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At a glance

A rare genetic myopathy presenting at birth with hypotonia and muscle weakness. Findings occurring later in life include short stature, progressive scoliosis, hip dislocation, and deformities of the feet.

Synonym

Congenital Fiber-type Disproportion Myopathy.

Incidence

The exact incidence of congenital myopathies is unknown; however, estimations are quoted as less than 1:50,000 live births. Congenital Myopathy with Fiber-Type Disproportion (CMFTD) seems to account for approximately 20% of all congenital myopathy cases.

Genetic inheritance

Autosomal recessive transmission is the most common form; however, autosomal dominant and X-linked inheritance as well as sporadic cases have been described. Approximately 20 to 50% of CMFTD patients have mutations in the TPM3 (Tropomyosin 3) gene located on chromosome 1q21.3 and inheritance is most often autosomal dominant. Up to 20% are caused by mutations in the RYR1 (Ryanodine Receptor 1) gene on chromosome 19q13.2. About 5% are associated with mutations in the ACTA1 (Skeletal Muscle Alpha Actin 1) gene, which has been mapped to chromosome 1q42.13. CMFTD as a result of mutations in TMP2 (Tropomyosin 2), MYH7 (myosin heavy chain 7) and Selenon (Selenoprotein N) genes are comparably rare. Mutations of TMP3 follow either autosomal recessive or dominant inheritance patterns, SELENON and RYR1 mutations have autosomal recessive transmission, while ACTA1, MYH7, and TPM2 mutations are transmitted in an autosomal dominant fashion.

Diagnosis

It is confirmed by muscle biopsy, which commonly shows small, atrophic type I (“slow twitch”) fibers and compensatory hypertrophic Type II (“fast twitch”) fibers. In CMFTD, Type I fiber mean diameter should be at least 12% smaller than that of Type II fibers, although some groups consider a difference of 25% more appropriate. In fact, most CMFTD patients with a confirmed mutation in a congenital myopathy gene have fiber size disproportion of at least 35 to 40%, whereas noncongenital myopathies rarely show fiber size disproportion of that extent. Rarely, a small number of Type I fibers may show signs of hypertrophy. The overlap of clinical and histologic features with other forms of congenital myopathy sometimes makes the diagnosis difficult. Fiber size disproportion is considered a secondary finding when it occurs in combination with rods, cores, or abundant central nuclei. Thus, for the diagnosis to be accurate, other forms of congenital myopathy must be excluded and it is not unheard of that the diagnosis of CMFTD later had to be revised to another form of congenital myopathy. Serum creatine phosphokinase (CK) concentration is typically not or only mildly elevated.

Clinical aspects

CMFTD can be detected in other forms of congenital myopathy and other diseases (eg, ☞Duchenne Muscular Dystrophy, ☞Spinal Muscular Atrophy, metabolic myopathies, central nervous system diseases such as leukodystrophies, ☞Lowe Syndrome, and ☞Moebius Syndrome); however, it also exists as a distinct diagnostic entity. Generalized hypotonia and weakness may already be ...

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