Further Evidence for a Dominant Form of Familial Persistent Hyperinsulinemic Hypoglycemia of Infancy: A Family with Documented Hyperinsulinemia in Two Generationsc

Hufnagel, Markus; Eichmann, Dirk; Stieh, J.; Santer, René

doi:10.1210/jc.83.6.2215-a

Cited by 4 publications

(2 citation statements)

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“…In eight cases hyperammonemia was documented, and in all eight cases in whom a leucine tolerance test was performed, significant leucine sensitivity was found. A clinical summary is given in Table 1, and some clinical aspects of family I have been reported elsewhere (Hufnagel et al 1998;Eichmann et al 1999 …”

Section: Patientsmentioning

confidence: 99%

Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome

Santer¹,

Kinner²,

Passarge

et al. 2001

Human Genetics

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The hyperinsulinism-hyperammonemia syndrome (HHS) has been shown to result from 'gain-of-function' mutations of the glutamate dehydrogenase (GlDH) gene, GLUD1. In the original report, all mutations were found in a narrow range of 27 base pairs within exons 11 and 12 which predicted an effect on the presumed allosteric domain of the enzyme and all these mutations were associated by a diminished inhibitory effect of guanosine triphosphate (GTP) on GlDH activity. We have investigated 14 patients from seven European families with mild hyperinsulinism. In four families, more than one member was affected. In eight cases hyperammonemia was documented, and eight cases had signs of significant leucine sensitivity. In one of the families, a novel heterozygous missense mutation in exon 6 [c.833C>T (R221C)] was detected, and in all other cases from six unrelated families the novel heterozygous missense mutation c.978G>A (R269H) was found in exon 7. When GIDH activity was measured in lymphocytes isolated from affected patients, both mutations were shown to result in a normal basal activity but a diminished sensitivity to GTP. It is the first time that this effect is reported for mutations located in the presumed catalytic site and outside the GTP allosteric domain of the enzyme. The observation of the high prevalence of the exon 7 mutation both in familial and sporadic cases of HHS suggests a mutation hot spot and justifies a mutation screening for this novel mutation by mismatch PCR-based restriction enzyme digestion in patients with hyperinsulinism.

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