Congenital Myopathy 2009

Abstract & Commentary

By Michael Rubin, MD, Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Rubin reports that he receives grant/research support from Pfizer and is on the speaker's bureau of Athena Diagnostics.

Synopsis: Great progress has been made in identifying the underlying genetic defects in congenital myopathies.

Source: Sharma MC, Jain D, Sarkar C, et al. Congenital myopathies—A comprehensive update of recent advancements. Acta Neurol Scand 2008;Dec. 29 (E-pub ahead of print).

With an incidence of 6/100,000 live births and comprising 10% of all neuromuscular disorders, congenital myopathies result from genetic abnormalities in the contractile apparatus of muscle. They demonstrate fixed, unique histochemical or ultrastructural changes on muscle biopsy, thus differentiating them from muscular dystrophies, which affect the stability of the sarcolemmal membrane and exhibit ongoing muscle degeneration and regeneration on muscle biopsy. Though congenital hypotonia with delayed motor milestones and slow progression is the usual presentation, adult onset and more rapid deterioration in childhood, may be seen. In the absence of any pathognomonic symptom or syndrome for any congenital myopathy, research in other areas is advancing our understanding and classification of these diseases.

Demonstrating significant clinical and histologic variability, central core myopathy, a calcium channel disorder and the first congenital myopathy to be identified, is associated with mutation of the ryanodine receptor gene (RYR1) on chromosome 19q13, also linked to malignant hyperthermia. Seen on oxidative stains as unstained areas, cores contain an antibody to the actin cross-linking protein, filamin C, and desmin, which may play a role in their formation. Multi-minicore disease demonstrates multiple cores on oxidative stains that, like the central cores they resemble ultrastructurally, are a non-specific finding on muscle biopsy. Selenoprotein N (SEPN1) and RYR1 gene mutations are both reported with multi-minicore disease, the latter with a severe neonatal form, but multi-minicore disease occurs with neither mutation, as well.

Rapidly fatal and affecting only newborn boys, X-linked myotubular myopathy (XLMTM) presents during pregnancy with polyhydramnios and decreased fetal movements, followed postpartum by hypotonia and respiratory insufficiency. It is associated with the XLMTM gene at Xq28 for myotubularin, which contains the consensus sequence for the active site of tyrosine phosphatases, a wide class of proteins involved in signal transduction. Immature muscle fibers fail to grow and differentiate, perhaps due to failure of myotubularin interaction with other proteins.

Mutation of either the myogenic factor-6 (MYF6) gene at chromosome 12q21 or the dynamin-2 (DNM2) gene at 19p13.2 is associated with the dominant form of centronuclear myopathy, while an amphiphysin 2 gene has recently been associated with the recessive form. All three proteins are involved in maintaining skeletal muscle fiber organization, including endocytosis, membrane trafficking, actin assembly, centrosome cohesion, and nuclear positioning.

Six genes, five related to thin filament proteins and one to sarcoplasmic reticulum protein, have thus far been shown to result in nemaline myopathy, the most common congenital myopathy, which may diversely present as a floppy infant; as childhood, adolescent, or adult onset myopathy; and be mild, moderate, or severe. Actin aggregate myopathy results from mutation of the skeletal muscle actin (ACTA1) gene at chromosome 1q42.1 and comprises three classes, based on muscle morphology demonstrating excess thin filamentous inclusions, intranuclear rod myopathy, or nemaline myopathy. Clinical symptomatology is similar to that seen with nemaline myopathy.

Accrual of desmin intermediate filaments characterize desmin related myopathies, presenting in the second to fourth decade of life as slowly progressive, distal, painless muscle weakness and atrophy, often associated with cardiac arrhythmia or cardiomyopathy. Primary desminopathies are associated with mutation of the desmin gene on chromosome 2q35, whereas secondary desminopathies, also designated as myofibrillar myopathies, may be caused by mutation of genes involving a-b-crystallin, selenoprotein N1, myotilin, or g-filamin.

Hyaline body myopathy, a rare congenital myopathy localized to chromosome 3p22.2-p21.32, demonstrates subsarcolemmal hyalinized bodies rich in myofibrillary ATPase and myosin, and is classified among the so-called protein aggregate myopathies. Awaiting characterization and further classification are the congenital myopathies designated as reducing body myopathy, Zebra body myopathy, fingerprint myopathy, and cap disease.


No curative therapy currently exists for congenital myopathy, but prenatal genetic diagnosis is available for many forms, and physical and occupational therapy, respiratory care, orthopedic intervention, and feeding management can prolong life and improve its quality. Future prospects for potential therapy include genetic manipulation by allelic-specific knock down of mutant alleles, dilution of mutant protein by administration of the normal isoform, upregulating genes that may produce surrogates for the absent protein, and inducing muscle fiber hypertrophy (North K. What's new in congenital myopathies? Neuromusc Disord 2008;18;433-442). Much research remains to be done, but each advance is a step in the right direction.