Background

The first report of a congenital myopathy was in 1956, when a patient with central core disease (CCD) was described. Since that time, other myopathies have been defined as congenital myopathies, which have the following characteristics:

• Onset in early life with hypotonia, hyporeflexia, generalized weakness that is more often proximal than distal, and poor muscle bulk
• Often with dysmorphic features that may be secondary to the weakness
• Relatively nonprogressive
• Hereditary
• Unique morphological features on histochemical or ultrastructural examination of the muscle biopsy sample that originate within the myofiber

Hypotonia is the clinical hallmark of congenital myopathies. It presents in the neonatal period as head lag; lack of flexion of the hips, knees, and elbows; external rotation of the hips; diffuse weakness in facial, limb, and axial muscles; and reduced muscle mass.

The above features do not apply to all cases of congenital myopathy. Some cases have been reported as adult onset or as a progressive course. Some of the morphological alterations are not disease specific but are seen in various congenital myopathies or in other myopathic or nonmyopathic conditions.

A recent review article^[1] divided the congenital myopathies based on genetic and morphological features into 4 main groups.

Myopathies with protein accumulation

• Nemaline myopathy
• Myosin storage myopathy
• Cap disease
• Reducing body myopathy

Myopathies with cores

• Central core disease
• Core-rod myopathy
• Multiminicore disease

Myopathies with central nuclei

• Myotubular myopathy
• Centronuclear myopathy

Myopathies with fiber size variation

• Congenital fiber type disproportion

With the advent of improved techniques such as electron microscopy, enzyme histochemistry, immunocytochemistry, and molecular genetics, the etiologies of many congenital myopathies are now well defined. This article focuses on the diseases with known mutations. The numerous rare congenital myopathies distinguished primarily based on a unique morphological feature on muscle biopsy are briefly discussed below (see Rare congenital myopathies).

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Pathophysiology

In the common, well-described congenital myopathies, mutations have been identified in genes that encode for muscle proteins. The loss or dysfunction of these proteins presumably leads to the specific morphological feature on muscle biopsy samples and to the clinical muscle disease. The specific pathogenesis for each congenital myopathy is discussed below.

The same principle presumably leads to the morphological features determined by muscle biopsy in congenital myopathies whose genetic defects are not yet known.

Epidemiology

Frequency

International

The true incidence of congenital myopathies is unknown. In a series of 250 infants with neonatal hypotonia described by Fardeau and Tome, muscle biopsy performed before age 2 months revealed that only 14% had a congenital myopathy. Central nervous system (CNS) disease is the most common cause of congenital hypotonia.

The same authors documented 180 cases of congenital myopathy over 20 years. The types were as follows:

• Nemaline rod myopathy (20%)
• Central core disease (16%)
• Centronuclear myopathy (14%)
• Multiminicore myopathy (10%)
• Congenital fiber-type disproportion or type 1 fiber predominance (21%)
• Six other miscellaneous congenital myopathies (19%)

Mortality/Morbidity

Associated morbidity and mortality rates have considerable variability.

• Some patients die within the neonatal period, while others can have a normal life span.
• Cardiopulmonary compromise is the most common cause of death.
• Other complications include skeletal deformities and malignant hyperthermia.

Sex

Both sexes are affected equally in most congenital myopathies since inheritance is usually autosomal recessive or autosomal dominant.

In X-linked forms, boys are affected almost exclusively, although occasional female carriers with clinical manifestations have been described.

Age

Congenital myopathies usually present in the neonatal period but can also present later in life (even into adulthood).

Clinical Presentation