Spinal muscular atrophy

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Target exams

Red flags

• A floppy infant with severe symmetric proximal weakness, areflexia, and tongue fasciculations has spinal muscular atrophy until genetic testing proves otherwise
• Paradoxical breathing with a bell-shaped chest and a weak cough signals diaphragmatic weakness and impending respiratory failure in type 1 disease
• Aspiration pneumonia and poor weight gain from bulbar weakness are leading causes of morbidity in untreated type 1 spinal muscular atrophy
• Intellect is always spared in spinal muscular atrophy, so cognitive preservation in a profoundly weak infant is a diagnostic clue, not reassurance that the child is well
• Early treatment changes everything; presymptomatic nusinersen in the NURTURE study let the great majority of infants sit and most walk, outcomes impossible in untreated type 1 disease
• Newborn screening with prompt therapy is now standard of care because motor neurons lost before treatment do not grow back

Life stages

Care settings

Clinical exam formats

Board mappings

• Recognises spinal muscular atrophy as the commonest inherited cause of infant death, an autosomal recessive loss of the SMN1 gene on chromosome 5q13, presenting as severe symmetric proximal hypotonia and areflexia with preserved intellect
• States that SMN2 copy number is the chief modifier of severity, that homozygous SMN1 deletion confirms the diagnosis, and that newborn screening with early treatment now defines the standard of care
• Names nusinersen risdiplam and onasemnogene abeparvovec as the three disease-modifying therapies and explains that treatment must start early because lost motor neurons do not recover
• Explains the exon 7 splicing defect by which SMN2 produces mostly truncated unstable survival motor neuron protein, and how nusinersen an antisense oligonucleotide and risdiplam an oral small molecule both promote exon 7 inclusion
• Justifies the choice of therapy by age SMN2 copy number and disease status using the ENDEAR CHERISH FIREFISH NURTURE and STR1VE trial evidence and the consensus standard of care
• Coordinates newborn screening confirmatory SMN1 deletion and SMN2 copy number testing and a presymptomatic treatment plan, and runs the multidisciplinary respiratory nutritional and orthopaedic care
• The SMN1 deletion on chromosome 5q13 and the inverse relationship of SMN2 copy number to severity across the five SMA types from type 0 to type 4
• The clinical picture of symmetric proximal weakness and areflexia with tongue fasciculations and paradoxical breathing but spared intellect
• The three disease-modifying therapies nusinersen risdiplam and onasemnogene abeparvovec with their mechanisms and routes
• Assesses a floppy infant distinguishes spinal muscular atrophy from the cerebral and other causes of hypotonia and arranges urgent SMN1 deletion testing
• Chooses and times disease-modifying therapy and runs the multidisciplinary respiratory nutritional and orthopaedic care and the newborn screening pathway
• Counsels the family on the cause the genetic recurrence risk of one in four the prognosis transformed by early treatment and the long-term care plan
• Level 1: Recognition that a floppy infant with severe symmetric proximal weakness areflexia and preserved intellect has spinal muscular atrophy until the SMN1 deletion test proves otherwise
• Level 2: Application of genetic testing the SMN2 copy number modifier and the three disease-modifying therapies with their trial evidence
• Level 3: Coordination of newborn screening presymptomatic treatment and lifelong multidisciplinary care and the genetic counselling of the family
• Spinal muscular atrophy as the commonest genetic cause of infant death its autosomal recessive SMN1 loss with the SMN2 copy number modifier and the five types from type 0 to type 4
• The clinical picture of symmetric proximal hypotonia areflexia tongue fasciculations and paradoxical breathing with spared intellect and the genetic diagnosis by homozygous SMN1 deletion
• The three disease-modifying therapies nusinersen risdiplam and onasemnogene abeparvovec and the principle that early and presymptomatic treatment gives the best outcome
• Structured assessment of a floppy infant distinguishing spinal muscular atrophy from cerebral hypotonia myopathy and neuromuscular junction disease
• Interpretation of the SMN1 deletion test and SMN2 copy number and the choice and timing of disease-modifying therapy
• Communication of the diagnosis the genetic recurrence risk the transformed prognosis and the long-term plan to the family
• Spinal muscular atrophy as the leading inherited cause of infant mortality in the United States its SMN1 deletion genetics and its addition to the recommended uniform screening panel for newborn screening
• The three disease-modifying therapies nusinersen risdiplam and onasemnogene abeparvovec with the ENDEAR FIREFISH and STR1VE trial evidence
• The clinical picture and the principle that presymptomatic treatment started through newborn screening gives the best motor outcome
• Recognition of the floppy infant with symmetric proximal weakness areflexia and spared intellect as spinal muscular atrophy and the exclusion of the mimics
• Stepwise management with urgent genetic confirmation disease-modifying therapy and multidisciplinary respiratory nutritional and orthopaedic care
• Newborn screening and the presymptomatic treatment pathway and the genetic counselling of the family
• Canadian approach to spinal muscular atrophy newborn screening and the SMN1 deletion and SMN2 copy number testing pathway
• The three disease-modifying therapies and the timing of treatment by age copy number and symptom status
• Coordination of lifelong multidisciplinary care and the genetic recurrence counselling