3-Hydroxyacyl-Coenzyme A Dehydrogenase Deficiency: Identification of a New Mutation Causing Hyperinsulinemic Hypoketotic Hypoglycemia, Altered Organic Acids and Acylcarnitines Concentrations

Abstract

The human HADH gene encodes the short-chain-L-3-hydroxyacyl-CoA dehydrogenase, the enzyme which catalyzes the third step of the β-oxidation of the fatty acids in the mitochondrial matrix. Loss-of-function mutations in the HADH gene lead to short-chain-L-3-hydroxyacyl-CoA dehydrogenase deficiency, an autosomal recessive genetic defect of unknown prevalence with a wide spectrum of phenotypic variability. As in other metabolic diseases, the diagnostic relevance of the biochemical evaluations, plasma acylcarnitines, and urinary organic acids, are crucially dependent on the clinical conditions of the patient during specimen collection.

This paper describes the eighth patient carrying a HADH gene mutation, a new homozygous deletion c.565delG leading to an early stop codon (p.V116Wfs124X), in an infant with hyperinsulininemic hypoglycemia, displaying abnormal patterns of plasma acylcarnitines and urinary organic acids. We conclude that, when the residual catalytic activity of the mutated enzyme is seriously reduced, the biochemical hallmarks of the disease, namely plasma 3-hydroxybutyrylcarnitine and urinary 3-hydroxyglutaric acid, are invariably present.

FIP and SP equally contributed to this paper and should be considered co-first authors.

Competing interests: None declared.

Appendices

Synopsis

Particularly reduced catalytic activity of the short-chain-L-3-hydroxyacyl-CoA-dehydrogenase leads to hyperinsulinemic hypoketotic hypoglycemia with enhanced plasma 3-hydroxybutyryl-carnitine and urine hydroxyglutaric acid.

Details of the Contributions of Individual Authors

• Florina Ion Popa performed the molecular analysis of HADH gene.

• Silvia Perlini followed the clinical case since patient hospitalization.

• Francesca Teofoli followed the clinical case and was responsible for diagnostic confirmation.

• Daniela Degani followed the clinical case since patient hospitalization.

• Silvia Funghini carried out the urine organic acids’ analysis.

• Giancarlo La Marca performed the derivatized tandem mass spectrometry analysis.

• Piero Rinaldo performed the derivatized tandem mass spectrometry analysis and reviewed the paper.

• Monica Vincenzi carried out the nonderivatized tandem mass spectrometry analysis.

• Franco Antoniazzi is responsible for clinical follow up.

• Attilio Boner coordinated the whole diagnostic/therapeutic pathway, which consisted in connecting and keeping in touch different laboratories and clinics.

• Marta Camilot planned and conducted the work described in the article. She wrote the paper.

All Authors edited and approved the final version of the manuscript.

Marta Camilot is the guarantor for the article. She accepts full responsibility for the work, has access to the data and controlled the decision to publish.

All authors have nothing to declare about competing interests.

Part of the funding required for this study was provided by Associazione Italiana Sostegno Malattie Metaboliche Ereditarie (AISSME). The authors confirm independence from the sponsors. The content of the article has not been influenced by the sponsors.

Ethics approval was not required. The patient’s parents signed an informed consent that is available upon request.