Abstract
Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra‐neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease.
Methods
We analyzed clinical data collected from a large cohort of pediatric SMA type I–III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA.
Results
We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn2B/‐ mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non‐alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation.
Interpretation
This work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life.
| Original language | English |
|---|---|
| Pages (from-to) | 1519-1532 |
| Number of pages | 14 |
| Journal | Annals of Clinical and Translational Neurology |
| Volume | 6 |
| Issue number | 8 |
| Early online date | 26 Jul 2019 |
| DOIs | |
| Publication status | Published - Aug 2019 |
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Abnormal fatty acid metabolism is a core component of spinal muscular atrophy. / Deguise, Marc‐Olivier; Baranello, Giovanni; Mastella, Chiara; Beauvais , Ariane; Michaud, Jean; Leone, Alessandro; De Amicis, Ramona; Battezzati, Alberto; Dunham, Christopher; Selby, Kathryn; Chardon, Jodi Warman; McMillan, Hugh J.; Huang, Yu‐Ting; Courtney, Natalie L.; Mole, Alannah J.; Kubinski, Sabrina; Claus, Peter; Murray, Lyndsay M.; Bowerman, Melissa; Gillingwater, Thomas H.; Bertoli, Simona; Parson, Simon H.; Kothary, Rashmi (Corresponding Author).
In: Annals of Clinical and Translational Neurology, Vol. 6, No. 8, 08.2019, p. 1519-1532.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Abnormal fatty acid metabolism is a core component of spinal muscular atrophy
AU - Deguise, Marc‐Olivier
AU - Baranello, Giovanni
AU - Mastella, Chiara
AU - Beauvais , Ariane
AU - Michaud, Jean
AU - Leone, Alessandro
AU - De Amicis, Ramona
AU - Battezzati, Alberto
AU - Dunham, Christopher
AU - Selby, Kathryn
AU - Chardon, Jodi Warman
AU - McMillan, Hugh J.
AU - Huang, Yu‐Ting
AU - Courtney, Natalie L.
AU - Mole, Alannah J.
AU - Kubinski, Sabrina
AU - Claus, Peter
AU - Murray, Lyndsay M.
AU - Bowerman, Melissa
AU - Gillingwater, Thomas H.
AU - Bertoli, Simona
AU - Parson, Simon H.
AU - Kothary, Rashmi
N1 - Acknowledgments We thank Jocelyn Coté and his student Andréanne Didillon for providing Smn‐/‐;SMN2;SMNΔ7 mice to the Kothary laboratory. We extend our gratitude to Eva Szunyogova, Sabrina Gibeault, My Tran Trung, and Rebecca Yaworski for assistance with experiments. RK was supported by Cure SMA/Families of SMA Canada (KOT‐1819); Muscular Dystrophy Association (USA) (grant number 575466); Canadian Institutes of Health Research (CIHR) (grant number PJT‐156379); and the E‐Rare‐2 program from the CIHR (grant number ERL‐138414). The Italian group (GB, CM, RDA, AB, AL) was funded by the Italian Association of SMA Families (Famiglie SMA, 2015–2016 contribution) and by Fondazione Telethon (Application GUP15014, 2015, Italy). LMM is supported by grants from Cure SMA (grant number MU1415); Fight SMA; Muscular Dystrophy Association (grant number 417757); Tenovus Scotland (E15/4); and Newlife foundation for disabled children (SG/14‐15/08). THG was supported by UK SMA Research Consortium and SMA Europe. SHP was supported by Tenovus (Scotland) and The Euan Macdonald Centre for Research into Motor Neurone Diseases. MB was supported by UK SMA Research Consortium and SMA Angels Charity. The Vanderbilt Mouse Metabolic Phenotyping Center was supported by National Institutes of Health (NIH) grant DK59637. The University of Massachusetts Medical School National Mouse Metabolic Phenotyping Center (MMPC) is supported by NIH grant (2U2C‐DK093000). MOD was supported by Frederick Banting and Charles Best CIHR Doctoral Research Award.
PY - 2019/8
Y1 - 2019/8
N2 - ObjectiveSpinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra‐neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease.MethodsWe analyzed clinical data collected from a large cohort of pediatric SMA type I–III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA.ResultsWe identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn2B/‐ mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non‐alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation.InterpretationThis work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life.
AB - ObjectiveSpinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra‐neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease.MethodsWe analyzed clinical data collected from a large cohort of pediatric SMA type I–III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA.ResultsWe identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn2B/‐ mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non‐alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation.InterpretationThis work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life.
U2 - 10.1002/acn3.50855
DO - 10.1002/acn3.50855
M3 - Article
VL - 6
SP - 1519
EP - 1532
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
SN - 2328-9503
IS - 8
ER -