Novel heterogeneous missense mutations in five families with congenital fiber type disproportion (CFTD) were identified in a study at Children's Hospital at Westmead, University of Sydney, and other centers in Australia, Canada, and France. In 11 affected patients with TPM3 gene mutations and CFTD, symptoms of hypotonia presented in the first year. Some had a “dropped head” posture while crawling. Five walked late at 18-60 months, while 6 walked at a normal age. Most improved functionally until adolescence, when motor ability stabilized or slowly declined. Four patients older than 30 years were still ambulant. Respiratory insufficiency occurred during sleep, despite good limb strength, and ventilatory support was required as early as 3.5 years in one patient and as late as 55 years in one. One died unexpectedly at 45 years old. Spinal changes were invariable, with lumbar lordosis and thoracic kyphosis in early childhood, becoming more severe in late childhood or adulthood. Neck muscle weakness and extensor contractures were common. Most had generalized amyotrophy, proximal limb weakness, and a waddling gait. Mild facial weakness and ptosis, and winged scapula were common. Intellectual function was normal. Cardiac function was normal, except for 1 patient with left ventricular hypertrophy. CK level was low normal and rarely, mildly increased. Nerve conduction studies were normal, and EMG normal or myopathic. In muscle biopsies, type 1 fibers were atrophied and 50% smaller than type 2 fibers. Type 2 fibers were hypertrophied, 1.6 times normal diameter, and 25% had internal nuclei. In a sixth family with TPM3 mutation, some patients had features of CFTD and others had nemaline myopathy. TPM3 mutation is the most common cause of CFTD in reported cases. [1]

COMMENT. Congenital fiber type disproportion (CFTD) is a rare cause of congenital myopathy and hypotonia. Clinical features are heterogeneous, and mutations in several genes have been identified. Diagnosis should exclude other causes for myopathy, since type 1 fiber hypotrophy is a common secondary feature in many neuromuscular disorders. The above authors have previously found mutations in ACTA1 and SEPN1 genes in a few patients with CFTD. The present report of TPM3 mutations involving 11 cases in 5 families is the largest series to date. Affected patients present with hypotonia before the first birthdate and show a slow progression of proximal muscle weakness, kyphoscoliosis, and respiratory insufficiency, but most remain ambulant and survive to adulthood.