brain sciences Review The Relationship between Body Composition, Fatty Acid Metabolism and Diet in Spinal Muscular Atrophy Katherine S. Watson 1, Imane Boukhloufi 2, Melissa Bowerman 2,3,* and Simon H. Parson 1,4,* 1 Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK; [email protected] 2 School of Medicine, Keele University, Staffordshire ST5 5BG, UK; imane.boukhloufi@gmail.com 3 Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK 4 Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh EH16 4SB, UK * Correspondence: [email protected] (M.B.); [email protected] (S.H.P.) Abstract: Spinal muscular atrophy (SMA) is an autosomal recessive condition that results in patho- logical deficiency of the survival motor neuron (SMN) protein. SMA most frequently presents itself within the first few months of life and is characterized by progressive muscle weakness. As a neuromuscular condition, it prominently affects spinal cord motor neurons and the skeletal muscle they innervate. However, over the past few decades, the SMA phenotype has expanded to include pathologies outside of the neuromuscular system. The current therapeutic SMA landscape is at a turning point, whereby a holistic multi-systemic approach to the understanding of disease patho- physiology is at the forefront of fundamental research and translational endeavours. In particular, there has recently been a renewed interest in body composition and metabolism in SMA patients, specifically that of fatty acids. Indeed, there is increasing evidence of aberrant fat distribution and fatty acid metabolism dysfunction in SMA patients and animal models. This review will explore fatty acid metabolic defects in SMA and discuss how dietary interventions could potentially be used to Citation: Watson, K.S.; Boukhloufi, I.; modulate and reduce the adverse health impacts of these perturbations in SMA patients. Bowerman, M.; Parson, S.H. The Relationship between Body Keywords: spinal muscular atrophy; survival motor neuron; fatty acid metabolism; nutrition; diet Composition, Fatty Acid Metabolism and Diet in Spinal Muscular Atrophy. Brain Sci. 2021, 11, 131. https:// doi.org/10.3390/brainsci11020131 1. Introduction Spinal muscular atrophy (SMA) is a debilitating neuromuscular disorder, which pre- Received: 12 December 2020 dominantly affects children within the first months of life, affecting 1:10,000 live births [1]. Accepted: 17 January 2021 SMA primarily impacts alpha motor neurons in the spinal cord, leading to their death, Published: 20 January 2021 resulting in muscle wasting, hypotonia and hyporeflexia [2]. SMA pathology is caused by a deficiency in the survival motor neuron (SMN) protein. Publisher’s Note: MDPI stays neutral In >90% of SMA patients, there is homozygous loss of the gene encoding this protein: with regard to jurisdictional claims in survival motor neuron 1 (SMN1)[3,4]. This gene was identified in 1995 on the telomeric published maps and institutional affil- region of chromosome 5 [5]. Interestingly, this stretch of genome contains a preserved iations. inverted duplication mutation such that there is a near identical gene located closer to the centromere, which is named SMN2 [4]. This is a unique feature and in some ways represents the existential cause of SMA, as without SMN2, humans would not live to develop the condition. There are only five nucleotides that are different between the paralogues, Copyright: © 2021 by the authors. which does not alter coding for amino acids but does affect pre-mRNA splicing [6]. The Licensee MDPI, Basel, Switzerland. substitution of a C for a T in the 6+ position of exon 7 of the SMN2 gene [7] primarily This article is an open access article results in the loss of a splicing enhancer, SF2/ASF [8], leading to the skipping of exon 7 in distributed under the terms and around 90% of transcripts. The truncated protein (SMND7) produced is unstable and conditions of the Creative Commons Attribution (CC BY) license (https:// less functional compared to the full-length version [9], but is not considered a negative creativecommons.org/licenses/by/ dominant. The remaining 10% of transcripts are structurally and functionally normal. 4.0/). SMN2 is extremely important in the context of SMA as gene copy number is a positive Brain Sci. 2021, 11, 131. https://doi.org/10.3390/brainsci11020131 https://www.mdpi.com/journal/brainsci Brain Sci. 2021, 11, x FOR PEER REVIEW 2 of 15 Brain Sci. 2021, 11, 131 2 of 14 dominant. The remaining 10% of transcripts are structurally and functionally normal. SMN2 is extremely important in the context of SMA as gene copy number is a positive modifier of the condition. Indeed, it has been shown that disease severity is inversely pro- modifier of the condition. Indeed, it has been shown that disease severity is inversely portional to the number of SMN2 copies [10]. In essence, this means that the loss of SMN1 proportional to the number of SMN2 copies [10]. In essence, this means that the loss of is compensated for, to a greater or lesser extent, by the number of SMN2 copies a person SMN1 is compensated for, to a greater or lesser extent, by the number of SMN2 copies a possesses and thus the amount of SMN that can still be produced. SMA, therefore, results person possesses and thus the amount of SMN that can still be produced. SMA, therefore, from the complete loss of SMN1 and the concurrent retention of at least one copy of SMN2 results from the complete loss of SMN1 and the concurrent retention of at least one copy of (Figure 1). SMN2 (Figure1). Figure 1. Genetics of spinal muscular atrophy (SMA). The SMN1 gene produces 100% full-length Figure 1. Genetics of spinal muscular atrophy (SMA). The SMN1 gene produces 100% full-length functional protein. The homologous SMN2 gene produces about 10% of full-length functional SMN functional protein. The homologous SMN2 gene produces about 10% of full-length functional SMNprotein protein and 90%and 90% of a truncatedof a truncated and rapidlyand rapidly degraded degraded SMN DSMN7 protein,Δ7 protein, due to due a C to to a T C substitution to T substi- in tutionexon in 7. exon Healthy 7. Healthy individuals individuals retain copies retain ofcopies both ofSMN1 bothand SMN1SMN2 andwhile SMN2 SMA while patients SMA patients have a loss haveof SMN1 a loss dueof SMN1 to mutations due to mutations and/or deletions. and/or deletions. SMASMA is isclinically clinically classified classified into into types types based based on on severity severity and and age age of of onset, onset, whereby whereby SMN2SMN2 genegene copy copy number number is isthe the major major disease disease modifier, modifier, as as a agreater greater number number of of SMN2SMN2 copiescopies results results in in a a larger larger amount ofof functionalfunctional full-length full-length SMN SMN protein protein being being produced produced [11 ]. [11].Type Type I, also I, also known known as Werdnig-Hoffman as Werdnig-Hoffman disease, disease, is the is most the severemost severe and common and common form of formthe condition,of the condition, accounting accounting for 50% for of50% cases of cases [2]. Type [2]. Type I presents I presents at <6 at months <6 months of ageof age and andthese these babies babies are are unable unable to sitto sit up up independently, independently, the the disease disease usually usually leading leading to ato premature a prem- death before they reach their second birthday [12]. Type II is an intermediate form of the ature death before they reach their second birthday [12]. Type II is an intermediate form disease with an onset between 6 and 18 months and a reduced lifespan [13]. Patients with of the disease with an onset between 6 and 18 months and a reduced lifespan [13]. Patients this form do not gain the ability to walk and even though they are usually unable to stand with this form do not gain the ability to walk and even though they are usually unable to without support, some can stand independently [2]. However, these motor aptitudes are stand without support, some can stand independently [2]. However, these motor apti- not necessarily maintained as although gain of functions are observed, over time, there tudes are not necessarily maintained as although gain of functions are observed, over time, is a net loss of function for all SMA patients [14]. Type III SMA occurs from 18 months there is a net loss of function for all SMA patients [14]. Type III SMA occurs from 18 onwards [15]. Type III children will at some point be able to walk and have a normal life months onwards [15]. Type III children will at some point be able to walk and have a expectancy, though with varying degrees of disability [16]. Type IV SMA is an adult onset normal life expectancy, though with varying degrees of disability [16]. Type IV SMA is an classification of the disease, whereby patients begin to exhibit muscle weakness between adult onset classification of the disease, whereby patients begin to exhibit muscle weak- their 30s and 40s, retain the ability to walk and have a typical lifespan [2,17]. Type IV nessis the between rarest their form 3 of0s SMAand 4 and0s, retain accounts the ability for <5% to ofwa caseslk and [18 have]. In a general,typical lifespan type I patients [2,17]. Typehave IV 1–3 is SMN2the rarestcopies, form type of SMA II patients and accounts 2–4 copies, for type <5% III of patients cases [18]. 2–5 In copies general, and typetype IVI patientspatients have 4–6 copies1–3 SMN2 [19]. copies, The overlap type II of patients copy number 2–4 copies, between type clinically III patients distinct 2–5 copies phenotypes and typedoes IV however patients suggest4–6 copies the presence[19].