Neonatal hypotonia and neuromuscular weakness — formative SAQs

SAQ 1 — The weak, areflexic, alert neonate (20 marks, ~15 minutes)

A term infant presents at 3 months with progressive floppiness, symmetric proximal weakness, tongue fasciculations and absent deep tendon reflexes. Between episodes the infant is alert and socially engaged. There is no encephalopathy or dysmorphism. The creatine kinase is normal. [10]

Questions

1. Define hypotonia, distinguish it from weakness, and state whether this infant has a central or a peripheral hypotonia, justifying your call from the clinical features. (5 marks) [10]
2. State the single most likely diagnosis, the genetic basis, and the confirming test. (4 marks) [3]
3. Outline the immediate supportive management priorities for the respiratory and feeding threat. (4 marks) [9]
4. Describe the disease-modifying therapy for which this infant is eligible, the supporting trial evidence, and the principle that governs its timing. (7 marks) [1]

Model answer (must-hit)

1. Hypotonia is reduced resistance to passive movement — a loss of postural tone — distinct from weakness, which is a loss of active force. This infant has a peripheral hypotonia: tone is reduced AND there is true weakness, absent reflexes and tongue fasciculations, yet the infant is alert and socially engaged with no encephalopathy or dysmorphism. The motor unit, not the brain, is failing. [10]

2. The most likely diagnosis is spinal muscular atrophy type 1 (Werdnig-Hoffmann). It arises from biallelic loss of the SMN1 gene, with severity set by SMN2 copy number (two copies → type 1). The confirming test is SMN1 deletion testing with SMN2 copy number. [3]

3. The respiratory and feeding threats take priority: monitor the work of breathing and the carbon dioxide (not just saturations) and escalate ventilatory support early; assess bulbar function and aspiration risk; and start safe feeding (nasogastric or gastrostomy) to protect nutrition and the airway. [9]

4. The infant is eligible for nusinersen (intrathecal antisense oligonucleotide that splices SMN2 to make more functional SMN protein) and/or onasemnene abeparvovec (one-time intravenous AAV9 gene therapy delivering a functional SMN1 gene). The ENDEAR trial (Finkel 2017) showed nusinersen improves motor function and survival versus sham in infantile-onset SMA; the SPR1NT trial (Strauss 2022) showed pre-symptomatic onasemnene-treated infants achieve sitting and walking. The governing principle is that motor neurons are lost irreversibly from birth, so therapy is most effective when started early — ideally pre-symptomatic — and must not be deferred while completing a non-essential work-up. [1] [2] [5]

SAQ 2 — The floppy neonate of an affected mother (20 marks, ~15 minutes)

A term neonate is profoundly hypotonic at birth with respiratory distress, a weak suck and facial weakness, but is alert. The mother is a 27-year-old with mild grip myotonia and bilateral cataracts that she has never had investigated. There was polyhydramnios and reduced fetal movements. [9]

Questions

1. State the most likely diagnosis, the inheritance pattern, and why the mother's phenotype is mild while the infant's is severe. (5 marks) [9]
2. Give the confirming investigation for the infant and the mother. (4 marks) [9]
3. Outline the supportive management priorities in the neonatal period. (4 marks) [9]
4. State two specific dangers this infant faces that change perioperative and anaesthetic care, and explain why. (7 marks) [9]

Model answer (must-hit)

1. The most likely diagnosis is congenital myotonic dystrophy. It is autosomal dominant, caused by a maternal DMPK CTG-trinucleotide-repeat expansion. The mother is mildly affected while the infant is severely affected because of anticipation — the CTG repeat enlarges across generations, especially through the maternal line, producing earlier and more severe disease in the child. [9]

2. The confirming test is a DMPK CTG-repeat assay — sent on BOTH the infant and the mother, because the mother may be undiagnosed and her result confirms the inheritance and guides her own counselling and surveillance. [9]

3. Management is supportive: respiratory support for the weak, hypoventilating neonate (monitor the CO2 and work of breathing); safe feeding with nasogastric or gastrostomy to protect against aspiration; and cardiac surveillance for conduction disease. There is no disease-modifying therapy. [9]

4. Two dangers change perioperative care. First, anaesthetic and sedative risk is high: the response to neuromuscular-blocking agents and volatile anaesthetics is abnormal and respiratory depression is prolonged, so sedation must be planned with anaesthesia and post-operative ventilation anticipated. Second, cardiac conduction disease (arrhythmia, heart block) is part of the disorder and needs surveillance, because sudden cardiac death is a recognised complication. These dangers exist because the toxic-RNA spliceopathy affects muscle, brain, heart and respiratory drive together. [9]