Spinal muscular atrophy: SAQ

This infant presents the textbook picture of type 1 spinal muscular atrophy, or Werdnig-Hoffmann disease: the reduced fetal movements, the severe symmetric proximal weakness with absent reflexes and tongue fasciculations, the paradoxical breathing with a bell-shaped chest, and the weak cough with pooled secretions, all in a bright and socially engaged child whose intellect is spared. The diagnosis is the homozygous SMN1 deletion test, and the treatment is disease-modifying therapy started urgently, layered on multidisciplinary respiratory and nutritional support. [1]

Question 1 (10 marks)

Outline your diagnosis, the investigations you would request, and your immediate management over the first 24 hours. [1]

The diagnosis is type 1 spinal muscular atrophy. The discriminating pattern is the symmetric proximal weakness worse in the legs, the absent deep tendon reflexes, the tongue fasciculations, and the paradoxical breathing, all in a bright, socially engaged infant whose intellect and social interaction are spared. The contrast between the alert face and the limp body is the signature clue, and it separates the spinal cause from the cerebral causes of hypotonia that give developmental delay and a poorly social infant. [1]

The diagnosis is genetic and made by a single blood test for the homozygous deletion of SMN1 exon 7, present in over ninety-five percent of affected individuals, which confirms the diagnosis in the right clinical picture without further testing. I would order the SMN1 deletion test together with the SMN2 copy number, which predicts the type and the urgency of treatment. I would not delay for electromyography or muscle biopsy, because the genetic test makes them unnecessary in the typical case. I would send a creatine kinase to help exclude a muscular dystrophy if the picture were atypical, a sleep study and pulmonary function testing to quantify the respiratory reserve, and a swallowing assessment to guide nutrition. [1]

My immediate management protects the airway and the breathing while the diagnosis is confirmed. This infant has paradoxical breathing and a weak cough with pooled secretions, which signal impending ventilatory failure, and I remember that carbon dioxide retention precedes hypoxaemia in neuromuscular respiratory failure, so a normal oxygen saturation does not exclude it. I would involve the paediatric intensive care team early, suction the secretions, position the child, assess the swallow, and introduce cough-assist and non-invasive ventilation. I would secure nutrition with a nasogastric tube given the bulbar weakness, and I would contact the paediatric neuromuscular service immediately, because the disease-modifying therapy should begin as soon as the diagnosis is confirmed. [2]

Question 2 (10 marks)

Discuss the disease-modifying treatment options, the evidence that supports each, and the prognosis and family counselling you would provide. [4]

Three disease-modifying therapies are licensed, and the principle that governs every decision is to start early, because motor neurons lost before treatment do not recover. Nusinersen is an intrathecal antisense oligonucleotide that binds the intronic splicing silencer in SMN2 and forces the inclusion of exon 7, raising the amount of functional survival motor neuron protein; it is given as a loading course on days one, fifteen, twenty-nine, and sixty-four then every four months. The ENDEAR trial showed it improved motor function and reduced the risk of death or permanent ventilation in type 1 disease, and the CHERISH trial showed a motor gain in later-onset disease. [4]

Risdiplam is a daily oral small molecule that stabilises the same SMN2 splicing step, and its advantage is the oral route and the systemic distribution. The FIREFISH trial showed it improved survival and motor function in type 1 disease, with a substantial proportion of infants sitting without support, an outcome rare in untreated disease. Onasemnogene abeparvovec is a single-infusion AAV9 gene therapy that delivers a working copy of the SMN1 gene, approved for children under two years of age; the Mendell 2017 trial showed dramatic motor gains, and the STR1VE trial confirmed the benefit in symptomatic infants with two SMN2 copies. [8][6]

I would tell the family that the prognosis has been transformed by early treatment, and that this is the single most important fact. Untreated type 1 disease was universally fatal before two years of age. With presymptomatic nusinersen in the NURTURE study the great majority of infants survived without permanent ventilation, most sat, and many walked, outcomes impossible in the natural history, and presymptomatic gene therapy shows even greater gains. [9][11]

I would be honest that this infant is symptomatic rather than presymptomatic, so the gains are real but less dramatic than in the screen-positive infant, and that the multidisciplinary respiratory, nutritional, and orthopaedic care is as important as the drug. I would explain that spinal muscular atrophy is autosomal recessive, that each future child has a one in four chance of being affected, and that carrier testing and prenatal or preimplantation diagnosis are available. I would arrange genetic counselling, peer support, and social work input, and I would emphasise that newborn screening and early treatment now define the standard of care for any future affected child. [1]