Traditionally, the pathology of Spinal Muscular Atrophy (SMA) was thought to be entirely confined to the anterior horn cells of the spinal cord.1 As more is known about the natural history of SMA, other cell types inside and outside the central nervous system appear affected by a loss of SMN1 gene product.2 Thus, patients with SMA appear to have primary pathology due to total SMN1 loss independent of motor neuron loss and weakness.3
Findings in animal models of SMA suggested that pancreatic derangement was a consequence of SMN1 deletion.4 Investigators noted that mice with heterozygous or homozygous loss of the SMN1 gene had abnormal glucose metabolism that was independent of neuronal pathology.4,5 SMN1 protein appears necessary for establishment and maintenance of a normal cell balance in the pancreas.5 Mice lacking SMN1 protein have many more glucagon-secreting α cells and fewer insulin-secreting β cells within the pancreas than SMN1 replete mice.4
Confirmatory evidence of a primary chronic pancreatic pathology in patients with SMA is evolving as patients with SMA survive to older ages and as researchers expand the scope of SMA beyond neurodegeneration.3 An α pancreatic islet cell-predominant pathology as was seen SMN1 depleted mice was reported in a post-mortem pancreas sample examined from a patient with type 1 SMA.4,6 Investigators have noted patients with SMA types 2 and 3 enrolled in clinical trials have co-morbid diagnoses of diabetes and glucose intolerance.4,6 Bowerman and colleagues suggested that as patients with SMA types 3 and 4 age, they will have higher than expected rates of hyperglycemia, type 2 diabetes, and insulin resistance.5 There is a need for therapies that correct low levels of SMN1 protein in extra-neuronal targets such as the pancreatic islet cells to definitively address this unique pathological consequence of SMA.3
Pancreatic dysfunction in SMA can manifest acutely. Acute pancreatitis without an obvious etiology occurs rarely in patients with type 1 SMA.7 There are published reports of severe diabetic ketoacidosis due to pancreatic insufficiency in patients with late onset forms of SMA.6,8 The ketoacidosis seen in SMA appears to be stress-induced and multifactorial in origin.8,9 Patients with SMA should not undergo prolonged fasting as it may precipitate a ketoacidosis episode.4 Treatment of ketoacidosis is symptomatic in the acute hospital setting.8
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. Nash LA, Burns JK, Chardon JW, Kothary R, Parks RJ. Spinal muscular atrophy: More than a disease of motor neurons? Current molecular medicine. 2016;16(9):779-792.
3. Simone C, Ramirez A, Bucchia M, et al. Is spinal muscular atrophy a disease of the motor neurons only: Pathogenesis and therapeutic implications? Cellular and molecular life sciences : CMLS. 2016;73(5):1003-1020.
4. Bowerman M, Swoboda KJ, Michalski JP, et al. Glucose metabolism and pancreatic defects in spinal muscular atrophy. Ann Neurol. 2012;72(2):256-268.
5. Bowerman M, Michalski JP, Beauvais A, Murray LM, DeRepentigny Y, Kothary R. Defects in pancreatic development and glucose metabolism in SMN-depleted mice independent of canonical spinal muscular atrophy neuromuscular pathology. Hum Mol Genet. 2014;23(13):3432-3444.
6. Lamarca NH, Golden L, John RM, Naini A, Vivo DC, Sproule DM. Diabetic ketoacidosis in an adult patient with spinal muscular atrophy type ii: Further evidence of extraneural pathology due to survival motor neuron 1 mutation? J Child Neurol. 2013;28(11):1517-1520.
7. Bach JR. Medical considerations of long-term survival of werdnig-hoffmann disease. American journal of physical medicine & rehabilitation. 2007;86(5):349-355.
8. Lakkis B, El Chediak A, Hashash JG, Koubar SH. Severe ketoacidosis in a patient with spinal muscular atrophy. CEN Case Rep. 2018.
9. Mulroy E, Gleeson S, Furlong MJ. Stress-induced ketoacidosis in spinal muscular atrophy: An under-recognized complication. J Neuromuscul Dis. 2016;3(3):419-423.