Genotype-phenotype correlations in TPM3-related myopathy


Translational Research

Poster Number: 233


Matthias Lambert, PhD, Boston Children's Hospital / Harvard Medical School, Emanuela Gussoni, PhD, Boston Children's Hospital / Harvard Medical School

The term congenital myopathies refers to a genetically heterogeneous group of early-onset skeletal muscle disorders characterized by variable degrees of muscle weakness and distinctive structural abnormalities in muscle biopsies. Several mutations in the TPM3 gene have been associated with the features of congenital myopathy. However, there exists no natural history of TPM3-related myopathy or evidence for genotype-phenotype correlations.
In this study, we surveyed the literature and identified sixty-four families including ninety-eight individuals affected by TPM3-related myopathy. So far, forty-three TPM3 mutations have been reported. The spectrum of disease severity ranges from severe to mild muscle weakness, and to clinically unrecognized forms. Respiratory muscles are more profoundly affected since nocturnal non-invasive ventilation is often required, even for patients that remain fully ambulant. Despite this wide heterogeneity, we have established that the pattern of inheritance, the type and location of mutations are one of the determinants of disease severity in TPM3-related myopathy. There also exists a broad range of pathological features in muscle biopsies. Congenital fiber type disproportion (CFTD) is the most common diagnosis made in TPM3 patients (56%), followed by the diagnosis of nemaline myopathy (28%), cap myopathy (13%), and 3% combining both nemaline and cap myopathy features. No correlation between the genotype and the structural abnormalities seen on muscle biopsies has been established. However, the degree of fiber size disproportion has been shown as another determinant of disease severity, as opposed to nemaline rods.
Altogether, this information is critical for the diagnosis, prognosis, care management, and the implementation of clinical trials for TPM3-related myopathy.