DO: 0050557;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q21.3 | Muscular dystrophy, congenital, with rapid progression | 254100 | Autosomal recessive | 3 | BET1 | 605456 |
A number sign (#) is used with this entry because of evidence that congenital muscular dystrophy with rapid progression (MDRP) is caused by homozygous or compound heterozygous mutation in the BET1 gene (605456) on chromosome 7q21.
Congenital muscular dystrophy with rapid progression (MDRP) is an autosomal recessive neurodegenerative disorder characterized by hypotonia and poor feeding apparent in infancy, delayed motor development with poor head control and inability to sit or walk, progressive weakness and lethargy, and respiratory insufficiency. Some patients may have features of central nervous system involvement, including poor or absent speech and seizures, as well as cataracts. Serum creatine kinase is elevated, and muscle biopsy shows nonspecific dystrophic or myopathic changes. The disorder is rapidly progressive, resulting in death in infancy or early childhood (Donkervoort et al., 2021).
Donkervoort et al. (2021) reported 3 patients from 2 unrelated families with a rapidly progressive form of congenital muscular dystrophy resulting in death in infancy or early childhood. P1 was a 5-year-old boy who presented in utero with decreased fetal movements and showed severe hypotonia with feeding difficulties at birth requiring a feeding tube. He had poor head control, delayed motor development (sitting unsupported at 12 months of age), and respiratory insufficiency requiring nighttime noninvasive ventilation. Physical examination at 23 months showed high-arched palate, restricted extraocular movements, head lag, scoliosis, and joint contractures. He also had speech delay with poor articulation and high myopia with cataracts, and developed refractory seizures at age 4 years, all of which suggested involvement of the central nervous system. The disorder was relentlessly progressive: by age 4 years, he had lost the ability to roll over and sit, had poor antigravity movements, became more lethargic, lost the ability to babble, and had respiratory insufficiency requiring a tracheostomy. P1 died at 5 years of age. P2 and P3 were sibs, born of unrelated parents, who presented soon after birth with axial hypotonia, poor feeding requiring feeding tubes, poor visual tracking, and bronchomalacia. Both became more lethargic and had progressive respiratory insufficiency resulting in death in both patients at 4 and 7 months of age. Brain imaging was unremarkable in all patients, although P1 had mild thinning of the corpus callosum and mild signal abnormalities. All patients had increased serum creatine kinase. Muscle biopsy in P1 showed dystrophic features, including fiber size variation, increased connective tissue, rare internal nuclei, and type 1 fiber atrophy. Western blot analysis of muscle showed reduced glycosylation of alpha-dystroglycan (DAG; 128239). Muscle biopsy in P3 showed nonspecific myopathic changes.
The transmission pattern of MDRP in the families reported by Donkervoort et al. (2021) was consistent with autosomal recessive inheritance.
In 3 patients from 2 unrelated families with MDRP, Donkervoort et al. (2021) identified homozygous or compound heterozygous mutations in the BET1 gene (605456.0001-605456.0003). The mutations were found by trio-based exome sequencing; 2 were present at low frequencies in the heterozygous state in gnomAD. The mutations in family 1 resulted in decreased BET1 levels, whereas the mutation in family 2 was a missense variant (I51S; 605456.0003) that resulted in normal levels of protein expression but impaired interaction with ERGIC53 (LMAN1; 601567). Interaction of mutant BET1 with other SNARE complex members was unaffected. In patient fibroblasts, localization of BET1 was shifted from the Golgi to the endoplasmic reticulum (ER), suggesting impaired ER-to-Golgi transport. SiRNA-mediated knockdown of BET1 in HeLa cells impaired ER-to-Golgi trafficking of a reporter construct. Patient fibroblasts showed defective Golgi reconstitution after disruption.
Congenital and rapidly progressive muscular dystrophy was reported by de Lange (1937) in 3 members of each of 2 sibships related as second cousins. The condition described by Short (1963) and by Wharton (1965) may be the same.
de Lange, C. Studien ueber angeborene Laehmungen bzw. angeborene Hypotonie. Acta Paediat. 20 (suppl. 3): 1-51, 1937.
Donkervoort, S., Krause, N., Dergai, M., Yun, P., Koliwer, J., Gorokhova, S., Geist Hauserman, J., Cummings, B. B., Hu, Y., Smith, R., Uapinyoying, P., Ganesh, V. S., and 17 others. BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy. EMBO Molec. Med. 13: e13787, 2021. [PubMed: 34779586] [Full Text: https://doi.org/10.15252/emmm.202013787]
Short, J. K. Congenital muscular dystrophy. A case report with autopsy findings. Neurology 13: 526-530, 1963. [PubMed: 13988674] [Full Text: https://doi.org/10.1212/wnl.13.6.526]
Wharton, B. A. An unusual variety of muscular dystrophy. Lancet 285: 248-249, 1965. Note: Originally Volume I. [PubMed: 14238070] [Full Text: https://doi.org/10.1016/s0140-6736(65)91528-x]