Scientific Knowledge & Personal Nutrition Stories for Rare Metabolic Conditions

Sudden Infant Death Syndrome (SIDS) is a significant cause of infant death worldwide ¹, and recent studies have shed new light on the potential role of metabolic biomarkers in predicting SIDS risk. Here, I will present two significant studies, one published in The Lancet eBioMedicine and another in JAMA Pediatrics, identifying specific metabolic profiles associated with an increased risk of SIDS^2,3.

Common findings in both studies include:

• Identification of multiple metabolites significantly associated with SIDS risk;

• Highlighted abnormalities in lipid metabolism.

• The two studies suggest that metabolic profiles could be used to identify infants with high-risk of SIDS.

Key differences:

• The Lancet study identified 35 significant metabolite predictors, including ornithine and sphingomyelins²;
• The JAMA Pediatrics study focused on 8 key metabolites, including acylcarnitines³.

Precision medicine approaches could help tailor interventions based on individual metabolic profiles. Newborn screening incorporating these metabolic markers could identify high-risk infants, allowing for closer monitoring and targeted preventive measures³. Future research should focus on:

• Validating these findings across diverse populations;
• Developing standardized risk assessment models;
• Investigating potential interventions based on specific metabolic profiles;
• Exploring the integration of metabolomic screening into routine newborn care.

Although these findings are promising, the current SIDS prevention guidelines are still primordial. More research is necessary before implementing widespread changes to newborn screening protocols.

In the following sections, I will present the carbohydrate, amino acid, and carnitine imbalances investigated or worth investigating if they are potentially involved in SIDS, together with the genetic alterations affecting these metabolic pathways.

Carbohydrate Metabolism Disruptions and Genetic Mutations Involved

Carbohydrate metabolism is crucial in maintaining energy homeostasis, particularly in infants. Table 1 presents a few carbohydrate biomarkers which may contribute to early detection and prevention.

Table 1: Carbohydrate biomarkers and potential significance

Carbohydrate Marker	Association with SIDS	Potential Significance
Ribitol	Significant predictor	Indicator of pentose phosphate pathway disruption
Arabitol/Xylitol	Elevated levels associated with SIDS	Possible marker of altered sugar alcohol metabolism
Glucose-6-phosphatase	Abnormalities observed in some SIDS cases	Key enzyme in glucose homeostasis
Glycogen storage	Altered patterns noted in SIDS victims	May indicate disrupted energy storage and utilisation

Ribitol, a sugar alcohol derived from ribose, has been identified as a significant predictor of SIDS risk. Elevated levels of ribitol may indicate disruptions in the pentose phosphate pathway, which is crucial for generating NADPH and ribose-5-phosphate and is an essential component for fatty acid and nucleotide synthesis. This finding suggests that alterations in carbohydrate metabolism may extend beyond energy production, potentially affecting broader cellular processes.

Arabitol and xylitol, other sugar alcohols, have also been associated with increased SIDS risk. While their exact role in SIDS pathophysiology remains unclear, elevated levels of these compounds may reflect alterations in sugar alcohol metabolism or indicate broader disruptions in carbohydrate processing².

Abnormalities in glucose-6-phosphatase, a key enzyme in glucose homeostasis, have been observed in some SIDS cases. This enzyme has a role in maintaining blood glucose levels, particularly during fasting periods. Defects in glucose-6-phosphatase function could lead to hypoglycaemic episodes, which may be particularly dangerous during sleep when feeding intervals are longer.

Studies have also noted altered glycogen storage patterns in the livers of some SIDS victims. Glycogen is an energy reserve necessary for maintaining glucose levels between feedings. Disruptions in glycogen metabolism may compromise an infant’s ability to maintain stable blood glucose levels during fasting or stress. These carbohydrate imbalances may reflect underlying metabolic disorders or genetic variations affecting multiple biochemical pathways³.

Genetic mutations affecting carbohydrate metabolism have emerged as potential contributors to SIDS risk. These mutations can disrupt the energy production pathways, potentially leading to metabolic crises during periods of stress or fasting. Key genetic mutations associated with carbohydrate metabolism are:

• Glucose-6-phosphatase (G6PC) gene: Mutations in this gene can cause glycogen storage disease type I. Affected infants may experience severe hypoglycaemia, particularly during fasting periods^4,5. It would be reasonable to investigate if they have an increased vulnerability to SIDS.
• Phosphorylase kinase (PHKA2) gene: Mutations in this gene can lead to glycogen storage disease type IX, potentially affecting the liver’s ability to maintain glucose homeostasis⁶. This condition can be studied if it may be associated with an increased risk of sudden death in infants.
• Aldolase B (ALDOB) gene: Mutations in this gene can cause hereditary fructose intolerance. Affected infants may experience severe metabolic decompensation when exposed to fructose-containing foods and is fatal⁷.
• Glucose transporter 1 (SLC2A1) gene: Mutations in this gene can lead to GLUT1 deficiency syndrome, which affects glucose transport across the blood-brain barrier⁸. While not directly linked to SIDS, this condition can cause seizures and developmental delays, potentially increasing vulnerability during sleep.

These genetic mutations highlight the critical role of carbohydrate metabolism in maintaining energy homeostasis, particularly in infants. Disruptions in these pathways can lead to severe metabolic imbalances, potentially contributing to the complex pathophysiology of SIDS. While these genetic factors may increase SIDS risk, they likely interact with environmental and developmental factors. Future research should focus on developing comprehensive genetic screening panels to identify at-risk infants and exploring targeted interventions to support carbohydrate metabolism in genetically susceptible individuals.

Amino Acid Imbalances in SIDS

Specific amino acid imbalances may also be associated with an increased risk of SIDS. These findings provide new insights into the metabolic factors potentially contributing to SIDS and offer promising avenues for early detection and intervention.

Table 2: Amino acid biomarkers and potential significance

Amino Acid	Association with SIDS	Potential Significance
Ornithine	Strong positive correlation	Key component of the urea cycle; may indicate disrupted ammonia metabolism
5-Hydroxylysine	Significant positive association	Involved in collagen formation; exact role in SIDS pathology unclear
Tyrosine	Enriched in metabolite cluster associated with SIDS	Precursor for neurotransmitters and thyroid hormones
Branched-chain amino acids (BCAAs)	Altered levels observed in some SIDS cases	Necessary for energy metabolism and protein synthesis

The strong association of ornithine with SIDS risk is particularly noteworthy. Ornithine is employed in the urea cycle and is responsible for ammonia detoxification. Elevated ornithine levels may indicate disruptions in ammonia metabolism, potentially leading to neurotoxicity and autonomic dysfunction.

5-Hydroxylysine, while significantly associated with SIDS risk, requires further investigation to understand its specific role in SIDS pathophysiology. This amino acid is primarily involved in collagen formation, suggesting potential links between connective tissue metabolism and SIDS risk that warrant exploration.

Enriching tyrosine metabolism pathways in SIDS-associated metabolite clusters highlights the potential importance of neurotransmitter synthesis in SIDS pathology. Tyrosine is a precursor for catecholamines, including dopamine and norepinephrine, which play critical roles in autonomic nervous system function².

Alterations in branched-chain amino acid (BCAA) metabolism have also been observed in some SIDS cases. BCAAs are essential for energy production and protein synthesis, particularly in muscle tissue. Disruptions in BCAA metabolism could contribute to energy deficits during periods of stress or fasting. These amino acid imbalances may reflect underlying metabolic disorders or genetic variations affecting multiple biochemical pathways. For instance, defects in enzymes involved in amino acid catabolism could accumulate certain amino acids and their metabolites, potentially contributing to the metabolic crisis associated with SIDS^9,10.

Metabolomic profiling techniques, such as tandem mass spectrometry (TMS), can detect many of these amino acid abnormalities in dried blood spots, with the potential of early identification of infants at higher risk for SIDS¹⁰. These findings also require further validation across diverse populations and full understanding of the significance of these metabolic markers.

Gene variants affecting amino acid metabolism can disrupt various metabolic pathways, potentially leading to toxic accumulations of specific amino acids or metabolites.

Ornithine transcarbamylase (OTC) deficiency, caused by mutations in the OTC gene, is another urea cycle disorder associated with sudden death in infants. Severe cases can lead to rapid accumulation of ammonia, causing cerebral oedema and potentially fatal outcomes. There is a documented case linking OTC deficiency to death initially misattributed to SIDS¹¹.

Variants in the BCKDHA gene, responsible for branched-chain keto acid dehydrogenase, have been associated with maple syrup urine disease (MSUD). MSUD can cause severe metabolic decompensation and neurological dysfunction, and may be increasing the vulnerability to sudden death during periods of metabolic stress¹².

The SLC25A13 gene, encoding a mitochondrial aspartate-glutamate carrier, has been linked to citrullinemia type II. Mutations in SLC25A13 are linked to the adult onset of citrullinemia, while in infants, the symptoms are dyslipidaemia, failure to thrive and intrahepatic cholestasis^13–15. The connection between citrullinemia (either type) and SIDS risk is not well-established in the current literature. However, it would be worth investigating.

These few genetic variants highlighted the critical role of amino acid metabolism in maintaining metabolic homeostasis and neurological function in infants. Disruptions in these pathways can lead to severe metabolic imbalances, potentially contributing to the complex pathophysiology of SIDS. Future research should focus on integrating genetic screening for these variants into comprehensive SIDS risk assessment strategies and exploring targeted interventions to support amino acid metabolism in genetically susceptible infants.

Carnitine Cycle Deficiencies and SIDS

Carnitine cycle deficiencies are a group of rare metabolic disorders that can significantly impact fatty acid oxidation and energy production in the body ¹⁶. These disorders have been linked to an increased risk of SIDS, highlighting the importance of understanding their role in infant metabolism and health^2,3. The carnitine cycle is involved in transporting long-chain fatty acids into the mitochondria for β-oxidation. Defects in this cycle can lead to severe metabolic decompensation, particularly in infants. An overview of key carnitine cycle deficiencies and their potential link to SIDS is presented in Table 3:

Table 3: Carnitine biomarkers and potential significance

Disorder	Description	SIDS Risk
Carnitine-acylcarnitine translocase (CACT) deficiency	Impairs the exchange of acylcarnitines for free carnitine across the inner mitochondrial membrane17	High; can present as sudden infant death
Carnitine palmitoyl transferase II (CPT II) deficiency	Affects the enzyme responsible for converting long-chain acylcarnitines back to acyl-CoAs inside the mitochondria18	Increased risk, especially in early-onset types
Primary carnitine deficiency (PCD)	Results in urinary carnitine wasting and low serum carnitine levels19	High; can manifest as sudden cardiac arrest

These disorders can present with severe symptoms in infancy, including:

• Hypoketotic hypoglycemia
• Hyperammonemia
• Cardiomyopathy and arrhythmias
• Hepatic dysfunction
• Skeletal muscle weakness
• Encephalopathy^17,19

The link between carnitine cycle deficiencies and SIDS is supported by several lines of evidence:

1. Post-mortem analyses have revealed abnormal acylcarnitine profiles in some SIDS cases, suggesting underlying fatty acid oxidation disorders²⁰.
2. Infants with carnitine cycle deficiencies may appear healthy initially but can rapidly decompensate during periods of fasting or illness, leading to sudden death ¹⁹.
3. Newborn screening for acylcarnitine profiles has identified infants at risk for these disorders, potentially preventing SIDS cases through early intervention¹⁰.

Early detection through expanded newborn screening is necessary for identifying infants at risk. Treatment strategies, including carnitine supplementation and dietary management, can significantly improve outcomes for affected infants.

Genetic mutations affecting lipid metabolism can disrupt energy production pathways and cellular functions, potentially increasing an infant’s vulnerability to sudden death.

The ACADM gene, encoding medium-chain acyl-CoA dehydrogenase, has been a focus of SIDS research. Mutations in this gene can lead to medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, impairing the breakdown of medium-chain fatty acids. This deficiency can result in energy production failures during periods of fasting or illness, potentially contributing to sudden death²¹.

Mutations in the HADHA gene, which encodes the alpha subunit of the mitochondrial trifunctional protein, can cause long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. This disorder affects the oxidation of long-chain fatty acids and has been associated with sudden cardiac events in infants ²².

Variants in the CPT2 gene, responsible for carnitine palmitoyltransferase II, have been reported in cases of sudden infant death. This enzyme is crucial for the transport of long-chain fatty acids into mitochondria for β-oxidation²¹.

The ACADVL gene, encoding very long-chain acyl-CoA dehydrogenase, is another important player in fatty acid oxidation. Deficiency in this enzyme can lead to severe hypoglycaemia and cardiac arrest, particularly during fasting periods. These genetic mutations highlight the critical role of lipid metabolism in maintaining energy homeostasis and cellular function in infants²³.

Disruptions in these pathways can lead to severe metabolic imbalances, potentially contributing to the complex pathophysiology of SIDS. Future research should focus on developing comprehensive genetic screening panels to identify at-risk infants and exploring targeted interventions to support lipid metabolism in genetically susceptible individuals.

Future Research Directions

The emerging research on metabolic markers and their potential link SIDS is a significant advancement in our understanding of this devastating condition. Studies have identified specific metabolic profiles at birth that may indicate an increased risk for SIDS, offering new possibilities for early identification and intervention.

Future research should focus on validating these metabolic markers across diverse populations, investigating the underlying mechanisms linking these metabolic imbalances to SIDS, developing standardized risk assessment models for clinical use and exploring potential interventions based on specific metabolic profiles.

References

1.            The global burden of sudden infant death syndrome from 1990 to 2019: a systematic analysis from the Global Burden of Disease study 2019 – PubMed. https://pubmed.ncbi.nlm.nih.gov/35385121/.

2.            Aldridge, C. M., Keene, K. L., Normeshie, C. A., Mychaleckyj, J. C. & Hauck, F. R. Metabolomic profiles of infants classified as sudden infant death syndrome: a case-control analysis. eBioMedicine 111, (2025).

3.            Oltman, S. P. et al. Early Newborn Metabolic Patterning and Sudden Infant Death Syndrome. JAMA Pediatrics 178, 1183–1191 (2024).

4.            Chou, J. Y. & Mansfield, B. C. Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease. Hum Mutat 29, 921–930 (2008).

5.            Froissart, R. et al. Glucose-6-phosphatase deficiency. Orphanet Journal of Rare Diseases 6, 27 (2011).

6.            Khan, H. H. et al. Glycogen Storage Disease Type IX due to a Novel Mutation in PHKA2 Gene. Case Rep Pediatr 2020, 8836534 (2020).

7.            Coffee, E. M. & Tolan, D. R. Mutations in the promoter region of the aldolase B gene that cause hereditary fructose intolerance. J Inherit Metab Dis 33, 715–725 (2010).

8.            Nsiah-Sefaa, A. & McKenzie, M. Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease. Bioscience Reports 36, e00313 (2016).

9.            Riviello, J. J., Rezvani, I., DiGeorge, A. M. & Foley, C. M. Cerebral edema causing death in children with maple syrup urine disease. J Pediatr 119, 42–45 (1991).

10.         van Rijt, W. J. et al. Inborn Errors of Metabolism That Cause Sudden Infant Death: A Systematic Review with Implications for Population Neonatal Screening Programmes. Neonatology 109, 297–302 (2016).

11.         OTC Deficiency Disorder: A Case Study. https://www.childrenscolorado.org/advances-answers/recent-articles/otc-deficiency-disorder/.

12.         Branched-Chain Amino Acid Metabolism Disorders – Children’s Health Issues. MSD Manual Consumer Version https://www.msdmanuals.com/home/children-s-health-issues/hereditary-metabolic-disorders/branched-chain-amino-acid-metabolism-disorders.

13.         Hayasaka, K. Metabolic basis and treatment of citrin deficiency. J of Inher Metab Disea 44, 110–117 (2021).

14.         Cheng, Z. et al. Identification of Novel Mutations in Chinese Infants With Citrullinemia. Front. Genet. 13, (2022).

15.         Yamaguchi, N. et al. Screening of SLC25A13 mutations in early and late onset patients with citrin deficiency and in the Japanese population: Identification of two novel mutations and establishment of multiple DNA diagnosis methods for nine mutations. Hum Mutat 19, 122–130 (2002).

16.         Merritt, J. L., Norris, M. & Kanungo, S. Fatty acid oxidation disorders. Ann Transl Med 6, 473 (2018).

17.         Orphanet: Carnitine-acylcarnitine translocase deficiency. https://www.orpha.net/en/disease/detail/159.

18.         Du, S.-H. et al. Sudden infant death from neonate carnitine palmitoyl transferase II deficiency. Forensic Science International 278, e41–e44 (2017).

19.         Louis, L. et al. Infantile primary carnitine deficiency: A severe cardiac presentation unresponsive to carnitine supplementation. JIMD Rep 64, 35–41 (2022).

20.         Chace, D. H. et al. Electrospray tandem mass spectrometry for analysis of acylcarnitines in dried postmortem blood specimens collected at autopsy from infants with unexplained cause of death. Clin Chem 47, 1166–1182 (2001).

21.         Brownstein, C. A., Poduri, A., Goldstein, R. D. & Holm, I. A. The Genetics of Sudden Infant Death Syndrome. in SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future (eds. Duncan, J. R. & Byard, R. W.) (University of Adelaide Press, Adelaide (AU), 2018).

22.         New genetic link found for some forms of SIDS. ScienceDaily https://www.sciencedaily.com/releases/2019/10/191011074723.htm.

23.         Singh, P. et al. Postmortem diagnosis of very long chain acyl‐CoA dehydrogenase (VLCAD) deficiency in a neonate with sudden cardiac death. JIMD Rep 64, 261–264 (2023).