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Ann Clin Transl Neurol. 2019 Aug;6(8):1519-1532. doi: 10.1002/acn3.50855. Epub 2019 Jul 26.

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

Author information

1
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
2
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
3
Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada, K1H 8M5.
4
UO Neurologia dello Sviluppo, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
5
The Dubowitz Neuromuscular Centre, NIHR BRC University College London Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, United Kingdom.
6
SAPRE-UONPIA, Fondazione IRCCS Cà' Granda Ospedale Maggiore Policlinico, Milan, Italy.
7
Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
8
International Center for the Assessment of Nutritional Status (ICANS), Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Milan, Italy.
9
Division of Anatomic Pathology, Children's and Women's Health Centre of B.C, Vancouver, British Columbia, Canada.
10
Division of Neurology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia, Canada.
11
Neuroscience Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
12
Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
13
Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
14
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
15
Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom.
16
College of Medicine & Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom.
17
Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, United Kingdom.
18
Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany.
19
Center of Systems Neuroscience, Hannover, Germany.
20
School of Medicine, Keele University, Staffordshire, United Kingdom.
21
Institute for Science and Technology in Medicine, Stoke-on-Trent, United Kingdom.
22
Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry, United Kingdom.
23
Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.

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.

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