Alternative titles; symbols
SNOMEDCT: 782883004; ORPHA: 280553; DO: 0080309;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q23.1 | Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related | 613869 | Autosomal recessive | 3 | CRYAB | 123590 |
A number sign (#) is used with this entry because of evidence that fatal infantile hypertonic myofibrillar myopathy is caused by homozygous mutation in the CRYAB gene (123590) on chromosome 11q23.
Fatal infantile hypertonic myofibrillar myopathy is a severe autosomal recessive muscular dystrophy with onset in the first weeks of life after a normal neonatal period. Affected infants show rapidly progressive muscular rigidity of the trunk and limbs associated with increasing respiratory difficulty resulting in death before age 3 years (summary by Del Bigio et al., 2011).
Lacson et al. (1994) reported 11 Canadian aboriginal infants of Cree ancestry with a similar form of fatal hypertonic muscular dystrophy. All presented in the first 8 weeks of life with respiratory insufficiency, except 1 who was hypertonic at age 3 weeks and died suddenly at age 6 weeks. The patients developed muscle stiffness and rigidity of the trunk and limb muscles with a progressive inability to ventilate due to decreased chest wall compliance. The hypertonicity did not respond to muscle relaxants or neuromuscular blockade. Cognition appeared normal, and facial muscle were not involved. Variable features included weak cry, apneic spells, anoxic seizures, and contractures. Several infants required continued ventilation, and 2 died suddenly. All died in infancy, except 1 child who survived to age 3 years. Electromyograms showed increased insertion activity and fibrillation potentials, and serum creatine kinase (CK) was increased. Muscle biopsies showed dystrophic changes, including variation in fiber size, eosinophilic inclusions, necrotic fibers, regeneration, and endomysial fibrosis. Electron microscopic studies showed a powdery, granular transformation of the Z-bands with Z-band streaming and granular deposits amid the sarcomeres. All these features were consistent with a myofibrillar myopathy. Cardiac muscle was unaffected. Del Bigio et al. (2011) found that muscle biopsies from affected patients had strong immunoreactivity to desmin (DES; 125660), but absence of staining for the full alpha-B-crystallin protein; however, there was some residual staining for antibodies directed against the first 10 residues of alpha-B-crystallin.
The transmission pattern of fatal infantile hypertonic myofibrillar myopathy in the families reported by Lacson et al. (1994) was consistent with autosomal recessive inheritance.
In 8 patients with fatal infantile hypertonic myofibrillar myopathy, including 3 reported by Lacson et al. (1994), Del Bigio et al. (2011) identified the same homozygous 1-bp deletion in the CRYAB gene (60delC; 123590.0005), resulting in a truncated protein of 44 amino acids, including 23 missense residues. Heterozygous parents were unaffected, although 1 mother had mild myopathic symptoms and normal CK levels. Del Bigio et al. (2011) noted that individuals with heterozygous CRYAB mutations resulting in alpha-B crystallin-related late-onset myofibrillar myopathy (MFM2; 608810) have been observed, and suggested that in the severe infantile disease, the parental phenotype may have been rescued by limited expression of the highly truncated nonfunctional gene product.
Del Bigio, M. R., Chudley, A. E., Sarnat, H. B., Campbell, C., Goobie, S., Chodirker, B. N., Selcen, D. Infantile muscular dystrophy in Canadian aboriginals is an alpha-B-crystallinopathy. Ann. Neurol. 69: 866-871, 2011. [PubMed: 21337604] [Full Text: https://doi.org/10.1002/ana.22331]
Lacson, A. G., Seshia, S. S., Sarnat, H. B., Anderson, J., DeGroot, W. R., Chudley, A., Adams, C., Darwish, H. Z., Lowry, R. B., Kuhn, S., Lowry, N. J., Ang, L. C., Gibbings, E., Trevenen, C. L., Johnson, E. S., Hoogstraten, J. Autosomal recessive, fatal infantile hypertonic muscular dystrophy among Canadian natives. Can. J. Neurol. Sci. 21: 203-212, 1994. [PubMed: 8000975] [Full Text: https://doi.org/10.1017/s0317167100041172]