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. 2011 Mar;96(3):E498-502.
doi: 10.1210/jc.2010-1906. Epub 2011 Jan 20.

Genome-wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinemic-hypoglycemia in consanguineous pedigrees

Sarah E Flanagan  1 , Ann-Marie Patch, Jonathan M Locke, Teoman Akcay, Enver Simsek, Mohammadreza Alaei, Zeinab Yekta, Meena Desai, Ritika R Kapoor, Khalid Hussain, Sian Ellard
Affiliations

Genome-wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinemic-hypoglycemia in consanguineous pedigrees

Sarah E Flanagan et al. J Clin Endocrinol Metab. 2011 Mar.

Abstract

Context and objective: Recessive mutations in the hydroxyacyl-CoA dehydrogenase (HADH) gene encoding the enzyme 3-hydroxyacyl-CoA dehydrogenase are a rare cause of diazoxide-responsive hyperinsulinemic hypoglycemia (HH) with just five probands reported to date. HADH deficiency in the first three identified patients was associated with detectable urinary 3-hydroxyglutarate and raised plasma 3-hydroxybutyryl-carnitine levels, but two recent cases did not have abnormal urine organic acids or acylcarnitines.

Research design and methods: We studied 115 patients with diazoxide-responsive HH in whom the common genetic causes of HH had been excluded. No patients were reported to have abnormal acylcarnitines or urinary organic acids. Homozygosity mapping was undertaken in probands from 13 consanguineous pedigrees to search for regions harboring mutations that are identical by descent.

Results: HADH sequencing was performed after genome-wide single nucleotide polymorphism analysis revealed a large shared region of homozygosity spanning the HADH locus in six unrelated probands. Homozygous mutations were identified in three of these patients and in a further two probands from consanguineous families. HADH analysis in the remainder of the cohort identified mutations in a further six probands for whom consanguinity was not reported, but who originated from countries with high rates of consanguinity. Six different HADH mutations were identified in 11/115 (10%) patients tested.

Conclusion: HADH mutations are a relatively common cause of diazoxide-responsive HH with a frequency similar to that of GLUD1 and HNF4A mutations. We recommend that HADH sequence analysis is considered in all patients with diazoxide-responsive HH when recessive inheritance is suspected.

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Figures

Fig. 1.
Fig. 1.
Schematic representation of the full-length HADH gene (Reference sequence NM_005327) and a variant transcript (cDNA accession number B1826991). Exons are represented by boxes, and introns are denoted by lines. Hatched boxes represent coding regions which differ between the two transcripts, and white boxes represent UTRs. An arrow with a star points to the approximate position of the novel variant, c.709 + 39C>G (nomenclature relating to RefSeq NM_005327) identified in patient 9.
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