New morphologic and genetic findings in cap disease associated with β-tropomyosin (TPM2) mutations

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Abstract

Objective:

Mutations in the β-tropomyosin gene (TPM2) are a rare cause of congenital myopathies with features of nemaline myopathy and cap disease and may also cause distal arthrogryposis syndromes without major muscle pathology. We describe the muscle biopsy findings in three patients with cap disease and novel heterozygous mutations in TPM2.

Methods:

Three unrelated patients with congenital myopathy were investigated by muscle biopsy and genetic analysis.

Results:

All three patients had early-onset muscle weakness of variable severity and distribution. Muscle biopsy demonstrated in all three patients near uniformity of type 1 fibers and an unusual irregular and coarse-meshed intermyofibrillar network. By electron microscopy, the myofibrils were broad and partly split, and the Z lines appeared jagged. In one of the patients caps structures were identified only by electron microscopy, and in one patient they were identified only in a second biopsy at adulthood. Three novel, de novo, heterozygous mutations in TPM2 were identified: a three–base pair deletion in-frame (p.Lys49del), a three-base pair duplication in-frame (p.Gly52dup), and a missense mutation (p.Asn202Lys).

Conclusions:

Mutations in TPM2 seem to be a frequent cause of cap disease. Because cap structures may be sparse, other prominent features, such as a coarse-meshed intermyofibrillar network and jagged Z lines, may be clues to correct diagnosis and also indicate that the pathogenesis involves defective assembly of myofilaments.

GLOSSARY

ATPase = adenosine triphosphatase; CK = creatine kinase; DA = distal arthrogryposis; NADH-TR = nicotinamide adenine dinucleotide–tetrazolium reductase; Tm = tropomyosin.

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