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]