HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article IMMEDIATE FREE ACCESS ARTICLE OA Free Full Text Full Text (PDF) Supplementary Table 1 OA All Versions of this Article: EJE-09-0615v1 161/5/731    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kapoor, R. R Articles by Hussain, K. PubMed PubMed Citation Articles by Kapoor, R. R Articles by Hussain, K.

Hyperinsulinism–hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype–phenotype correlations

Developmental Endocrinology Research Group, Molecular Genetics Unit, London Centre for Paediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children NHS Trust, and The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK¹ Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter EX2 5DW, UK² Department of Inherited Metabolic Disorders, Birmingham Children's Hospital, Birmingham B4 6NH, UK³ Metabolic Biochemistry, Hôpital Necker – Enfants Malades, Université Paris Descartes, Paris, France⁴ Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation and Weil-Cornell Medical College, Doha, Qatar⁵ Department of Paediatric Endocrinology, Royal Manchester Children's Hospital and Alder Hey Children's Hospital, Manchester M27 4HA, UK⁶ Department of Child Health, Bristol Royal Hospital for Children, Bristol BS2 8BJ, UK

(Correspondence should be addressed to K Hussain; Email: k.hussain{at}ich.ucl.ac.uk)

This is an Open Access article distributed under the terms of the European Journal of Endocrinology's Re-use Licence which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background: Activating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism–hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion.

Objectives: To study the genotype–phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA.

Patients and methods: Twenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed.

Results: Heterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 µmol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified.

Conclusion: Patients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations.