Can you explain nemaline myopathy, including its genetics, clinical presentation, diagnosis, management, and prognosis?

Nemaline Myopathy Overview

Nemaline myopathy is a congenital myopathy characterized by muscle weakness and pathognomonic rod-like structures (nemaline bodies) within muscle fibers, caused by mutations in genes encoding sarcomeric thin filament proteins, with clinical severity ranging from neonatal death to mild adult-onset weakness. 1, 2

Genetics

Eleven genes have been definitively established to cause nemaline myopathy, all encoding proteins that are components of the sarcomeric thin filament or contribute to its stability and turnover 1, 3:

• ACTA1 (muscle alpha-skeletal-actin) accounts for approximately 15% of cases and typically presents as de novo dominant mutations with marked clinical variability 4
• NEB (nebulin) is the most prevalent genetic cause, with mutations in RYR1 (ryanodine receptor 1) being the most common overall among congenital myopathies at approximately 1 in 90,000 5
• CFL2 (cofilin-2) mutations cause nemaline myopathy with minicores and F-actin accumulation 6
• Additional genes include those encoding other thin filament-associated proteins 3

Inheritance is typically autosomal dominant with nearly complete penetrance but highly variable expressivity, though autosomal recessive patterns occur 4. The overall prevalence is estimated at 1 in 26,000 to 28,000 5.

Clinical Presentation

Neonatal and Early Childhood Features

Hypotonia at birth predicts increased odds of requiring gastrostomy tubes long-term, while respiratory distress at birth predicts need for both gastrostomy tubes and invasive ventilation 1:

• Generalized hypotonia and weakness, usually from birth 5
• Prominent facial weakness with or without ptosis 5
• Hyporeflexia and poor muscle bulk 5
• Feeding problems requiring gastrostomy support 1, 2
• Repeated respiratory infections and potential ventilator dependence 1, 2
• Proximal muscle weakness and dysfunction of respiratory and bulbar muscles 5

Severity Spectrum

Clinical phenotype ranges from severe neonatal-onset weakness with death from respiratory failure in the first year to mild childhood-onset myopathy with survival into adulthood 4:

• Severe congenital form: Generalized life-threatening weakness in neonates, often with ACTA1 mutations 5, 4
• Intermediate form: Childhood presentation (first five years) with slowly progressive or nonprogressive weakness 2
• Mild form: Subtle proximal muscle weakness in older patients 5

Distinguishing Features

Cognitive abilities and sensation remain relatively normal, contrasting with the prominent motor dysfunction 5. This helps distinguish nemaline myopathy from congenital muscular dystrophies and other hypotonic disorders 5.

Genotype-Phenotype Correlations

ACTA1-related nemaline myopathy shows higher odds of requiring feeding tubes and invasive ventilation in the first year compared to NEB-related disease, though ventilation requirements become similar after the first year 1. However, marked intrafamilial variability indicates that genotype alone does not determine phenotype 4.

Diagnosis

Laboratory Testing

• Creatine phosphokinase (CPK) levels are typically normal 2
• Electromyography reveals myopathic changes with polyphasic motor unit action potentials of short duration and low amplitude 2

Muscle Biopsy

Histopathology is diagnostic and reveals 2, 4:

• Characteristic red-colored rod-like material on modified Gomori trichrome staining that is immunopositive to alpha-actinin 2
• Minimal changes on routine microscopy 2
• Abnormal fiber type differentiation, glycogen accumulation, and myofibrillar disruption 4
• "Whorling" of actin thin filaments on ultrastructural examination 4
• Occasional minicores, concentric laminated bodies, and F-actin accumulation (particularly with CFL2 mutations) 6

The percentage of fibers with rods does not correlate with clinical severity, but severe lethal phenotypes show generalized disorganization of sarcomeric structure and abnormal sarcomeric actin localization 4.

Genetic Testing

Genetic testing with targeted gene panel or whole exome sequencing confirms the diagnosis and identifies the specific causative mutation 1, 3. This is essential for genetic counseling and prognostication 1.

Cardiac Involvement

Cardiac involvement in nemaline myopathy is rare but has been reported 5:

• In 143 cases, 6 neonates developed transient heart failure and 1 infant developed left ventricular dysfunction with congenital long-QT syndrome 5
• Hypertrophic, dilated, and left ventricular noncompaction cardiomyopathy phenotypes have been described 5
• Sudden death has occurred 5

Cardiac evaluation should be performed before anesthesia or sedation in any patient with nemaline myopathy, and for those with cardiac symptoms, evaluation should occur within 3-6 months of the procedure 5.

Management

Multidisciplinary Approach

All neurologists managing nemaline myopathy should collaborate with a cardiologist experienced in neuromuscular diseases or at minimum an electrophysiologist or heart failure specialist 5:

• For childhood-onset cases, referral to a pediatric heart failure specialist is reasonable 5
• Cardiac monitoring by an anesthesiologist experienced in neuromuscular diseases should occur during major surgery at centers with appropriate intensive care facilities 5

Respiratory Support

Patients with respiratory distress at birth have significantly increased odds of requiring invasive ventilation long-term 1:

• Pulmonary function monitoring is essential 1
• Ventilator support ranges from noninvasive to invasive mechanical ventilation depending on severity 1, 2

Nutritional Support

Patients with hypotonia at birth have increased odds of requiring gastrostomy tubes 1:

• Early feeding assessment and intervention prevent aspiration and ensure adequate nutrition 1, 2

Physical Therapy

Supportive care with physical therapy helps maintain function and prevent contractures, though no curative treatment currently exists 3.

Prognosis

Neonatal findings strongly correlate with long-term outcomes 1:

• Severe congenital-onset cases may result in death from respiratory failure in the first year 4
• Mild cases allow normal lifespan with near-normal motor function 3
• The clinical course is typically static or slowly progressive 5

Better clinical and molecular predictors of outcome are needed for accurate prognostic counseling and clinical trial readiness 1.