Abnormal fatty acid metabolism is a core component of spinal muscular atrophy

Marc‐Olivier Deguise, Giovanni Baranello, Chiara Mastella, Ariane Beauvais , Jean Michaud, Alessandro Leone, Ramona De Amicis, Alberto Battezzati, Christopher Dunham, Kathryn Selby, Jodi Warman Chardon, Hugh J. McMillan, Yu‐Ting Huang, Natalie L. Courtney, Alannah J. Mole, Sabrina Kubinski, Peter Claus, Lyndsay M. Murray, Melissa Bowerman, Thomas H. Gillingwater & 3 others Simona Bertoli, Simon H. Parson, Rashmi Kothary

Research output: Contribution to journalArticle

Abstract

Objective
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 languageEnglish
Pages (from-to)1519-1532
Number of pages14
JournalAnnals of Clinical and Translational Neurology
Volume6
Issue number8
Early online date26 Jul 2019
DOIs
Publication statusPublished - Aug 2019

Fingerprint

Spinal Muscular Atrophy
Fatty Acids
Dyslipidemias
Motor Neuron Disease
Muscular Atrophy
Liver
Denervation
Fatty Liver
Lipid Metabolism
Paralysis
Histology
Triglycerides
Guidelines
Pediatrics
Phenotype
Lipids

Cite this

Deguise, MO., Baranello, G., Mastella, C., Beauvais , A., Michaud, J., Leone, A., ... Kothary, R. (2019). Abnormal fatty acid metabolism is a core component of spinal muscular atrophy. Annals of Clinical and Translational Neurology, 6(8), 1519-1532. https://doi.org/10.1002/acn3.50855

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 journalArticle

Deguise, MO, Baranello, G, Mastella, C, Beauvais , A, Michaud, J, Leone, A, De Amicis, R, Battezzati, A, Dunham, C, Selby, K, Chardon, JW, McMillan, HJ, Huang, YT, Courtney, NL, Mole, AJ, Kubinski, S, Claus, P, Murray, LM, Bowerman, M, Gillingwater, TH, Bertoli, S, Parson, SH & Kothary, R 2019, 'Abnormal fatty acid metabolism is a core component of spinal muscular atrophy' Annals of Clinical and Translational Neurology, vol. 6, no. 8, pp. 1519-1532. https://doi.org/10.1002/acn3.50855
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. / Abnormal fatty acid metabolism is a core component of spinal muscular atrophy. In: Annals of Clinical and Translational Neurology. 2019 ; Vol. 6, No. 8. pp. 1519-1532.
@article{9d1cc60e1ecc4071800572e30ecfbb29,
title = "Abnormal fatty acid metabolism is a core component of spinal muscular atrophy",
abstract = "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.",
author = "Marc‐Olivier Deguise and Giovanni Baranello and Chiara Mastella and Ariane Beauvais and Jean Michaud and Alessandro Leone and {De Amicis}, Ramona and Alberto Battezzati and Christopher Dunham and Kathryn Selby and Chardon, {Jodi Warman} and McMillan, {Hugh J.} and Yu‐Ting Huang and Courtney, {Natalie L.} and Mole, {Alannah J.} and Sabrina Kubinski and Peter Claus and Murray, {Lyndsay M.} and Melissa Bowerman and Gillingwater, {Thomas H.} and Simona Bertoli and Parson, {Simon H.} and Rashmi Kothary",
note = "Acknowledgments We thank Jocelyn Cot{\'e} and his student Andr{\'e}anne 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.",
year = "2019",
month = "8",
doi = "10.1002/acn3.50855",
language = "English",
volume = "6",
pages = "1519--1532",
journal = "Annals of Clinical and Translational Neurology",
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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 -