Spinal muscular atrophy type 0 is the most severe phenotype of the disease, with patients presenting with contractures, weakness, and respiratory failure at birth, and is typically fatal within weeks. We describe the case of a patient with spinal muscular atrophy type 0 who was treated with both nusinersen and onasemnogene abeparvovec. She has made modest motor improvements since treatment initiation with a 30-point improvement in CHOP-INTEND score, and continues to make motor gains at age 13 months without regression of function, although she remains profoundly weak. Although she has had motor improvements, she has also had continued systemic complications from her spinal muscular atrophy, including chronic respiratory failure, dysphagia, congenital heart malformation, digit necrosis, and diffuse macular rash. This case highlights the challenges in treating those with more severe disease phenotypes and raises questions of how some systemic complications may respond to current SMN replacement therapies.
WaldropMAKolbSJ. Current treatment options in neurology—SMA therapeutics. Curr Treat Options Neurol. 2019;21(6):25.
2.
SwobodaKJPriorTWScottCB, et al.Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Ann Neurol. 2005;57(5):704–712.
3.
CaluchoMBernalSAlíasL, et al.Correlation between SMA type and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscul Disord. 2018;28(3):208–215.
4.
GrottoSCuissetJMMarretS, et al.Type 0 spinal muscular atrophy: further delineation of prenatal and postnatal features in 16 patients. J Neuromuscul Dis. 2016;3(4):487–495.
BürglenLAmielJViolletL, et al.Rapid publication survival motor neuron gene deletion in the arthrogryposis multiplex congenita-spinal muscular atrophy association. Clin Invest. 1996;98(5):1130–1132.
KorinthenbergRSauerMKetelsenU-P, et al.Congenital axonal neuropathy caused by deletions in the spinal muscular atrophy region. Ann Neurol. 1997;42(3):364–368.
10.
SanctisRDePaneMCorattiG, et al.Clinical phenotypes and trajectories of disease progression in type 1 spinal muscular atrophy. Neuromuscul Disord. 2018;28(1):24–28.
FinkelRSMercuriEDarrasBT, et al.Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723–1732.
13.
MercuriEDarrasBTChiribogaCA, et al.Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med. 2018;378(7):625–635.
14.
DarrasBTChiribogaCAIannacconeST, et al.Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies. Neurology. 2019;92(21):e2492–e2506.
15.
FinkelRSChiribogaCAVajsarJ, et al.Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017–3026.
16.
MendellJRAl-ZaidySShellR, et al.Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377(18):1713–1722.
17.
De VivoDCTopalogluHSwobodaKJ, et al.Nusinersen in infants who initiate treatment in a presymptomatic stage of spinal muscular atrophy (SMA): interim efficacy and safety results from the phase 2 NURTURE Study (S25.001). Neurology. 2019;92(15)(suppl):S25.001. http://n.neurology.org/content/92/15_Supplement/S25.001.abstract.
18.
Al-ZaidySAMendellJR. From clinical trials to clinical practice: practical considerations for gene replacement therapy in SMA type 1. Pediatr Neurol. 2019;100:3–11.
19.
ShababiMLorsonCLRudnik-SchönebornSS. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease?J Anat. 2014;224(1):15–28.
20.
GroenEJNPerenthalerECourtneyNL, et al.Temporal and tissue-specific variability of SMN protein levels in mouse models of spinal muscular atrophy. Hum Mol Genet. 2018;27(16):2851–2862.
21.
RamosDMCrawfordTOSumnerCJ. Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment. J Clin Invest. 2019;129(11):4817–4831.
22.
FarrarMAParkSBVucicS, et al.Emerging therapies and challenges in spinal muscular atrophy. Ann Neurol. 2017;81:355–368.
23.
HamiltonGGillingwaterTH. Spinal muscular atrophy: going beyond the motor neuron. Trends Mol Med. 2013;19(1):40–50.
24.
WijngaardeCABlankACStamMWadmanRIVan Den BergLHVan Der PolWL. Cardiac pathology in spinal muscular atrophy: a systematic review. Orphanet J Rare Dis. 2017;12(1):67.
25.
GlascockJSampsonJHaidet-PhillipsA, et al.Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis. 2018;5(2):145–158.
26.
MendonçaRHRochaAJLozano-ArangoA, et al.Severe brain involvement in 5q spinal muscular atrophy type 0. Ann Neurol. 2019;86(3):458–462.
27.
Araujo A prufer de QC, AraujoMSwobodaKJ. Vascular perfusion abnormalities in infants with spinal muscular atrophy. J Pediatr. 2009;155(2):292–294.
28.
Rudnik-SchönebornSVogelgesangSArmbrustSGraul-NeumannLFuschCZerresK. Digital necroses and vascular thrombosis in severe spinal muscular atrophy. Muscle Nerve. 2010;42(1):144–147.
29.
SalminFAlbamonteEMorettiniVGaglianoNMercuriESansoneVA. Resolution of skin necrosis after nusinersen treatment in an infant with spinal muscular atrophy. Muscle Nerve. 2019;59(6):E42–E44.
30.
DominguezEMaraisTChatauretN, et al.Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum Mol Genet. 2011;20(4):681–693.
