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

Kapoor, Ritika R; Flanagan, Sarah E.; Fulton, Piers; Chakrapani, Anupam; Chadefaux, B.; Ben‐Omran, Tawfeg; Banerjee, Indraneel; Shield, Julian P H; Ellard, Sian; Hussain, Khalid

doi:10.1530/eje-09-0615

Cited by 87 publications

(114 citation statements)

References 20 publications

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“…(b) Enzyme Defects I.Hyperinsulinism-Hyperammonaemia Syndrome (HI/HA): HI/HA syndrome, the second most common form of CHI, is caused by activating mutations in the GLUD1 gene, which encodes for the intramitochondrial enzyme glutamate dehydrogenase (GDH) (12,51,52,53,54,55,56). GDH activity is regulated by allosteric inhibitors (GTP) and activators (ADP and leucine).…”

Section: Introductionmentioning

confidence: 99%

Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management

Senniappan

Balasubramaniam

James

et al. 2012

J of Inher Metab Disea

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118

121

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Hyperinsulinaemic hypoglycaemia (HH) is due to the unregulated secretion of insulin from pancreatic β‐cells. A rapid diagnosis and appropriate management of these patients is essential to prevent the potentially associated complications like epilepsy, cerebral palsy and neurological impairment. The molecular basis of HH involves defects in key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and UCP2) which regulate insulin secretion. The most severe forms of HH are due to loss of function mutations in ABCC8/KCNJ11 which encode the SUR1 and KIR6.2 components respectively of the pancreatic β‐cell KATP channel. At a histological level there are two major forms (diffuse and focal) each with a different genetic aetiology. The diffuse form is inherited in an autosomal recessive (or dominant) manner whereas the focal form is sporadic in inheritance and is localised to a small region of the pancreas. The focal form can now be accurately localised pre‐operatively using a specialised positron emission tomography scan with the isotope Fluroine‐18L‐3, 4‐dihydroxyphenyalanine (18F‐DOPA‐PET). Focal lesionectomy can provide cure from the hypoglycaemia. However the diffuse form is managed medically or by near total pancreatectomy (with high risk of diabetes mellitus). Recent advances in molecular genetics, imaging with 18F‐DOPA‐PET/CT and novel surgical techniques have changed the clinical approach to patients with HH.

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Section: Introductionmentioning

confidence: 99%

Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management

Senniappan

Balasubramaniam

James

et al. 2012

J of Inher Metab Disea

Self Cite

118

121

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“…She was hence evaluated for leucine sensitivity at the age of 13, by an oral leucine tolerance test. In response to an oral leucine load, the patient developed symptomatic hypoglycemia (8). Our patient, in contrast, had a high serum ammonia concentration on presentation which persisted in the following measurements.…”

Section: Case Reportmentioning

confidence: 52%

“…Accurate and timely diagnosis depends on a critical sample collection during a hypoglycemic episode and a glucagon stimulation test performed when plasma glucose is <50 mg/ dl. An interesting clinical aspect of HI/HA syndrome is that epilepsy is an unusually frequent finding; in a cohort of 16 patients, 15 presented with seizures and 43% later developed epilepsy (8). Potential explanations of this include recurrent hypoglycemia or chronic hyperammonemia, but especially decreased brain concentrations of the neurotransmitter GABA due to increased GDH activity in the brain (8).…”

Section: Case Reportmentioning

confidence: 99%

“…An interesting clinical aspect of HI/HA syndrome is that epilepsy is an unusually frequent finding; in a cohort of 16 patients, 15 presented with seizures and 43% later developed epilepsy (8). Potential explanations of this include recurrent hypoglycemia or chronic hyperammonemia, but especially decreased brain concentrations of the neurotransmitter GABA due to increased GDH activity in the brain (8). To date, GLUD1 mutations have been described in the exons 6, 7, 10, 11 and 12 which all encode amino acids in the allosteric regions of GDH (9).…”

Section: Case Reportmentioning

confidence: 99%

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Seizures and diagnostic difficulties in hyperinsulinism-hyperammonemia syndrome

Aka¹,

Alanay²,

Boodhansingh³

et al. 2016

Turk J Pediatr

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Hyperinsulinism/hyperammonemia (HI/HA) syndrome is a rare disorder presented with recurrent hypoglycemia and elevated serum ammonia, which may lead to development delays, permanent neurologic damages, if it remains underdiagnosed. It is caused by activating mutations in the GLUD1 gene which encodes the intra-mitochondrial enzyme glutamate dehydrogenase (GDH).HI/HA syndrome is considered the second most common form of hyperinsulinism (HI), and usually associated with epileptic seizures, mental retardation and generalized dystonia.We reported a patient who was diagnosed as HI/HA with multiple episodes of seizures; and previously had been diagnosed and treated for epilepsy. She has heterozygous mutation in GLUD1 gene. Treatment with diazoxide enabled complete resolution of the seizures.One year later, when her brother was six months old, he was also diagnosed with HI/HA. Later, the same mutation of GLUD1 was detected in both her father and brother too.

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“…In 2002, in a multicenter series of 175 patients, hyperammonaemia was found in 12 out of 69 tested patients with hyperinsulinemic hypoglycemia (12). Although the disease is rare, several case reports and some reviews have been published (2,9,(13)(14)(15)(16)(17)(18)). An interesting clinical aspect of HI-HA syndrome is that epilepsy is a frequent finding; in a cohort of 16 patients, 15 presented seizures and 43% of them developed epilepsy.…”

Section: G6pmentioning

confidence: 99%

Hyperinsulinism/hyperammonemia (HI/HA) syndrome due to a mutation in the glutamate dehydrogenase gene

Corrêa-Giannella

Freire

Cavaleiro

et al. 2012

Arq Bras Endocrinol Metab

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SUMMARYThe hyperinsulinism/hyperammonemia (HI/HA) syndrome is a rare autosomal dominant disea se manifested by hypoglycemic symptoms triggered by fasting or highprotein meals, and by elevated serum ammonia. HI/HA is the second most common cause of hyperinsulinemic hypo glycemia of infancy, and it is caused by activating mutations in GLUD1, the gene that encodes mitochondrial enzyme glutamate dehydrogenase (GDH). Biochemical evaluation, as well as direct sequencing of exons and exonintron boundary regions of the GLUD1 gene, were per formed in a 6year old female patient presenting fasting hypoglycemia and hyperammonemia. The patient was found to be heterozygous for one de novo missense mutation (c.1491A>G; p.Il497Met) previously reported in a Japanese patient. Treatment with diazoxide 100 mg/day promoted complete resolution of the hypoglycemic episodes. Arq Bras Endocrinol Metab. 2012;56(8):485-9 SUMÁRIO A síndrome de hiperinsulinemia/hiperamonemia (HI/HA) é uma condição rara, de herança autos sômica dominante, que se manifesta por sintomas de hipoglicemia desencadeada por je jum ou refeições de alto conteúdo proteico, juntamente com elevação da concentração de amô nia sérica. HI/HA é a segunda causa de hipoglicemia hiperinsulinêmica da infância e é causa da por mutações ativadoras no GLUD1, o gene que codifica a enzima mitocondrial glutamato desidrogenase (GDH). A avaliação bioquímica, bem como o sequenciamento direto dos éxons e junções éxoníntron do gene GLUD1, foi realizada em uma paciente de 6 anos de idade com hi poglicemia de jejum e hiperamonemia. A paciente apresentava uma mutação de novo missense (c.1491A>G; p.Il497Met) em heterozigose, que havia sido previamente relatada em um paciente japonês. O tratamento com diazóxido 100 mg/dia promoveu resolução completa dos episódios hipoglicêmicos. Arq Bras Endocrinol Metab. 2012;56(8):485-9

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

Cited by 87 publications

References 20 publications

Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management

Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management

Seizures and diagnostic difficulties in hyperinsulinism-hyperammonemia syndrome

Hyperinsulinism/hyperammonemia (HI/HA) syndrome due to a mutation in the glutamate dehydrogenase gene

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