathogenic mutations in genes (myopathogenes) that associate with muscle disorders, to evaluate clinical and muscle pathological hallmarks that define dysfunctional satellite cells. We deploy transcriptomic analysis and comparison between muscular dystrophies and myopathies to determine the contribution of satellite cell dysfunction using literature, expression dynamics of myopathogenes and their response to the satellite cell regulator PAX7. Our multimodal approach extends current pathological classifications to define Satellite Cell-opathies: muscle disorders in which satellite cell dysfunction contributes to pathology. Primary Satellite Cell-opathies are conditions where mutations in a myopathogene directly affect satellite cell function, such as in Progressive Congenital Myopathy with Scoliosis (MYOSCO) and Carey-Fineman-Ziter Syndrome (CFZS). Primary satellite cell-opathies are generally characterised as being congenital with general hypotonia, and specific involvement of respiratory, trunk and facial muscles, although serum CK levels are usually within the normal range. Secondary Satellite Cell-opathies have mutations in myopathogenes that affect both satellite cells and muscle fibres. Such classification aids diagnosis and predicting probable disease course, as well as informing on treatment and therapeutic development.

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Section: Gene Mutations That Cause Primary Satellite Cell-opathiesmentioning

confidence: 99%

Defining and identifying satellite cell-opathies within muscular dystrophies and myopathies

Ganassi

Muntoni

Zammit

2022

Experimental Cell Research

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“…Two individuals, a brother and a sister, presented in the clinic with a phenotype highly reminiscent of CFZS ( 22 ), a human disease caused by pathogenic variants in the MYMK gene ( 17 – 21 ). Diagnostic trio-exome sequencing of the affected patients did not identify any known pathogenic variants in myopathy-related genes, including MYMK .…”

Section: Resultsmentioning

confidence: 99%

“…Whereas numerous muscle structural proteins have been associated with severe myopathies ( 16 ), relatively little is known about the potential contributions of the muscle fusion apparatus to human disease. Recently, hypomorphic variants in MYMK were shown to cause the congenital myopathy known as Carey-Fineman-Ziter syndrome (CFZS; OMIM #254940) ( 17 – 20 ). CFZS patients display an array of abnormalities, including hypotonia, myofiber size disproportion, Moebius sequence, Pierre Robin complex, and growth defects ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome

Ramirez-Martinez¹,

Zhang²,

Boogaard³

et al. 2022

Journal of Clinical Investigation

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Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker ( MYMK ) and Myomixer ( MYMX ). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity. Homozygosity of this human variant resulted in a spectrum of abnormalities that mimicked the clinical presentation of Carey-Fineman-Ziter syndrome (CFZS), caused by hypomorphic MYMK variants. Myoblasts generated from patient-derived induced pluripotent stem cells displayed defective fusion, and mice bearing the human MYMX variant died perinatally due to muscle abnormalities. In vitro assays showed that the human MYMX variant conferred minimal cell-cell fusogenicity, which could be restored with CRISPR/Cas9–mediated base editing, thus providing therapeutic potential for this disorder. Our findings identify MYMX as a recessive, monogenic human disease gene involved in CFZS, and provide new insights into the contribution of myoblast fusion to neuromuscular diseases.

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“… 174 CFZS is a congenital myopathy with clinical manifestations such as hypotonia, Moebius sequence, Robin sequence, facial anomalies, motor delays, and growth failure. 175 Recently, researchers found that CFZS is associated with a recessive mutation in the myomaker gene through muscle biopsy and whole‐genome sequencing of patients, which was verified in a zebrafish animal experiment. 176 , 177 Mutations in myomergers are also involved in CFZS, and deletion of its extracellular region (MYMX R46* variant) can result in the loss of cell fusion ability and the occurrence of disease in mice.…”

Section: Myopathymentioning

confidence: 93%

“…Carey–Fineman–Ziter syndrome (CFZS) was first reported in 1982 174 . CFZS is a congenital myopathy with clinical manifestations such as hypotonia, Moebius sequence, Robin sequence, facial anomalies, motor delays, and growth failure 175 . Recently, researchers found that CFZS is associated with a recessive mutation in the myomaker gene through muscle biopsy and whole‐genome sequencing of patients, which was verified in a zebrafish animal experiment 176,177 .…”

Section: Myopathymentioning

confidence: 96%

Skeletal muscle: molecular structure, myogenesis, biological functions, and diseases

Feng,

Chen,

Bian

2024

MedComm

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Skeletal muscle is an important motor organ with multinucleated myofibers as its smallest cellular units. Myofibers are formed after undergoing cell differentiation, cell–cell fusion, myonuclei migration, and myofibril crosslinking among other processes and undergo morphological and functional changes or lesions after being stimulated by internal or external factors. The above processes are collectively referred to as myogenesis. After myofibers mature, the function and behavior of skeletal muscle are closely related to the voluntary movement of the body. In this review, we systematically and comprehensively discuss the physiological and pathological processes associated with skeletal muscles from five perspectives: molecule basis, myogenesis, biological function, adaptive changes, and myopathy. In the molecular structure and myogenesis sections, we gave a brief overview, focusing on skeletal muscle‐specific fusogens and nuclei‐related behaviors including cell–cell fusion and myonuclei localization. Subsequently, we discussed the three biological functions of skeletal muscle (muscle contraction, thermogenesis, and myokines secretion) and its response to stimulation (atrophy, hypertrophy, and regeneration), and finally settled on myopathy. In general, the integration of these contents provides a holistic perspective, which helps to further elucidate the structure, characteristics, and functions of skeletal muscle.

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Carey-Fineman-Ziter Syndrome: A MYMK-Related Myopathy Mimicking Brainstem Dysgenesis

Cited by 8 publications

References 15 publications

Defining and identifying satellite cell-opathies within muscular dystrophies and myopathies

Defining and identifying satellite cell-opathies within muscular dystrophies and myopathies

Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome

Skeletal muscle: molecular structure, myogenesis, biological functions, and diseases

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