3-Hydroxyacyl-coenzyme A dehydrogenase deficiency and hyperinsulinemic hypoglycemia: characterization of a novel mutation and severe dietary protein sensitivity.
BACKGROUND
HADH encodes for the enzyme 3-hydroxyacyl-coenzyme A dehydrogenase (HADH) and catalyses the penultimate reaction in the beta-oxidation of fatty acids. All previously reported patients with mutations in HADH gene and hyperinsulinemic hypoglycemia (HH) showed raised plasma hydroxybutyrylcarnitine and urinary 3-hydroxyglutarate.


OBJECTIVE
The aims of the study were: 1) to report a novel HADH gene mutation not associated with abnormal acylcarnitine or urinary organic acid profile; and 2) to report the novel observation of severe protein-sensitive HH in three patients with HADH gene mutations.


METHODS
The index case presented at 4 months of age with hypoglycemic seizures. Her HH responded to diazoxide, but she continued to have episodes of hypoglycemia even on diazoxide, especially when consuming high-protein foods.


RESULTS
Investigations confirmed HH (blood glucose level of 1.8 mmol/liter with simultaneous serum insulin level of 58 mU/liter) with normal acylcarnitines and urine organic acids. Sequencing of the HADH gene identified a homozygous missense mutation (c.562A>G; p.Met188Val). Hydroxyacyl-coenzyme A dehydrogenase activity was significantly decreased compared with controls (index patient, mean +/- sem, 26.8 +/- 4.8 mU/mg protein; controls, 48.0 +/- 8.1 mU/mg protein; P = 0.029) in skin fibroblasts. This patient was severely protein sensitive. Two other children with HH due to HADH gene mutations also demonstrated marked protein sensitivity.


CONCLUSIONS
Mutations in the HADH gene are associated with protein-induced HH, and patients with HH due to HADH gene mutations may have normal acylcarnitines and urine organic acids.
Kapoor
Ritika R
RR
London Centre for Paediatric Endocrinology and Metabolism, Hospital for Children National Health Service Trust, London WC1N 3JH, United Kingdom.
James
Chela
C
Flanagan
Sarah E
SE
Ellard
Sian
S
Eaton
Simon
S
Hussain
Khalid
K
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000172:deficiency / Q000235:genetics*; D044903:Congenital Hyperinsulinism / Q000150:complications / Q000235:genetics*; D004252:DNA Mutational Analysis; D004044:Dietary Proteins / Q000009:adverse effects*; D005260:Female; D005512:Food Hypersensitivity / Q000150:complications* / Q000235:genetics; D006801:Humans; D007223:Infant; D020125:Mutation, Missense
D004044:Dietary Proteins; D015094:3-Hydroxyacyl CoA Dehydrogenases