Final Diagnosis -- 4 year old boy with desmin cardiomyopathy

FINAL DIAGNOSIS: DESMIN CARDIOMYOPATHY

DISCUSSION:

The presence of intra-myocyte inclusions composed of myofibrillar material, places this in the broad category of a myofibrillar myopathy. The term myofibrillar myopathy was proposed in 1996 to encompass the spectrum of disorders characterized by an accumulation of myofiber degradation products with abnormal expression of various proteins. The most commonly expressed proteins are myotilin, desmin, ?B-crystallin, dystrophin, and ?-amyloid precursor protein(1). In patients with cardiomyopathy associated with the skeletal myopathy, desmin is the most commonly expressed protein, and the term, "desmin myopathy," is sometimes used. Desmin, a 52kD intermediate filament protein, is found in cardiac, skeletal, and some smooth muscle cells, and is responsible for structural integrity of cardiac myofibrils. Various missense mutations of the desmin gene have been reported.

Myofibrillar myopathy is a rare condition with subtle histologic findings and varied clinical presentations and inheritance patterns. Slowly progressive muscle weakness, which may be either proximal or distal, is the most common symptom and typically manifests between the ages of 25 and 45(2). Reports of associated cardiomyopathy vary greatly, from 16% - 63%(1,2). Arrhythmias and congestive heart failure are frequent associations, but sudden death from conduction defects may be the initial clinical manifestation. Although the majority of cases are sporadic, the most common pattern of inheritance is autosomal dominant. Autosomal recessive inheritance of desmin mutations has been described in a few patients with aggressive myopathy and cardiomyopathy(3).

It is rare for patients with myofibrillar myopathy to present clinically before 20 years of age, although the age at first manifestations varies from infancy to 64 years. Profound cardiomyopathy requiring heart transplantation by 4 years of age is almost unique. The pediatric-specific implications are clear. The child has a new heart, but with the life-threatening element eliminated, will live with severe skeletal myopathy. He is now chimeric for the defect, and a living natural experiment. Will inclusions accumulate in the implanted heart, or will the deficiency be ameliorated by the microchimerism as reported previously in patients with glycogen storage disease and Gaucher disease following liver transplantation(5)? Unlike the situation in adult pathology where follow-up is limited, the opportunity exists to track the progress of this child for decades. The diagnosis, which was not made prior to transplantation, has profound implications for inheritance and family planning.

REFERENCES:

1. Seleen D et al. Myofibrillar myopathy: clinical, morphological and genetic studies in 63 patients. Brain. 2003;127:439-451.
2. Amato AA et al. The wide spectrum of myofibrillar myopathy suggests a multifactorial etiology and pathogenesis. Neurology. 1998;51:1646-1655.
3. Goldfarb LG et al. Missense mutations in desmin associated with familial cardiac and skeletal myopathy. Nat Genet (letter). 1998;19:402-403.
4. Dalakas MC et al. Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. Engl Med. 2000;342:770-780.
5. Starzl TE et al. Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher's disease. Engl Med. 1993;328:745-749.

Contributed by Amy Davis, MD