Besides intact cognitive and sensory function, what features distinguish nemaline myopathy from other congenital muscular dystrophies?

Distinguishing Features of Nemaline Myopathy from Other Congenital Muscular Dystrophies

Nemaline myopathy is distinguished from congenital muscular dystrophies by the presence of characteristic nemaline rods (rod bodies) on muscle biopsy, normal or only mildly elevated creatine kinase levels, preserved cognitive and sensory function, prominent facial weakness with dysmorphic features (particularly high-arched palate and feet), and a predominantly myopathic rather than dystrophic pattern on histopathology. 1, 2

Key Distinguishing Histopathologic Features

Nemaline Bodies (Rods)

• The pathognomonic feature is the presence of purple-colored rod-like structures (nemaline bodies) visible on modified Gömöri trichrome staining, which are not seen in muscular dystrophies. 2
• Electron microscopy reveals high electron-dense rectangular structures with a lattice-like appearance originating from Z-disk material, representing disorganized thin filaments. 2, 3, 4
• Rods accumulate predominantly in type I muscle fibers, which show marked predominance and atrophy. 2

Muscle Fiber Architecture

• Nemaline myopathy demonstrates myopathic changes with fiber type I predominance and selective type I fiber atrophy, rather than the progressive replacement of muscle with fat and connective tissue characteristic of muscular dystrophies. 5, 2
• Myofibrillar disorganization with broken myofilaments and irregular Z-lines is present, but without the dystrophic features (necrosis, regeneration, endomysial fibrosis) typical of muscular dystrophies. 2, 4

Clinical Distinguishing Features

Creatine Kinase Levels

• Serum CK is normal or only mildly elevated in nemaline myopathy, whereas it is markedly elevated (often 10-100 times normal) in most muscular dystrophies, particularly Duchenne muscular dystrophy. 6, 2, 3

Pattern of Weakness

• Proximal-dominant limb weakness with prominent facial weakness, ptosis, and bulbar involvement (dysphagia, dysarthria) is characteristic of nemaline myopathy. 1, 2
• Hypotonia with reduced or absent deep tendon reflexes is typical, contrasting with the pseudohypertrophy of calves seen in Duchenne muscular dystrophy. 2

Dysmorphic Features

• High-arched palate, high-arched feet, elongated facies, and skeletal abnormalities (pectus excavatum, scoliosis) are common dysmorphic features in nemaline myopathy that are not prominent in most muscular dystrophies. 2

Cognitive and Sensory Function

• Cognitive abilities and sensation remain intact in nemaline myopathy, contrasting with some muscular dystrophies (e.g., myotonic dystrophy) that can involve cognitive impairment. 1

Cardiac Involvement Patterns

Nemaline Myopathy

• Cardiac involvement is rare in nemaline myopathy; when present, it may manifest as transient heart failure in neonates or isolated cases of left ventricular dysfunction, but is not a defining feature. 1

Muscular Dystrophies

• Progressive dilated cardiomyopathy is a hallmark of Duchenne muscular dystrophy, occurring in the majority of patients and representing a major cause of mortality. 5
• Laminopathies (LMNA mutations) demonstrate early cardiac conduction disease and arrhythmias with 25% mortality from sudden cardiac death by age 50. 1
• Emery-Dreifuss muscular dystrophy characteristically shows atrial standstill and requires early pacing, typically before age 30. 1

Genetic and Inheritance Patterns

• Nemaline myopathy is most commonly caused by mutations in genes encoding thin filament proteins (ACTA1, NEB, TPM3, TNNT1), with both autosomal dominant (often de novo ACTA1 mutations) and recessive inheritance patterns. 4
• Muscular dystrophies typically result from mutations in genes encoding structural proteins of the dystrophin-glycoprotein complex (dystrophin in DMD, sarcoglycans, laminin-α2) or nuclear envelope proteins (lamin A/C, emerin). 1, 5

Clinical Course and Prognosis

Nemaline Myopathy

• Clinical heterogeneity ranges from severe neonatal forms with early respiratory failure and death in infancy to mild childhood or adult-onset forms with slow progression and prolonged survival. 2, 3, 4, 7
• Respiratory muscle involvement (diaphragm, intercostals) is the primary cause of morbidity and mortality, particularly in severe forms. 7

Muscular Dystrophies

• Duchenne muscular dystrophy follows a predictable progressive course with loss of ambulation by early teens, respiratory failure, and death typically in the late 20s without intervention. 5
• The dystrophic process involves relentless replacement of functional muscle with fat and connective tissue over time. 5

Diagnostic Approach

• When CK is normal or mildly elevated with proximal weakness and facial involvement, nemaline myopathy should be strongly considered, and muscle biopsy with modified Gömöri trichrome staining is diagnostic. 6, 2, 3
• Electromyography reveals myopathic changes (short-duration, low-amplitude polyphasic potentials) in both conditions, but cannot reliably distinguish between them. 2, 3
• Genetic testing targeting thin filament genes (ACTA1, NEB) confirms nemaline myopathy, while dystrophin gene analysis or dystrophin immunostaining on muscle biopsy confirms muscular dystrophy. 5, 4