Diabetic Ketoacidosis in an Adult Patient With Spinal Muscular Atrophy Type II

LaMarca, Nicole Holuba; Golden, Lauren; John, Rita Marie; Naini, Ali; Vivo, Darryl C. De; Sproule, Douglas M.

doi:10.1177/0883073812460096

Cited by 13 publications

(9 citation statements)

References 24 publications

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“…Our work defines for the first time a perturbed regulation of circadian rhythm genes in SMA CNS and peripheral tissues, which may contribute to and/or be a consequence of the many metabolic and sleep dysfunctions reported in SMA mice and patients ( 27 , 28 , 30–32 ). We also demonstrate that Smn itself displays a diurnal expression pattern in a tissue- and age-dependent manner.…”

Section: Discussionmentioning

confidence: 82%

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice

Walter

Koch

Betts

et al. 2018

Human Molecular Genetics

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Physiology and behaviour are critically dependent on circadian regulation via a core set of clock genes, dysregulation of which leads to metabolic and sleep disturbances. Metabolic and sleep perturbations occur in spinal muscular atrophy (SMA), a neuromuscular disorder caused by loss of the survival motor neuron (SMN) protein and characterized by motor neuron loss and muscle atrophy. We therefore investigated the expression of circadian rhythm genes in various metabolic tissues and spinal cord of the Taiwanese Smn−/−;SMN2 SMA animal model. We demonstrate a dysregulated expression of the core clock genes (clock, ARNTL/Bmal1, Cry1/2, Per1/2) and clock output genes (Nr1d1 and Dbp) in SMA tissues during disease progression. We also uncover an age- and tissue-dependent diurnal expression of the Smn gene. Importantly, we observe molecular and phenotypic corrections in SMA mice following direct light modulation. Our study identifies a key relationship between an SMA pathology and peripheral core clock gene dysregulation, highlights the influence of SMN on peripheral circadian regulation and metabolism and has significant implications for the development of peripheral therapeutic approaches and clinical care management of SMA patients.

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Section: Discussionmentioning

confidence: 82%

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice

Walter

Koch

Betts

et al. 2018

Human Molecular Genetics

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“…Here, we highlight the fact that patients with milder forms of SMA (types II, III and IV), may, overtime, exhibit metabolic dysfunction that is a direct result of ‘low’ level Smn protein reduction. Indeed, a type II adult SMA patient has recently been described as developing diabetes mellitus and diabetic ketoacidosis (54). Of note, while the Smn +/− mice used in this study display an array of metabolic abnormalities, their overall phenotype is not typical of other diabetic models, which are normally characterized by glucose intolerance, random-fed hyperglycemia, hepatic insulin resistance, β-cell hyperplasia and hyperglucagonemia.…”

Section: Discussionmentioning

confidence: 99%

Defects in pancreatic development and glucose metabolism in SMN-depleted mice independent of canonical spinal muscular atrophy neuromuscular pathology

Bowerman

Michalski

Beauvais

et al. 2014

Human Molecular Genetics

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Spinal muscular atrophy (SMA) is characterized by motor neuron loss, caused by mutations or deletions in the ubiquitously expressed survival motor neuron 1 (SMN1) gene. We recently identified a novel role for Smn protein in glucose metabolism and pancreatic development in both an intermediate SMA mouse model (Smn2B/−) and type I SMA patients. In the present study, we sought to determine if the observed metabolic and pancreatic defects are SMA-dependent. We employed a line of heterozygous Smn-depleted mice (Smn+/−) that lack the hallmark SMA neuromuscular pathology and overt phenotype. At 1 month of age, pancreatic/metabolic function of Smn+/−mice is indistinguishable from wild type. However, when metabolically challenged with a high-fat diet, Smn+/−mice display abnormal localization of glucagon-producing α-cells within the pancreatic islets and increased hepatic insulin and glucagon sensitivity, through increased p-AKT and p-CREB, respectively. Further, aging results in weight gain, an increased number of insulin-producing β cells, hyperinsulinemia and increased hepatic glucagon sensitivity in Smn+/−mice. Our study uncovers and highlights an important function of Smn protein in pancreatic islet development and glucose metabolism, independent of canonical SMA pathology. These findings suggest that carriers of SMN1 mutations and/or deletions may be at an increased risk of developing pancreatic and glucose metabolism defects, as even small depletions in Smn protein may be a risk factor for diet- and age-dependent development of metabolic disorders.

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“…ROCK inhibition could therefore have a positive effect on overall cardiac physiology and function in SMA mice. Finally, SMA patients and mice show defects in glucose and fatty acid metabolism as well as in pancreatic islet development (Quarfordt et al, 1970; Dahl and Peters, 1975; Tein et al, 1995; Crawford et al, 1999; Bowerman et al, 2012c, 2014; Lamarca et al, 2013). Given that the RhoA/ROCK pathway enhances β cell proliferation, insulin expression, glucose-stimulated insulin secretion and glucose uptake in muscle cells (Furukawa et al, 2005; Nakamura et al, 2006; Hammar et al, 2009; Aly et al, 2013), treatment of SMA mice with ROCK inhibitors may modulate key glucose homeostasis pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Over the years, an accumulating number of studies have reported metabolism defects in SMA patients, which mostly concern glucose metabolism (Lamarca et al, 2013), and fatty acid metabolism (Quarfordt et al, 1970; Dahl and Peters, 1975; Tein et al, 1995; Crawford et al, 1999). More recently, glucose metabolism and pancreatic abnormalities were uncovered in an intermediate SMA mouse model and Type 1 SMA patients such as a dramatic predominance of glucagon-producing α cells at the expense of insulin-producing β cells within pancreatic islets, fasting hyperglycemia, hyperglucagonemia, glucose resistance and increased hepatic insulin sensitivity (Bowerman et al, 2012c).…”

Section: Pancreas and Glucose Homeostasismentioning

confidence: 99%

ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets

2014

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Spinal muscular atrophy (SMA) is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the Survival Motor Neuron 1 (SMN1) gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK), which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myoblasts, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice.

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Diabetic Ketoacidosis in an Adult Patient With Spinal Muscular Atrophy Type II

Cited by 13 publications

References 24 publications

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice

Defects in pancreatic development and glucose metabolism in SMN-depleted mice independent of canonical spinal muscular atrophy neuromuscular pathology

ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets

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