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Homa Tajsharghi, PhD; Eva Kimber, MD; Anna-Karin Kroksmark, PhD; Ragnar Jerre, MD; Mar Tulinius, MD, PhD; Anders Oldfors, MD, PhD

Arch Neurol. 2008;65(8):1083-1090.

Background  Myosin is a molecular motor and the essential part of the thick filament of striated muscle. The expression of myosin heavy-chain (MyHC) isoforms is developmentally regulated. The embryonic isoform encoded from MYH3 (OMIM *160720) is expressed during fetal life. Recently, mutations in MYH3 were demonstrated to be associated with congenital joint contractures, that is, Freeman-Sheldon and Sheldon-Hall syndromes, which are both distal arthrogryposis syndromes. Mutations in other MyHC isoforms cause myopathy. It is unknown whether MYH3 mutations cause myopathy because muscle tissue has not been studied.

Objectives  To determine whether novel MYH3 mutations are associated with distal arthrogryposis and to demonstrate myopathic changes in muscle biopsy specimens from 4 patients with distal arthrogryposis and MYH3 mutations.

Design  In a cohort of patients with distal arthrogryposis, we analyzed the entire coding sequence of MYH3. Muscle biopsy specimens were obtained, and in addition to morphologic analysis, the expression of MyHC isoforms was investigated at the protein and transcript levels.

Results  We identified patients from 3 families with novel MYH3 mutations. These mutations affect developmentally conserved residues that are located in different regions of the adenosine triphosphate–binding pocket of the MyHC head. The embryonic (MYH3) isoform was not detected in any of the muscle biopsy samples, indicating a normal developmental downregulation of MYH3 in these patients. However, morphologic analysis of muscle biopsy specimens from the 4 patients revealed mild and variable myopathic features and a pathologic upregulation of the fetal MyHC isoform (MYH8) in 1 patient.

Conclusions  Distal arthrogryposis associated with MYH3 mutations is secondary to myosin myopathy, and postnatal muscle manifestations are variable.

Author Affiliations: Departments of Pathology (Drs Tajsharghi and Oldfors) and Orthopedics (Dr Jerre), Sahlgrenska University Hospital; Departments of Pediatrics, Institute for Clinical Sciences, Sahlgrenska Academy at Göteborg University (Drs Kimber, Kroksmark, and Tulinius) and Queen Silvia's Children's Hospital (Drs Kroksmark and Tulinius), Göteborg; and Department of Neuropediatrics, Uppsala University Childres Hospital, Uppsala (Dr Kimber); Sweden.

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