Spinal muscular atrophy: Viva

Branch 1: Making the diagnosis

A strong candidate recognises this at once as 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 is 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. The diagnosis is genetic and is 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. [1]

Branch 2: The genetics and the mechanism

When the examiner asks the candidate to explain the genetics, the answer is that spinal muscular atrophy is autosomal recessive and caused by loss of the SMN1 gene on chromosome 5q13, with a carrier frequency of around one in fifty to one in sixty and a one in four recurrence risk for each future child. The severity is set by the SMN2 copy number, because the nearly identical backup SMN2 gene carries a single change that disrupts a splicing enhancer so most of its messenger RNA skips exon 7 and produces a short, unstable protein, with each copy making only about ten to fifteen percent of the functional protein of an SMN1 copy. One SMN2 copy predicts type 0 or severe type 1, two copies classic type 1, three copies type 2 or 3, and four or more the milder forms. [1]

Branch 3: Choosing and timing the treatment

When asked how the candidate chooses the therapy, the answer is to start early because motor neurons lost before treatment do not recover. Three therapies are licensed. Nusinersen is an intrathecal antisense oligonucleotide that forces SMN2 exon 7 inclusion, established by the ENDEAR trial in type 1 and the CHERISH trial in later-onset disease. Risdiplam is a daily oral small molecule with the same splicing target, established by the FIREFISH trial in type 1. Onasemnogene abeparvovec is a single-infusion AAV9 gene therapy approved for children under two years, established by the Mendell 2017 trial and the STR1VE trial. The choice turns on the age, the SMN2 copy number, the symptom status, and the local funding, and the candidate stresses that this symptomatic infant is treated urgently. [4][6][8]

Branch 4: Newborn screening and the presymptomatic infant

The examiner then offers a presymptomatic infant found on newborn screening, and the strong candidate explains that the SMN2 copy number sets the timing. An infant with two copies is treated urgently, ideally before six weeks of age, because the motor neurons are lost from the first weeks of life. An infant with three copies is treated early, and an infant with four copies is monitored closely with treatment at the first clinical or neurophysiological sign. The candidate quotes the NURTURE study, in which presymptomatic nusinersen let the great majority of infants survive without permanent ventilation, most sit, and many walk, outcomes impossible in untreated type 1 disease, and the principle that newborn screening with early treatment now defines the standard of care. [9][11]

Branch 5: Multidisciplinary and respiratory care

When asked how the candidate runs the multidisciplinary care, the answer is that the drug is only part of the treatment. The immediate threats are ventilatory failure from intercostal and diaphragmatic weakness and aspiration from bulbar weakness, and the candidate reminds the examiner that carbon dioxide retention precedes hypoxaemia in neuromuscular respiratory failure, so a normal oxygen saturation does not exclude it. Cough-assist devices and non-invasive ventilation are introduced early, the swallow is assessed and a gastrostomy secures nutrition when it is unsafe, and the orthopaedic surveillance for scoliosis and contractures runs throughout. The physiotherapist, the orthotist, the respiratory nurse, and the school complete the team. [2]

Branch 6: Prognosis and the family

Asked what to tell the family, the candidate gives the single most important fact: early treatment changes everything. Untreated type 1 was universally fatal before two years; with presymptomatic nusinersen in NURTURE the great majority survived without permanent ventilation, most sat, and many walked. The candidate is honest that this symptomatic infant will gain but less dramatically than a screen-positive infant, and that the multidisciplinary care is as important as the drug. The candidate explains the autosomal recessive inheritance, the one in four recurrence risk, and the availability of carrier testing and prenatal and preimplantation diagnosis, and arranges genetic counselling and peer support. [9][1]

The examiner rewards a candidate who names the bright-and-floppy pattern, who sends the SMN1 deletion test early, who explains the SMN2 copy number and the exon 7 splicing defect, who chooses the therapy from the trial evidence and treats urgently, and who gives the family the honest and hopeful prognosis of the treatment era. [1]