Paeds · neurology-neurodisability-and-neuromuscular

Spinal muscular atrophy

Also known as SMA · Werdnig-Hoffmann disease · Type 1 SMA · Dubowitz disease · Type 2 SMA · Kugelberg-Welander disease · Type 3 SMA · Proximal spinal muscular atrophy

Fellowship guide to spinal muscular atrophy in children. Covers the autosomal recessive SMN1 deletion on chromosome 5q13 with the inverse relationship to SMN2 copy number and the exon 7 splicing defect that depletes survival motor neuron protein and causes anterior horn cell degeneration, the five SMA types from the lethal type 0 and the Werdnig-Hoffmann type 1 to the milder type 3 and adult type 4, the clinical picture of severe symmetric proximal hypotonia and areflexia with tongue fasciculations and paradoxical breathing but preserved intellect, the genetic diagnosis by SMN1 deletion testing and SMN2 copy number, the three disease-modifying therapies nusinersen the intrathecal antisense oligonucleotide risdiplam the oral small molecule and onasemnogene abeparvovec the AAV9 gene therapy, the ENDEAR CHERISH FIREFISH SUNFISH NURTURE and STR1VE trial evidence, newborn screening and presymptomatic treatment, and the multidisciplinary respiratory nutritional and orthopaedic care.

high12 referencesUpdated 16 July 202625 min readVerification in progress

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Red flags

A floppy infant with severe symmetric proximal weakness, areflexia, and tongue fasciculations has spinal muscular atrophy until genetic testing proves otherwiseParadoxical breathing with a bell-shaped chest and a weak cough signals diaphragmatic weakness and impending respiratory failure in type 1 diseaseAspiration pneumonia and poor weight gain from bulbar weakness are leading causes of morbidity in untreated type 1 spinal muscular atrophyIntellect 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 wellEarly 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 diseaseNewborn screening with prompt therapy is now standard of care because motor neurons lost before treatment do not grow back

Life stages

fetalneonateinfanttoddlerpreschoolschool-ageadolescentyoung-adult-transition

Care settings

preventive-medical-homeoutpatientwardnicupicuretrievalrural-remotetelehealth

Clinical exam formats

written-onlyracp-dce-long-caseracp-dce-short-casemrcpch-developmentmrcpch-history-managementmrcpch-communicationrcpsc-structured-oral

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 intellectStates 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 careNames nusinersen risdiplam and onasemnogene abeparvovec as the three disease-modifying therapies and explains that treatment must start early because lost motor neurons do not recoverExplains 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 inclusionJustifies 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 careCoordinates newborn screening confirmatory SMN1 deletion and SMN2 copy number testing and a presymptomatic treatment plan, and runs the multidisciplinary respiratory nutritional and orthopaedic careThe 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 4The clinical picture of symmetric proximal weakness and areflexia with tongue fasciculations and paradoxical breathing but spared intellectThe three disease-modifying therapies nusinersen risdiplam and onasemnogene abeparvovec with their mechanisms and routesAssesses a floppy infant distinguishes spinal muscular atrophy from the cerebral and other causes of hypotonia and arranges urgent SMN1 deletion testingChooses and times disease-modifying therapy and runs the multidisciplinary respiratory nutritional and orthopaedic care and the newborn screening pathwayCounsels the family on the cause the genetic recurrence risk of one in four the prognosis transformed by early treatment and the long-term care planLevel 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 otherwiseLevel 2: Application of genetic testing the SMN2 copy number modifier and the three disease-modifying therapies with their trial evidenceLevel 3: Coordination of newborn screening presymptomatic treatment and lifelong multidisciplinary care and the genetic counselling of the familySpinal 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 4The clinical picture of symmetric proximal hypotonia areflexia tongue fasciculations and paradoxical breathing with spared intellect and the genetic diagnosis by homozygous SMN1 deletionThe three disease-modifying therapies nusinersen risdiplam and onasemnogene abeparvovec and the principle that early and presymptomatic treatment gives the best outcomeStructured assessment of a floppy infant distinguishing spinal muscular atrophy from cerebral hypotonia myopathy and neuromuscular junction diseaseInterpretation of the SMN1 deletion test and SMN2 copy number and the choice and timing of disease-modifying therapyCommunication of the diagnosis the genetic recurrence risk the transformed prognosis and the long-term plan to the familySpinal 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 screeningThe three disease-modifying therapies nusinersen risdiplam and onasemnogene abeparvovec with the ENDEAR FIREFISH and STR1VE trial evidenceThe clinical picture and the principle that presymptomatic treatment started through newborn screening gives the best motor outcomeRecognition of the floppy infant with symmetric proximal weakness areflexia and spared intellect as spinal muscular atrophy and the exclusion of the mimicsStepwise management with urgent genetic confirmation disease-modifying therapy and multidisciplinary respiratory nutritional and orthopaedic careNewborn screening and the presymptomatic treatment pathway and the genetic counselling of the familyCanadian approach to spinal muscular atrophy newborn screening and the SMN1 deletion and SMN2 copy number testing pathwayThe three disease-modifying therapies and the timing of treatment by age copy number and symptom statusCoordination of lifelong multidisciplinary care and the genetic recurrence counselling

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Target exams

RACP DWERACP DCEMRCPCH TheoryMRCPCH ClinicalABP General Pediatrics

Red flags

Life stages

fetalneonateinfanttoddlerpreschoolschool-ageadolescentyoung-adult-transition

Care settings

preventive-medical-homeoutpatientwardnicupicuretrievalrural-remotetelehealth

Clinical exam formats

written-onlyracp-dce-long-caseracp-dce-short-casemrcpch-developmentmrcpch-history-managementmrcpch-communicationrcpsc-structured-oral

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Overview & Definition

A floppy infant whose limbs lie limp and splayed, whose reflexes have vanished, but whose eyes track and follow and whose face is bright and alert, is presenting one of the most important diagnoses in paediatric neurology. Spinal muscular atrophy is an autosomal recessive disorder in which loss of the survival motor neuron 1 gene, or SMN1, on chromosome 5q13 depletes the survival motor neuron protein and causes progressive degeneration of the anterior horn cells of the spinal cord and the motor nuclei of the brainstem. The result is severe, symmetric, proximal muscle weakness and atrophy, with the legs more affected than the arms and the trunk and breathing muscles progressively involved. It is the commonest genetic cause of infant death. [1]

The reason this disease is now central to the paediatric exam, and to clinical practice, is that the prognosis has been transformed. For decades type 1 spinal muscular atrophy was a relentless disease in which an infant never sat, lost the ability to swallow and breathe, and died before two years of age. Three disease-modifying therapies have changed that trajectory. Nusinersen, an antisense oligonucleotide given into the cerebrospinal fluid, risdiplam, an oral small molecule, and onasemnogene abeparvovec, a single-infusion gene therapy, each raise the functional survival motor neuron protein and preserve motor neurons. The cardinal lesson of the past decade is that motor neurons lost before treatment do not grow back, so the earlier the therapy the better the outcome, and presymptomatic treatment begun through newborn screening is now the standard of care. [9][11]

The framing concept for the paediatrician is the floppy infant, and within it the spinal cord cause of hypotonia. The same bedside picture hides cerebral causes such as hypoxic injury, muscle disease such as congenital myopathy, and neuromuscular junction disorders such as congenital myasthenia. The discriminating clue is the pattern of the weakness and the preservation of the intellect. Spinal muscular atrophy gives symmetric, proximal, areflexic weakness with a bright and engaged child, and the diagnosis is confirmed by a single genetic test for the homozygous SMN1 deletion. [1]

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References12Show ledger

[1]Mercuri E, Finkel RS, Muntoni F, et al Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord, 2018.PMID 29290580
[2]Finkel RS, Mercuri E, Meyer OH, et al Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord, 2018.PMID 29305137
[3]Mercuri E, Lucibello S, Perulli M, et al. Longitudinal natural history of type I spinal muscular atrophy: a critical review. Orphanet J Rare Dis, 2020.PMID 32248834
[4]Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med, 2017.PMID 29091570
[5]Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med, 2018.PMID 29443664
[6]Mendell JR, Al-Zaidy S, Shell R, et al Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med, 2017.PMID 29091557
[7]Day JW, Chiriboga CA, Crawford TO, et al Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol, 2021.PMID 33743238
[8]Baranello G, Darras BT, Day JW, et al. Risdiplam in Type 1 Spinal Muscular Atrophy. N Engl J Med, 2021.PMID 33626251
[9]De Vivo DC, Bertini E, Swoboda KJ, et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscul Disord, 2019.PMID 31704158
[10]Glascock J, Sampson J, Connolly AM, et al. Revised Recommendations for the Treatment of Infants Diagnosed with Spinal Muscular Atrophy Via Newborn Screening Who Have 4 Copies of SMN2. J Neuromuscul Dis, 2020.PMID 32007960
[11]Cooper K, Nalbant G, Sutton A, et al. Systematic Review of Presymptomatic Treatment for Spinal Muscular Atrophy. Int J Neonatal Screen, 2024.PMID 39189228
[12]Dangouloff T, Vrščaj E, Servais L, et al. Newborn screening programs for spinal muscular atrophy worldwide: Where we stand and where to go. Neuromuscul Disord, 2021.PMID 33985857

Spinal muscular atrophy

Also known as SMA · Werdnig-Hoffmann disease · Type 1 SMA · Dubowitz disease · Type 2 SMA · Kugelberg-Welander disease · Type 3 SMA · Proximal spinal muscular atrophy

high12 referencesUpdated 16 July 202625 min readVerification in progress

Practise this topic

Overview & Definition

Paediatrics Fellowship Pro

You have read the opening of this topic. The complete unit — every section and its primary-source references — is part of the Paediatrics Fellowship fellowship atlas.

References12Show ledger

[1]Mercuri E, Finkel RS, Muntoni F, et al Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord, 2018.PMID 29290580
[2]Finkel RS, Mercuri E, Meyer OH, et al Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord, 2018.PMID 29305137
[3]Mercuri E, Lucibello S, Perulli M, et al. Longitudinal natural history of type I spinal muscular atrophy: a critical review. Orphanet J Rare Dis, 2020.PMID 32248834
[4]Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med, 2017.PMID 29091570
[5]Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med, 2018.PMID 29443664
[6]Mendell JR, Al-Zaidy S, Shell R, et al Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med, 2017.PMID 29091557
[7]Day JW, Chiriboga CA, Crawford TO, et al Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol, 2021.PMID 33743238
[8]Baranello G, Darras BT, Day JW, et al. Risdiplam in Type 1 Spinal Muscular Atrophy. N Engl J Med, 2021.PMID 33626251
[9]De Vivo DC, Bertini E, Swoboda KJ, et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscul Disord, 2019.PMID 31704158
[10]Glascock J, Sampson J, Connolly AM, et al. Revised Recommendations for the Treatment of Infants Diagnosed with Spinal Muscular Atrophy Via Newborn Screening Who Have 4 Copies of SMN2. J Neuromuscul Dis, 2020.PMID 32007960
[11]Cooper K, Nalbant G, Sutton A, et al. Systematic Review of Presymptomatic Treatment for Spinal Muscular Atrophy. Int J Neonatal Screen, 2024.PMID 39189228
[12]Dangouloff T, Vrščaj E, Servais L, et al. Newborn screening programs for spinal muscular atrophy worldwide: Where we stand and where to go. Neuromuscul Disord, 2021.PMID 33985857