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 b-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.

Successful diagnosis of HIBCH deficiency from exome sequencing and positive retrospective analysis of newborn screening cards in two siblings presenting with Leigh's disease

“…Of importance, for NBS programs using underivatized methods, hydroxy-C4-carnitine is isobaric to malonyl-carnitine (C3DC) and subsequently indistinguishable from this metabolite. Therefore, when underivatized methodology is used, it is necessary that follow-up for samples that screen positive for C3DC include confirmatory testing for both elevated malonyl-carnitine and hydroxy-C4-carnitine [35]. …”

Acetate provokes mitochondrial stress and cell death in Ustilago maydis

“…Also, peroxisomal β‐oxidation requires the carnitine shuttle into mitochondria, and it is known that interference with the shuttle in the peroxisome by loss of the peroxisomal acetyl transferase impairs growth on fatty acids and acetate in the fungal pathogen Sclerotinia sclerotiorum (Liberti et al ., ). A defect in the human hydroxyacyl‐coenzyme A dehydrogenase (HADH), a homologue to the Ustilago mitochondrial Had1 protein, leads to an over accumulation of C4‐OH acylcarnitine, suggesting an imbalance and improper usage of acylcarnitine in HADH deficient patients (Van Hove et al ., ; Popa et al ., ). The over‐accumulation of shorter and longer acyl‐carnitine derivates leads to a depletion of carnitine for transport of acyl and acetyl groups from the peroxisome.…”

A Deep Intronic HADH Splicing Mutation (c.636+471G>T) in a Congenital Hyperinsulinemic Hypoglycemia Case: Long Term Clinical Course

“…Recessive mutations in the HADH gene were first described by Clayton et al ( 3 ) in a four-month-old infant with hypoketotic hypoglycemia, inappropriately elevated insulin levels and elevated blood spot hydroxybutyrylcarnitine concentration. Since then, another 36 patients have been reported with HADH mutations ( 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ). The clinical presentation of CHH due to HADH mutations is heterogeneous with some patients presenting with severe neonatal hypoglycemia and others - with mild infancy-onset hypoglycemia.…”

“…Birth weight of patients with HADH gene mutation were usually reported as normal from 2730 g to 4350 g ( 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ). Early admitted patients usually had hypoglycemic seizure as our case ( 3 , 4 , 5 , 8 , 9 , 10 , 13 , 14 , 15 ). Martins et al ( 4 ) reported four new cases and reviewed seven reported cases with HH due to HADH deficiency.…”

“…HADH mutations are recessively inherited and most of the reported cases are from consanguineous families. So far, approximately 40 patients with CHH resulting from a mutation in the HADH gene have been reported ( Table 1 ) ( 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ).The mechanism behind unregulated insulin secretion in SCHAD deficiency is currently not understood but may involve changes in protein-protein interactions with glutamate dehydrogenase (GDH) ( 16 , 17 ).…”