ClinVar

In 8 patients with fatal infantile hypertonic myofibrillar myopathy (613869), including 3 reported by Lacson et al. (1994), Del Bigio et al. (2011) identified the same homozygous 1-bp deletion in the CRYAB gene (123590.0005), resulting in a ser21-to-ala (S21A) change and a stop codon after 23 missense residues. All patients were Canadian aboriginals of Cree descent, consistent with a founder effect. The phenotype was characterized by onset in the first weeks of life of rapidly progressive muscular rigidity of the trunk and limbs associated with increasing respiratory difficulty resulting in death before age 3 years. Muscle biopsies showed dystrophic changes, endomysial fibrosis, eosinophilic deposits, and Z-band streaming. Immunohistochemistry using an antibody against the full-length CRYAB protein showed absence of staining, but an antibody against the first 10 residues of the protein showed some residual staining. Heterozygous parents were unaffected, including 1 mother with mild myopathic symptoms but normal CK levels. Del Bigio et al. (2011) noted that late-onset myofibrillar myopathy (608810) is typically seen in heterozygous individuals; however, in this disease, the parental phenotype may be rescued by limited expression of the 44-amino acid truncated nonfunctional gene product. Del Bigio et al. (2011) postulated that a disruption of CRYAB interaction with titin (TTN; 188840) may contribute to reduced muscle elasticity.