Alternative titles; symbols
SNOMEDCT: 723439002; ORPHA: 168572; DO: 0060346;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.3 | Congenital myopathy 13 | 255995 | Autosomal recessive | 3 | STAC3 | 615521 |
A number sign (#) is used with this entry because of evidence that congenital myopathy-13 (CMYO13) is caused by homozygous or compound heterozygous mutation in the STAC3 gene (615521) on chromosome 12q13.
Congenital myopathy-13 (CMYO13), also known as Bailey-Bloch congenital myopathy and Native American myopathy (NAM), is an autosomal recessive disorder characterized by congenital weakness and arthrogryposis, cleft palate, ptosis, myopathic facies, short stature, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia provoked by anesthesia. It was first reported in the Lumbee Indian tribe in North Carolina (summary by Stamm et al., 2008).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Bailey and Bloch (1987) first described Native American myopathy in a 3-month-old American Indian infant of Lumbee descent with multiple congenital anomalies including cleft palate, micrognathia, talipes equinus, and arthrogryposis. The Lumbee population are a mixture of Cheraw Indian, English settlers, and African American ancestry and originate from the Lumber River region of south-central North Carolina (Stamm et al., 2008).
Stewart et al. (1988) described 6 Lumbee Indian children with congenital weakness, cleft palate, and multiple skeletal anomalies. All had ptosis and kyphosis/scoliosis. By photograph, the configuration of the sternum was that found in Noonan syndrome (163950). Myopathic facies was also demonstrated by the illustrations. Malignant hyperthermia occurred in 1 patient in whom cleft palate was undergoing repair and was aborted during the initial stages of anesthesia in another. Stewart et al. (1988) noted the similarities to King syndrome (see 145600). All 6 came from the same ethnic group; 3 were known to be related as brother, sister, and first cousin. All parents were normal and there were no known instances of consanguinity although remote consanguinity is likely. The Lumbee Indians, said to number more than 30,000, are thought to have ancestors that are a mixture of coastal Indians and English colonists (Berry, 1963).
Stamm et al. (2008) reported 14 Lumbee individuals from 5 families with Native American myopathy. All had myopathic facies, and most had ptosis, downturned corners of the mouth, high-arched palate, or cleft palate. Other dysmorphic features included downslanting or short palpebral fissures, telecanthus, and micrognathia. The patients had generalized muscle weakness and atrophy, congenital joint contractures, diminished reflexes, and a high frequency of foot deformities. Most also had oral hypotonia, poor feeding, progressive scoliosis, and variable restrictive respiratory insufficiency. Three died within the first year of life. Four (29%) had malignant hyperthermia. Despite significantly delayed motor development, all had normal cognition. Muscle biopsies showed small type I and II fibers in some, and fiber-type disproportion in others.
Grzybowski et al. (2017) reported a 19-year-old man, born of unrelated Turkish parents, with a congenital myopathy. He presented in the neonatal period with hypotonia, poor feeding, talipes, and some dysmorphic features, such as low-set ears, micrognathia, and high-arched palate. He walked at age 30 months and later showed proximal muscle weakness with positive Gowers sign, absent deep tendon reflexes, marked scoliosis, mild contractures of the ankles, and facial weakness with mild ptosis and downturned corners of the mouth. The muscle weakness was progressive, but he was able to walk; he also had short stature. EMG showed a myopathic pattern, muscle biopsy showed nonspecific myopathic changes with increased intermyofibrillar and subsarcolemmal lipid droplets, and MRI of the lower limbs showed fatty degeneration of the muscles. Creatine kinase was normal.
Telegrafi et al. (2017) reported 4 patients from 2 unrelated families with congenital myopathy. One family was consanguineous from Qatar and the other was nonconsanguineous of Puerto Rican origin. The patients had hypotonia, growth delay with short stature, cleft palate, myopathic facies, and kyphoscoliosis. They had delayed motor development, but were able to walk in childhood and had no cognitive impairment. Dysmorphic features included small head circumference, brachycephaly, long face with bitemporal narrowing, midface hypoplasia, downslanting palpebral fissures, ptosis, epicanthal folds, downturned corners of the mouth, open mouth with tented upper lip, and kyphoscoliosis. One patient had malignant hyperthermia and 2 had conductive hearing loss. More variable features included respiratory insufficiency, short trunk, pectus excavatum, and decreased skin creases on the palms and soles. One patient had a tracheostomy and feeding tube at age 16 years, but intelligence was normal. Telegrafi et al. (2017) noted that the initial clinical diagnoses in these patients included Moebius syndrome (MBS; 157900) and Carey-Fineman-Ziter syndrome (CFZS; 254940).
Zaharieva et al. (2018) reported 18 patients, ranging in age from 6 months to 23 years, from 12 apparently unrelated families with Bailey-Bloch congenital myopathy. The patients were of African, Middle Eastern, Afro-Caribbean, Comorian, and South American descent. In all cases, onset was at birth, with clinical severity ranging from severe prenatal/neonatal onset to a mild, slowly progressive congenital myopathy phenotype. Prenatal findings included polyhydramnios in 3 pregnancies and reduced fetal movements in additional pregnancies. The majority of patients had congenital hypotonia and talipes. Contractures (neck, elbows, wrists, fingers or toes) were noted in 6 infants. A cleft or high palate was seen in 10 patients. Low birth weight was seen in 4 patients. Feeding difficulties at birth or in infancy were seen in 15 patients. Respiratory difficulties of variable degree were seen in 8 infants at birth. Al patients developed the ability to walk for at least short distances. All had mild to moderate upper and lower limb weakness with proximal more than distal involvement. Ptosis and facial weakness was seen in all. Joint laxity was seen in 7 patients, and scoliosis, kyphosis, or spinal rigidity in was seen in 11 patients. Dental malocclusion, jaw prominence, and/or malar hypoplasia was seen in 8 patients. Six children had speech delay or dysarthria, and 7 had documented hearing loss. Among the 11 male patients, 7 had cryptorchidism. Adverse reaction to general anesthetics was seen in 10 patients. Myopathic changes were seen in patients in whom muscle biopsies were performed.
The transmission pattern of CMYO13 in the families reported by Stamm et al. (2008) was consistent with autosomal recessive inheritance.
By homozygosity mapping of 5 Lumbee families with Native American myopathy, Stamm et al. (2008) identified a common homozygous 5.6-Mb region on chromosome 12q13.13-q14.1 between markers D12S398 and rs3842936 in affected individuals. Mutation screening of 4 candidate genes, ITGA7 (600536), PIP5K2C, PDE1B (171891), and MLC1SA (609930), failed to identify pathogenic changes.
Horstick et al. (2013) sequenced the coding regions of the STAC3 gene in a cohort of 5 families with Native American myopathy that included 5 affected and 13 unaffected individuals. All affected individuals were homozygous for a missense mutation (W284S; 615521.0001), whereas all obligate carriers were heterozygous for the mutation. The mutation was not found in 3 unaffected, unrelated Lumbee individuals, in 13 Caucasian control individuals, or in the 1000 Genomes Project database. Horstick et al. (2013) created zebrafish with the W284S mutation, which exhibited decreased Ca(2+) transients. Conversely, expression of the normal human STAC3 gene in mutant fish rescued their phenotype.
In a 19-year-old man, born of unrelated Turkish parents, with CMYO13, Grzybowski et al. (2017) identified compound heterozygous mutations in the STAC3 gene (615521.0002 and 615521.0003). The mutations, which were identified by next-generation sequencing of a panel of genes and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function.
In 2 sibs, born of consanguineous parents from Qatar with CMYO13, Telegrafi et al. (2017) identified a homozygous W284S mutation. Two sibs from Puerto Rico with the same phenotype were found to be compound heterozygous for the W284S mutation and a 4-bp deletion (c.763_766delCTCT; 615521.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed, but the report demonstrated that the W284S mutation is not restricted to the Native American population.
In 17 patients from 11 apparently unrelated, non-Native American families with Bailey-Bloch congenital myopathy, Zaharieva et al. (2018) identified homozygosity for the W84S mutation in the STAC3 gene; in another patient (PN5) of Afro-Caribbean ancestry, they identified compound heterozygosity for W84S and a splice site mutation (615521.0005). The mutations, which were identified by whole-exome sequencing or targeted panel sequencing of known congenital myopathy genes, were confirmed by Sanger sequencing. The mutations segregated with the phenotype in all of the families.
Bailey, A. G., Bloch, E. C. Malignant hyperthermia in a three-month-old American Indian infant. Anesth. Analg. 66: 1043-1045, 1987. [PubMed: 3631569]
Berry, B. Almost White. New York: Macmillan (pub.) 1963. Pp. 152-159.
Grzybowski, N., Schanzer, A., Pepler, A., Heller, C., Neubauer, B. A., Hahn, A. Novel STAC3 mutations in the first non-American patient with Native American myopathy. Neuropediatrics 48: 451-455, 2017. [PubMed: 28411587] [Full Text: https://doi.org/10.1055/s-0037-1601868]
Horstick, E. J., Linsley, J. W., Dowling, J. J., Hauser, M. A., McDonald, K. K., Ashley-Koch, A., Saint-Amant, L., Satish, A., Cui, W. W., Zhou, W., Sprague, S. M., Stamm, D. S., Powell, C. M., Speer, M. C., Franzini-Armstrong, C., Hirata, H., Kuwada, J. Y. Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy. Nature Commun. 4: 1952, 2013. Note: Electronic Article. [PubMed: 23736855] [Full Text: https://doi.org/10.1038/ncomms2952]
Stamm, D. S., Aylsworth, A. S., Stajich, J. M., Kahler, S. G., Thorne, L. B., Speer, M. C., Powell, C. M. Native American myopathy: congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia. Am. J. Med. Genet. 146A: 1832-1841, 2008. [PubMed: 18553514] [Full Text: https://doi.org/10.1002/ajmg.a.32370]
Stamm, D. S., Powell, C. M., Stajich, J. M., Zismann, V. L., Stephan, D. A., Chesnut, B., Aylsworth, A. S., Kahler, S. G., Deak, K. L., Gilbert, J. R., Speer, M. C. Novel congenital myopathy locus identified in Native American Indians at 12q13.13-14.1. Neurology 71: 1764-1769, 2008. [PubMed: 18843099] [Full Text: https://doi.org/10.1212/01.wnl.0000325060.16532.40]
Stewart, C. R., Kahler, S. G., Gilchrist, J. M. Congenital myopathy with cleft palate and increased susceptibility to malignant hyperthermia: King syndrome? Pediat. Neurol. 4: 371-374, 1988. [PubMed: 3245876] [Full Text: https://doi.org/10.1016/0887-8994(88)90086-0]
Telegrafi, A., Webb, B. D., Robbins, S. M., Speck-Martins, C. E., FitzPatrick, D., Fleming, L., Redett, R., Dufke, A., Houge, G., van Harssel, J. J. T., Verloes, A., Robles, A., Manoli, I., Engle, E. C., Moebius Syndrome Research Consortium, Jabs, E. W., Valle, D., Carey, J., Hoover-Fong, J. E., Sobreira, N. L. M. Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome. Am. J. Med. Genet. 173A: 2763-2771, 2017. [PubMed: 28777491] [Full Text: https://doi.org/10.1002/ajmg.a.38375]
Zaharieva, I. T., Sarkozy, A., Munot, P., Manzur, A., O'Grady, G., Rendu, J., Malfatti, E., Amthor, H., Servais, L., Urtizberea, J. A., Neto, O. A., Zanoteli, E., and 23 others. STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. Hum. Mutat. 39: 1980-1994, 2018. [PubMed: 30168660] [Full Text: https://doi.org/10.1002/humu.23635]