Myopathy, Congenital, Bailey-Bloch

A number sign (#) is used with this entry because of evidence that Bailey-Bloch congential myopathy (MYPBB) is caused by homozygous or compound heterozygous mutation in the STAC3 gene (615521) on chromosome 12q13.

Description

Bailey-Bloch congenital myopathy, also known as 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).

Clinical Features

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 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).

Inheritance

Native American myopathy is transmitted in an autosomal recessive pattern; several affected individuals have been born of consanguineous parents, and presumed carrier parents are unaffected (Stamm et al., 2008).

Mapping

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.

Molecular Genetics

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 MYPBB, 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 MYPBB, 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.