Makindo Medical Notes

🧠 About

Centronuclear myopathies are a group of congenital muscle disorders defined by centrally placed myonuclei on biopsy (resembling fetal “myotubes”). The core biology reflects disturbed membrane remodelling and excitation–contraction coupling in skeletal muscle, especially at the triad (T-tubule–SR junction). Phenotypes range from severe neonatal hypotonia and respiratory failure to milder, slowly progressive adolescent–adult weakness. CNM is genetically heterogeneous with X-linked, autosomal dominant, and autosomal recessive forms.

🧬 Genetics & Inheritance

• X-linked (MTM1) — “X-linked myotubular myopathy”; typically severe neonatal disease in boys; carrier females can have mild signs (e.g., ptosis, exercise intolerance).
• Autosomal dominant (DNM2) — dynamin-2–related CNM; often childhood/adolescent onset, facial weakness and ophthalmoparesis common; course usually milder than MTM1.
• Autosomal recessive (BIN1, RYR1, TTN and others) — variable severity; BIN1 affects amphiphysin-2 crucial for T-tubule biogenesis; RYR1 forms the SR calcium channel with implications for anaesthetic risk.

Teaching tip: Link the gene to its job: MTM1 (phosphoinositide phosphatase → membrane lipid signalling), DNM2 (endocytic scission → membrane trafficking), BIN1 (membrane curvature → T-tubule formation). Disruption → malformed triads → weak calcium release → myopathic weakness.

🧩 Pathophysiology (why nuclei are central)

Healthy myofibres push nuclei to the periphery as sarcomeres mature. In CNM, altered lipid signalling and membrane remodelling hinder triad assembly and myofibrillogenesis, so fibres retain immature, centrally located nuclei. Secondary features include disorganised oxidative fibres and “radial strands” on NADH staining, reflecting abnormal organelle/triad orientation.

👶 Clinical Phenotypes

• Neonatal/infantile (MTM1 typical): marked hypotonia (“floppy infant”), weak cry/suck, respiratory failure, ptosis/ophthalmoparesis; often ventilatory support needed from birth.
• Childhood/adolescent (DNM2/BIN1): proximal > distal weakness, facial weakness, ptosis, external ophthalmoplegia, high-arched palate; delayed motor milestones but many remain ambulant for years.
• Adult-onset: mild limb-girdle pattern, exercise intolerance, cramps; ptosis/ophthalmoparesis are helpful clues in a “limb-girdle” presentation.

🔎 Examination Clues

• Ptosis ± ophthalmoparesis, facial weakness, reduced neck flexion strength.
• Proximal limb weakness; often absent or depressed reflexes; contractures may develop.
• Respiratory muscle weakness (reduced sniff nasal pressure, nocturnal hypoventilation); scoliosis in longer-surviving patients.

🧪 Investigations

• Bloods: Creatine kinase (CK) normal or mildly ↑ (often < 3× ULN), which helps separate from dystrophies.
• Neurophysiology: Myopathic EMG; phrenic nerve/diaphragm ultrasound if respiratory involvement suspected.
• Muscle biopsy: Central nuclei in many fibres; type-1 fibre predominance; oxidative stains show “radial sarcoplasmic strands”; electron microscopy may reveal triad disarray.
• Genetics (first-line): Congenital myopathy NGS panel covering MTM1, DNM2, BIN1, RYR1, TTN etc.; cascade testing and carrier assessment where relevant.
• Respiratory/Cardiac: Spirometry (supine FVC), capillary/venous CO₂, overnight oximetry; echocardiography (cardiomyopathy is uncommon but assess baseline).

🩺 Differential Diagnosis

• Other congenital myopathies: central core disease (RYR1; cores on biopsy), nemaline myopathy (rods), congenital fibre-type disproportion.
• Congenital myotonic dystrophy (maternal history, myotonia later, cataracts).
• Congenital myasthenic syndromes (fatigability, decrement on RNS, response to AChE inhibitors).

🧯 Acute & Peri-operative Considerations

• Airway/respiratory: anticipate hypoventilation; early non-invasive ventilation (NIV) and cough-assist during infections.
• Anaesthesia: If RYR1 is implicated, manage as malignant hyperthermia susceptible (avoid triggering agents, dantrolene available). For others, avoid suxamethonium due to hyperkalaemia risk in myopathies and use short-acting agents where possible.
• Plan peri-operative respiratory support and physiotherapy; vigilant post-op monitoring.

🧑‍⚕️ Management (multidisciplinary, lifelong)

• Respiratory: regular surveillance (FVC seated/supine, nocturnal oximetry/capnography), vaccination, airway clearance devices, NIV if nocturnal hypoventilation.
• Physio & rehab: gentle strengthening, contracture prevention, posture/scoliosis management; adaptive equipment and orthotics as needed.
• Feeding & speech: swallow assessment; gastrostomy in severe bulbar weakness.
• Ophthalmic: ptosis tapes, lubricants; surgical correction in selected cases.
• Genetic counselling: crucial for X-linked and dominant pedigrees; discuss reproductive options (carrier testing, prenatal/PGT).
• Specialist referral (UK): coordinate care via a neuromuscular centre with access to respiratory physio, clinical genetics, and transition services.

🧪 Disease-Modifying Research

Experimental approaches include gene replacement for MTM1, antisense/allele-specific strategies for DNM2, and small-molecule modulators of membrane trafficking. Early trials show biological promise but safety and durability remain under active evaluation; outside research protocols, treatment is supportive. Patients should be signposted to registries and specialist centres for trial eligibility assessment.

📈 Prognosis

Outcomes vary by genotype and severity at presentation. Classic MTM1 disease often presents with life-limiting neonatal respiratory failure, though survivorship into childhood/adulthood is possible with modern respiratory support. DNM2/BIN1 forms typically progress slowly; many remain ambulant for decades but may need respiratory support later. Quality of life improves with proactive respiratory care, contracture prevention, and timely supportive interventions.

🧭 Practical Tips for Juniors

• Think CNM in limb-girdle weakness plus ptosis/ophthalmoparesis and a low–normal CK.
• Order a congenital myopathy gene panel before biopsy where feasible; biopsy remains helpful if genetics are inconclusive.
• Always screen for nocturnal hypoventilation—even in “mild” cases; document a peri-operative plan.
• Flag potential RYR1 involvement to anaesthetics; avoid suxamethonium across myopathies.
• In the UK, link families with neuromuscular charities and specialist centres; organise coordinated school/college support plans for children.