The fatal autosomal recessive infantile hypertonic muscular dystrophy observed in Canadian Aboriginals shows the pathologic features of MFM. The clue to a defect in αBC came from the absence of αBC immunoreactivity using a monoclonal antibody raised against the entire αBC protein. This finding differed sharply from those in previously reported MFM patients with autosomal dominant CRYAB
mutations whose muscles showed markedly increased and ectopic expression of αBC.6, 7, 14
The most likely explanation was a biallelic null mutation that behaves in a genetic recessive manner. However, a monoclonal antibody raised against the first 10 residues of αBC did reveal some immunoreactivity in some muscle fibers. These findings are readily reconciled by the position of the identified mutation that may allow expression of the first 20 αBC residues, though expression is likely attenuated by nonsense mediated mRNA decay. Presence of the same mutation in affected children in different regions of Canada points to a founder mutation.
knockout is not embryonic or neonatal lethal in mice. After 40 weeks of age, the mice lose weight and body fat, and develop kyphosis and a myopathy involving the posterior tongue and axial muscles with lesser involvement of the extremity muscles. Our patients show a similar selective involvement of neck and truncal muscles, but are more severely affected than the knockout mice.15
Tongue, examined at autopsy in one patient, showed advanced pathologic changes. The predilection for truncal muscles may be related to the greater expression of αBC in type 1 fibers which are enriched in large postural muscles.16
As in our patients, the heart of the knockout mice is unaffected.15
αBC is a small heat shock protein that inhibits aggregation and precipitation of denatured proteins.17, 18
The myofibrils, and especially the Z-disks, are constantly stressed by physical activity but are protected from unfolding and denaturation by molecular chaperones.19
The close association of αBC with the Z-disk implies that αBC is particularly important in protecting the Z-disk from disintegration that results in myofibrillar breakdown. Specifically, αBC appears to have a high affinity for desmin20
under situations of cellular stress. We postulate that the interaction of αBC with titin is relevant in this novel myopathy as titin is largely responsible for muscle elasticity. Thus the lack of αBC could derange titin in such a way to contribute to reduced muscle elasticity. There is some indirect evidence for this pathophysiology in the αBC/HSPB2 deficient mouse model wherein cardiac ischemia induces more rapid and sustained resting muscle tension compared to controls.22
Hypertonia is not typically seen in myopathic conditions and will need to be adequately addressed in any proposed model of this muscle disease. In addition, αBC protects myosin from thermal denaturation.23
An additional pathogenetic factor in this disease is the marked and early endomysial fibrosis that impairs chest wall compliance and contributes to early respiratory failure. Similar early and marked endomysial fibrosis has not been documented in other types of MFM, suggesting the αBC may have an additional role in regulating connective tissue proliferation in muscle as has been suggested in skin wound healing.24
Although some pathogenetic aspects of the fatal αB-crystallinopathy of the Canadian Aboriginals remain to be elucidated, deciphering the gene defect has important implications for diagnosis, genetic counseling, carrier detection, preconceptional and prenatal testing, and eventual prevention of the disease.