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; Simona Bertoli; Simon H. Parson; Rashmi Kothary

doi:10.1002/acn3.50855

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. GillingwaterSimona Bertoli, Simon H. Parson, Rashmi Kothary^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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 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	https://doi.org/10.1002/acn3.50855
Publication status	Published - 1 Aug 2019

Keywords

MOTOR-NEURON PROTEIN
GLUCOSE-METABOLISM
INTRINSIC DEFECTS
CARDIAC DEFECTS
MOUSE MODEL
PREVALENCE
CHILDREN
LIVER
DYSLIPIDEMIA
ADOLESCENTS

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Deguise_et_al_ACTN_Abnormal_Fatty_Acid_VOR
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Cite this

Deguise, MO., Baranello, G., Mastella, C., Beauvais , A., Michaud, J., Leone, A., De Amicis, R., Battezzati, A., Dunham, C., Selby, K., Chardon, J. W., McMillan, H. J., Huang, YT., Courtney, N. L., Mole, A. J., Kubinski, S., Claus, P., Murray, L. M., Bowerman, M., ... 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

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

@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.",

keywords = "MOTOR-NEURON PROTEIN, GLUCOSE-METABOLISM, INTRINSIC DEFECTS, CARDIAC DEFECTS, MOUSE MODEL, PREVALENCE, CHILDREN, LIVER, DYSLIPIDEMIA, ADOLESCENTS",

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 = "Funding 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 = aug,

day = "1",

doi = "10.1002/acn3.50855",

language = "English",

volume = "6",

pages = "1519--1532",

journal = "Annals of Clinical and Translational Neurology",

issn = "2328-9503",

publisher = "Wiley",

number = "8",

}

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 - Funding 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 - 2019/8/1

Y1 - 2019/8/1

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.

KW - MOTOR-NEURON PROTEIN

KW - GLUCOSE-METABOLISM

KW - INTRINSIC DEFECTS

KW - CARDIAC DEFECTS

KW - MOUSE MODEL

KW - PREVALENCE

KW - CHILDREN

KW - LIVER

KW - DYSLIPIDEMIA

KW - ADOLESCENTS

UR - http://www.mendeley.com/research/abnormal-fatty-acid-metabolism-core-component-spinal-muscular-atrophy

U2 - 10.1002/acn3.50855

DO - 10.1002/acn3.50855

M3 - Article

C2 - 31402618

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 -

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

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

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Simon Parson

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