Carey-Fineman-Ziter Syndrome Research Articles

Aberrant myonuclear domains and impaired myofiber contractility despite marked hypertrophy in MYMK-related, Carey-Fineman-Ziter Syndrome

Carey Fineman Ziter Syndrome (CFZS) is a rare autosomal recessive disease caused by mutations in the MYMK locus which encodes the protein, myomaker. Myomaker is essential for fusion and concurrent myonuclei donation of muscle progenitors during growth and development. Strikingly, in humans, MYMK mutations appear to prompt myofiber hypertrophy but paradoxically, induce generalised muscle weakness. As the underlying cellular mechanisms remain unexplored, the present study aimed to gain insights by combining myofiber deep-phenotyping and proteomic profiling. Hence, we isolated individual muscle fibers from CFZS patients and performed mechanical, 3D morphological and proteomic analyses. Myofibers from CFZS patients were ~ 4x larger than controls and possessed ~ 2x more myonuclei than those from healthy subjects, leading to disproportionally larger myonuclear domain volumes. These greater myonuclear domain sizes were accompanied by smaller intrinsic cellular force generating-capacities in myofibers from CFZS patients than in control muscle cells. Our complementary proteomic analyses indicated remodelling in 233 proteins particularly those associated with cellular respiration. Overall, our findings suggest that myomaker is somewhat functional in CFZS patients, but the associated nuclear accretion may ultimately lead to non-functional hypertrophy and altered energy-related mechanisms in CFZS patients. All of these are likely contributors of the muscle weakness experienced by CFZS patients.

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

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.

Scoliosis in Carey-Fineman-Ziter Syndrome: Clinical Course, Association with Pierre Robin Sequence and Treatment

Objective − We present a female patient with Carey-Fineman-Ziter Syndrome (CFZS) and 4 patients with Pierre Robin sequence who developed a progressive thoracic scoliosis in early child life. Material and Methods − We reviewed the medical notes and spinal radiographs of these 5 patients who were treated for progressive scoliosis, underwent a posterior spinal fusion and were followed in our service to skeletal maturity. Results − We describe the patients’ response to treatment including bracing which was unsuccessful, and scoliosis correction. We compared the evolution of scoliosis and surgical outcome between the patient with CFZS and our 4 patients with Pierre-Robin sequence and hypotonia who were managed for scoliosis under our care in order to understand possible aetiological relations between the underlying myopathic condition and the development of scoliosis. Conclusion − Scoliosis in children with CFZS and Pierre Robin sequence occurred in early childhood with rapid progression around puberty and poor effectiveness of bracing. We suggest that generalised hypotonia is a likely causative factor in the development and rapid deterioration of scoliosis in these 2 conditions. Spinal surgery through a posterior spinal fusion produced excellent deformity correction and functional outcomes that were maintained through to skeletal maturity in all 5 patients.

Can we talk about myoblast fusion?

Can we talk about myoblast fusion?

EP.121Carey-Fineman-Ziter syndrome: a MYMK-related myopathy mimicking brainstem dysgenesis

Carey-Fineman-Ziter syndrome (CFZS) is clinically defined by the combination of hypotonia, Moebius sequence, Robin sequence, facial anomalies, motor delay and growth failure. The etiology has remained elusive, although brainstem dysgenesis has been suggested. Recently CFZS was found to be associated with autosomal recessive mutations in the gene MYMK, which impair the fusion of mononuclear myoblasts to multinucleate myocytes in the skeletal muscle. We report a new case and define the clinical phenotype. The patient was the first boy from non-consanguineous parents. Pregnancy was unremarkable, but at birth he presented with hypotonia and bilateral facial palsy without external ophthalmoplegia. His facial appearance included small nose, retromicrognathia, downslanting palpebral fissures, low-set ears and a high arched palate. He also had feeding difficulties and needed nasogastric tube for a few months. There was generalized joint laxity and global muscular hypoplasia. During the first years of life his motor development was delayed; independent walking was acquired at age 2 and he used the Gowers’ maneuver to come to an upright position. CK levels, nerve conduction study and electromyography were normal. Cranial MRI did not show any abnormalities, but a muscular MRI disclosed mild fatty infiltration of thigh adductors, gluteus and soleus muscles. Nevertheless, a muscle biopsy from quadriceps showed no myopathic features. Genetic testing by Whole-Exome-Sequencing detected two mutations in the MYMK gene: c.271C>A and c.399+5G>A. Nowadays he is 3.5 years old, he has no cognitive impairment and his motor abilities are improving slowly. CFZS is a congenital myopathy with prominent facial involvement, which is a diagnostic clue. There is variability in the pathology findings that may be explained by the muscle selected for biopsy or patient’s age. Clinical course is static or slowly progressive, but the identification of new well characterized genetic cases will help to delineate the complete phenotype.

Carey-Fineman-Ziter syndrome with mutations in the myomaker gene and muscle fiber hypertrophy.

ObjectiveTo describe the long-term clinical follow-up in 3 siblings with Carey-Fineman-Ziter syndrome (CFZS), a form of congenital myopathy with a novel mutation in the myomaker gene (MYMK).MethodsWe performed clinical investigations, repeat muscle biopsy in 2 of the siblings at ages ranging from 11 months to 18 years, and whole-genome sequencing.ResultsAll the siblings had a marked and characteristic facial weakness and variable dysmorphic features affecting the face, hands, and feet, and short stature. They had experienced muscle hypotonia and generalized muscle weakness since early childhood. The muscle biopsies revealed, as the only major abnormality at all ages, a marked hypertrophy of both type 1 and type 2 fibers with more than twice the diameter of that in age-matched controls. Genetic analysis revealed biallelic mutations in the MYMK gene, a novel c.235T>C; p.(Trp79Arg), and the previously described c.271C>A; p.(Pro91Thr).ConclusionsOur study expands the genetic and clinical spectrum of MYMK mutations and CFZS. The marked muscle fiber hypertrophy identified from early childhood, despite apparently normal muscle bulk, indicates that defective fusion of myoblasts during embryonic muscle development results in a reduced number of muscle fibers with compensatory hypertrophy and muscle weakness.