Spinal Muscular Atrophy: Cardiac Disease

Spinal Muscular Atrophy: Cardiac Disease

Spinal Muscular Atrophy (SMA) is an inherited neurodegenerative disease,1 but it is increasingly clear that the pathology of SMA extends beyond ventral horn spinal cord neurons and includes the heart among other organs.2 In patients with SMA, tissue levels of SMN1 protein are reduced in heart tissues,3 and numerous mouse models of SMA exhibit cardiac developmental abnormalities which together suggest that low SMN1 protein is a possible risk factor and potential cause of heart defects. 4,5,6

Patients with most severe, fatal forms of SMA, types 0 and 1, appear to have a higher than average risk of cardiac abnormalities.7,8 SMA type 1 specifically has an historical association with congenital heart defects.9 A survey of the literature revealed that 33 out of 77 SMA type 1 patients identified with any cardiac abnormalities had electrocardiogram (ECG) abnormalities, and 42 of 77 patients had  structural defects. The predominant ECG finding was bradycardia (heart rate < 40 beats per minute), and the most common cardiac defect was an isolated atrial (26%) or ventricular (12%) septal defect.8 There is a suggestion that SMA type 1 with congenital heart defects represents a distinct subtype of SMA 1, not merely a coincidental association.9 The number of copies of the protective SMN2 gene may correlate with the presence of cardiac pathology in SMA type 1.8

The association between SMA type 2 and cardiac pathology is not robust. The most common abnormality reported in the extant medical literature are ECG abnormalities such as sinus tachycardia or right bundle branch block.8 ECG abnormalities can differentiate type 2 from type 1 SMA.10

Over half (54%) of patients with type 3 SMA in published patients had baseline tremors in ECG and 31% SMA type 3 patients had other cardiac rhythm disturbances.8 Some suggest that ECG abnormalities are so typical that ECG may be used to diagnose type 3 SMA.11 A small minority of patients with type 3 SMA and comorbid heart disease have both ECG and cardiac structural abnormalities.8 ECG findings consistent with myocardial damage and postmortem studies of patients with type 3 SMA showing cardiac fibrosis suggest that type 3 SMA, in which patients live to adulthood, may have an associated risk of early heart disease.8

There does not appear to be SMA-related cardiac pathology in patients with type 4 (adult-onset) SMA.4

References

1. Prior TW, Finanger E. Spinal Muscular Atrophy. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews((R)). Seattle (WA): University of Washington, Seattle University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993.

2. Simone C, Ramirez A, Bucchia M, et al. Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications? Cell Mol Life Sci. Mar 2016;73(5):1003-1020.

3. Shababi M, Lorson CL, Rudnik-Schoneborn SS. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J Anat. Jan 2014;224(1):15-28.

4. Palladino A, Passamano L, Taglia A, et al. Cardiac involvement in patients with spinal muscular atrophies. Acta Myol. Dec 2011;30(3):175-178.

5. Maxwell GK, Szunyogova E, Shorrock HK, et al. Developmental and degenerative cardiac defects in the Taiwanese mouse model of severe spinal muscular atrophy. J Anat. Jun 2018;232(6):965-978.

6. Sheng L, Wan B, Feng P, et al. Downregulation of Survivin contributes to cell-cycle arrest during postnatal cardiac development in a severe spinal muscular atrophy mouse model. Hum Mol Genet. Feb 1 2018;27(3):486-498.

7. Grotto S, Cuisset JM, Marret S, et al. Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients. J Neuromuscul Dis. Nov 29 2016;3(4):487-495.

8. Wijngaarde CA, Blank AC, Stam M, et al. Cardiac pathology in spinal muscular atrophy: a systematic review. Orphanet J Rare Dis. Apr 11 2017;12(1):67.

9. Menke LA, Poll-The BT, Clur SA, et al. Congenital heart defects in spinal muscular atrophy type I: a clinical report of two siblings and a review of the literature. Am J Med Genet A. Mar 15 2008;146a(6):740-744.

10. Falsaperla R, Vitaliti G, Collotta AD, et al. Electrocardiographic Evaluation in Patients With Spinal Muscular Atrophy: A Case-Control Study. J Child Neurol. Jun 2018;33(7):487-492.

11. Haliloglu G, Gungor M, Anlar B. The role of electrocardiography in the diagnosis of spinal muscular atrophy type III. J Pediatr. Apr 2015;166(4):1092.