Makindo Medical Notes

🧠 About

Nemaline myopathy (NM) is a congenital myopathy defined by the presence of rod-like inclusions (“nemaline bodies”) within skeletal muscle fibres. These rods derive from Z-line material, reflecting disruption of sarcomeric actin–myosin organisation. NM presents with variable severity, from severe neonatal hypotonia and respiratory failure to mild, slowly progressive weakness in adulthood. Unlike muscular dystrophies, muscle fibre necrosis is absent and serum CK is usually normal or only mildly raised.

🧬 Genetics & Inheritance

• Common genes: NEB (nebulin), ACTA1 (skeletal α-actin), TNNI2, TPM2, TPM3, CFL2, KBTBD13.
• Patterns: Autosomal recessive (NEB) is most frequent; autosomal dominant (ACTA1, TPM2/3, KBTBD13) also occur.
• Pathophysiology: Mutations disrupt thin filament assembly or regulation → impaired sarcomere contractility → chronic weakness without fibre death.

Teaching tip: Link the gene to function: NEB (structural scaffolding of actin), ACTA1 (core contractile protein), TPM/TNNI2 (regulatory proteins). All converge on thin filament biology. ⚙️

🧩 Pathophysiology

Nemaline rods are aggregates of Z-line proteins seen on modified Gomori trichrome stain as dark red rods. They interfere with force transmission along myofibrils. Muscle fibres show type-1 fibre predominance and hypotrophy. The rods themselves are diagnostic but not directly pathogenic—rather, they are the histological hallmark of disrupted thin filament assembly.

👶 Clinical Phenotypes

• Severe neonatal: Profound hypotonia (“floppy infant”), weak cry, respiratory failure; often life-limiting early.
• Intermediate congenital: Onset in infancy/childhood with delayed milestones, facial weakness, feeding/swallow problems; survival into childhood/adolescence with support.
• Mild childhood/adult-onset: Slowly progressive proximal weakness, sometimes only exercise intolerance; normal lifespan possible.

🔎 Examination Clues

• Facial weakness and long narrow face (“myopathic facies”).
• High-arched palate, dysarthria.
• Axial and proximal limb weakness; delayed motor development.
• Respiratory muscle weakness — a major morbidity determinant.
• Skeletal deformities: scoliosis, chest wall deformities, contractures.

🧪 Investigations

• Bloods: CK usually normal or mildly ↑.
• EMG: Myopathic pattern.
• Muscle biopsy: Nemaline rods (Gomori trichrome); type-1 fibre predominance.
• Genetics: NGS myopathy panel; confirms diagnosis and informs counselling.
• Respiratory: Spirometry, nocturnal oximetry/capnography.

🧯 Differential Diagnosis

• Other congenital myopathies (CNM, central core disease, congenital fibre-type disproportion).
• Congenital muscular dystrophies (present earlier, dystrophic biopsy, higher CK).
• Congenital myasthenic syndromes (fatigability, decrement on RNS, AChE responsiveness).
• Mitochondrial myopathies (multisystem, ragged-red fibres, lactic acidosis).

🧑‍⚕️ Management

• Respiratory: monitor regularly; early use of non-invasive ventilation (NIV); airway clearance techniques.
• Physiotherapy: contracture prevention, posture support, scoliosis surveillance.
• Feeding/swallow: multidisciplinary input; gastrostomy if recurrent aspiration.
• Orthopaedics: scoliosis correction, orthotics for mobility.
• Speech & language therapy: for dysarthria and feeding support.
• Genetic counselling: key for families; NEB carriers are common in certain populations.

🧪 Research & Prognosis

No disease-modifying therapy yet. Gene therapy and exon-skipping approaches are under study (especially for ACTA1 and NEB). Prognosis depends on subtype: severe neonatal can be life-limiting; milder forms allow survival into adulthood with slowly progressive weakness. Respiratory care is the single most important prognostic modifier. 📈