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Marked phenotypic heterogeneity associated with a heterozygous pathogenic variant in the acetyl-CoA acyltransferase 2 gene. 

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction:
The ACAA2 gene encodes for the acetyl-CoA acyltransferase 2 enzyme, also known as mitochondrial 3-oxoacyl-CoA thiolase (OMIM 604770). This enzyme catalyzes the last step in mitochondrial fatty acid beta-oxidation, along with the mitochondrial trifunctional protein. At this time, there is not an established disease phenotype associated acetyl-CoA acyltransferase 2 deficiency. We report marked phenotypic heterogeneity associated with a novel pathogenic variant, c.688G>A, p.E230K, in ACAA2.

 

Methods:
Methods: All patients and their relatives underwent whole exome sequencing in a commercial laboratory or in a research setting. All of them gave informed consent for genetic testing. A retrospective chart review was performed for phenotypic characterization.

 

Results:
Results: Four patients belonging to the same family predominantly presented in infancy, with failure to thrive, hepatomegaly, liver dysfunction with hyperbilirubinemia and significantly elevated liver enzymes, and risk for severe hypoglycemic episodes. One patient experienced a catastrophic hypoglycemic episode that resulted in neurologic devastation. Hypoglycemic episodes were ameliorated in other affected family members through frequent feedings and strict avoidance of fasting for the first 1-2 years of life. Liver dysfunction and risk for hypoglycemia typically resolved after 1-2 years of life. Their plasma acylcarnitine profile, plasma carnitine, plasma amino acids, urine amino acids, and urine organic acids were unremarkable. Additional features shared by these individuals include lipomas localized to the neck, which developed in childhood, and features of lipodystrophy. Notably, one individual received a presumed clinical diagnosis of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, and adhered to a fat-restricted diet during childhood and did not develop a lipoma. This presentation, with an autosomal dominant mode of inheritance, is uncommon for inborn errors of metabolism, thus adding to the complexity of this novel disease phenotype.

 

Probands of three other unrelated families had the same variant in ACAA2 inherited de novo or in autosomal dominant fashion and presented with familial partial lipodystrophy phenotype along with metabolic complications, such as diabetes, hyperlipidemia and hepatic steatosis with abnormal liver function tests. One of them also had large (up to 20 cm) lipomas in the upper back. None of these patients had hypoglycemia during childhood.

 

Conclusion:
Conclusions: The precise reasons for this marked phenotypic heterogeneity related to the ACAA2 c.688G>A, p.E230K variant are not clear at this time and require further investigation and deep phenotyping of all affected patients for metabolic complications, including hypoglycemia during infancy and abnormal body fat distribution characteristic of lipodystrophy, as well as complications of insulin resistance, such as diabetes, hypertriglyceridemia, and hepatic steatosis later during adulthood.

 

This work was supported by grant from the National Institutes of Health, R01-DK105448, and by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases.

 

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