caution!

Patients with mutations in SEPN1 and TPM3 may develop nocturnal hypoventilation while fully ambulant and monitoring of respiratory function from early ages is advised in proven or suspected cases.

The Different Types of Congenital Myopathy

Nemaline Myopathy

Nemaline myopathy (NM) is one of the most common forms of congenital myopathy and is defined by the presence of numerous dense rod-like protein inclusions in skeletal muscles (nemaline rods or nemaline bodies). Rods tend to increase with age and vary in number between muscles and sometimes re-biopsy is required to establish the diagnosis. Rods are best seen on Gomori trichrome stain as dark red/purple dense bodies. The spectrum of muscle weakness in NM extends from children who never establish independent respiration to patients with mild weakness that has little impact on daily life into adulthood. A clinical categorization based on early disease severity is useful to predict prognosis and genetic cause (see Ryan et al. in the Bibliography at the end of the chapter).

There are six known genetic causes that overlap in clinical phenotype. A diagnostic difficulty is the expense of genetic testing for NEB, an enormous gene encoding nebulin which likely accounts for over half of NM families worldwide. All NEB families to date have autosomal recessive inheritance. ACTA1 encodes α-skeletal actin and is the second most common cause, accounting for around 25% of NM patients, but around 50% of those with severe congenital weakness. Over 90% of ACTA1 mutations are autosomal dominant and many are new mutations; however, 10% of families have recessive disease. Two tropomyosin genes (TPM2 and TPM3) each account for around 5% of NM and may be either dominant or recessive. The NEB, TPM3, and TPM2 genes cause a very similar range of clinical phenotypes, with prominent neck and ankle dorsiflexor weakness in mild or moderately affected patients. At present muscle MRI appears less useful in NM than in other congenital myopathies.

Currently, genetic testing for NM usually begins with ACTA1, particularly in patients with severe weakness, numerous nemaline rods, or if there is a dominant family history. When rods are confined to slow muscle fibers, a mutation in TPM3 is likely because α-tropomyosin_slow is expressed only in slow fibers. Mutation analysis of TPM3 and TPM2 is often undertaken before NEB because testing is less expensive despite their relative rarity. TNNT1 and CFL2 also cause NM but these forms are so rare that these genes are not usually tested for.

The Core Myopathies

There are two main forms of core myopathy, central core disease (CCD) and multi-minicore disease (MmD). Although there is overlap between these entities, the distinction remains useful because the genetic basis differs. The “cores” in all core myopathies are regions within muscle fibers that lack staining on the oxidative stains (SDH and NADH) due to marked reduction or absence of mitochondria in those areas. In CCD, the cores are often single, large, and central with well-defined borders that extend along the fiber a considerable distance (best appreciated on longitudinal muscle sections). In contrast, in MmD, the cores are usually smaller, multiple, often have less well defined boundaries, and involve only a few adjacent sarcomeres. Electron microscopy (EM) is particularly helpful to confirm the diagnosis in MmD because poorly defined cores can be difficult to distinguish from staining artifacts.

Classic CCD is usually due to mutations in RYR1 and there is a strong co-association with malignant hyperthermia (MH). Most CCD mutations are dominant (heterozygous) changes that cluster in three CCD/MH hotspot regions. Most patients with CCD present in infancy or childhood with delayed gross motor skills, mild or moderate proximal limb weakness, and facial weakness, and remain ambulant in adulthood. Most patients do not have ophthalmoplegia, difficulty swallowing, or significant respiratory muscle involvement, but scoliosis and congenital hip dislocation are common. A few patients with CCD have severe weakness and resemble patients with MmD due to RYR1 (see below).

Multi-Minicore Disease

This has two common genetic causes identified to date. Up to half of MmD patients have autosomal recessive disease due to mutations in SEPN1, which encodes the protein selenoprotein N. Mutations in SEPN1 result in variable histological abnormalities that include mild dystrophic changes, as well as multiple cores. The clinical phenotype is more consistent and recognizable, particularly in older children; the clinical features and muscle MRI offer the best clues for diagnosis. Children with SEPN1-related myopathy are usually well at birth and walk and sit at normal ages, but may present with hypotonia and axial weakness in infancy (a dropped-head phenotype). They usually have slight builds and mild limb weakness during childhood. Facial and eye movements are normal but spinal rigidity and neck weakness may be marked. CK levels can be mildly elevated or normal. Most children require surgical stabilization of scoliosis in adolescence and, even though they remain fully ambulant, most require nocturnal respiratory support from late childhood to late adolescence.

The second common cause of MmD is the RYR1 gene. In contrast to CCD, MmD due to RYR1 is most often autosomal recessive and more severe, although the range of disease severity is wide. Patients may present from birth with generalized hypotonia and weakness, poor head control, and difficulty swallowing. Axial weakness is usually prominent and scoliosis common. The presence of facial weakness, ptosis, and ophthalmoplegia (which may develop only during childhood) is helpful in discriminating MmD due to RYR1 from that due to SEPN1. Muscle MRI also shows a relatively consistent pattern. All patients with possible, suspected, or known mutations in RYR1 have a high risk of MH during general anesthesia and precautions are required.

The RYR1 gene is large and contains many harmless sequence variants in the general population (polymorphisms), and both dominant and recessive patterns are common. This complicates the interpretation of genetic testing results. It is prudent to ask the advice of a specialist laboratory or neuromuscular service if there is any uncertainty.