MCID: HYP101
MIFTS: 42

Hyperinsulinism-Hyperammonemia Syndrome

Categories: Genetic diseases, Rare diseases, Metabolic diseases, Endocrine diseases

Aliases & Classifications for Hyperinsulinism-Hyperammonemia Syndrome

MalaCards integrated aliases for Hyperinsulinism-Hyperammonemia Syndrome:

Name: Hyperinsulinism-Hyperammonemia Syndrome 54 50 56 71 29 13 52
Hyperinsulinemic Hypoglycemia, Familial, 6 69
Hyperinsulinemic Hypoglycemia Familial 6 50
Familial Hyperinsulinemic Hypoglycemia 6 71
Hyperinsulinism Hyperammonemia Syndrome 50
Ha/hi Syndrome 50
Hi/ha Syndrome 56
Hhf6 71
Hhs 71

Characteristics:

Orphanet epidemiological data:

56
hyperinsulinism-hyperammonemia syndrome
Inheritance: Autosomal dominant; Age of onset: Infancy,Neonatal;

OMIM:

54
Inheritance:
autosomal dominant

Miscellaneous:
genetic heterogeneity (see hhf1 )
mean age at onset of hypoglycemia may be delayed (median, 9 months, diagnosis sometimes made in adulthood)


HPO:

32
hyperinsulinism-hyperammonemia syndrome:
Inheritance autosomal dominant inheritance heterogeneous


Classifications:



External Ids:

OMIM 54 606762
Orphanet 56 ORPHA35878
ICD10 via Orphanet 34 E72.8
MedGen 40 C1847555

Summaries for Hyperinsulinism-Hyperammonemia Syndrome

NIH Rare Diseases : 50 the following summary is from orphanet, a european reference portal for information on rare diseases and orphan drugs.orpha number: 35878disease definitionhyperinsulinism-hyperammonemia syndrome (hiha) is a frequent form of diazoxide-sensitive diffuse hyperinsulinism (see this term), characterized by an excessive/ uncontrolled insulin secretion (inappropriate for the level of glycemia), asymptomatic hyperammonemia and recurrent episodes of profound hypoglycemia induced by fasting and protein rich meals, requiring rapid and intensive treatment to prevent neurological sequelae. epilepsy and cognitive deficit that are unrelated to hypoglycemia may also occur.epidemiologyprevalence is estimated at 1 in 200,000.clinical descriptionclinical features are similar to those described in congenital isolated hyperinsulinism (see this term), but the manifestations are milder with diagnosis delayed until late infancy. hypoglycemia is triggered by fasting or a protein-rich meal (leucine sensitive hypoglycemia) and is easily controlled by diazoxide. asymptomatic and persistent hyperammonemia (about 3 to 5 times the normal range) is observed. children with hiha frequently present seizures (most commonly atypical or absence) and learning difficulties. neurologic abnormalities appear to be unrelated to hypoglycemia.etiologyglutamate dehydrogenase (gdh) is a mitochondrial matrix enzyme that catalyzes the oxidative deamination of glutamate, yielding alpha-ketoglutarate and an ammonia by-product. production of alpha-ketoglutarate leads to an increase in intracellular atp causing the closure of atp-sensitive potassium channels (sur1/kir6.2). this in turn leads to an influx of calcium ions and the ensuing cellular depolarization triggers the secretion of insulin from pancreatic beta-cells. gdh is under a complex regulatory control of allosterically activating leucine and inhibiting gtp. dominantly expressed, missense mutations of glud1 (10q23.3) that encodes gdh, increase enzyme activity by reducing its sensitivity to allosteric inhibition by guanosine triphosphate (gtp). the role of hyperammonemia is not known; it may primarily be the result of the renal expression of altered forms of gdh.genetic counselingmost activating mutations of the geneglud1 are de novo, but the familial forms that have been reported are dominant. incomplete variance and clinical variability are noted within the same families.visit the orphanet disease page for more resources. last updated: 4/1/2015

MalaCards based summary : Hyperinsulinism-Hyperammonemia Syndrome, also known as hyperinsulinemic hypoglycemia, familial, 6, is related to acute insulin response and hypotrichosis 1, and has symptoms including intellectual disability, hyperinsulinemic hypoglycemia and hypoglycemic coma. An important gene associated with Hyperinsulinism-Hyperammonemia Syndrome is GLUD1 (Glutamate Dehydrogenase 1), and among its related pathways/superpathways are Carbon metabolism and Amino Acid metabolism. Affiliated tissues include liver and testes.

UniProtKB/Swiss-Prot : 71 Familial hyperinsulinemic hypoglycemia 6: Familial hyperinsulinemic hypoglycemia [MIM:256450], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. In HHF6 elevated oxidation rate of glutamate to alpha- ketoglutarate stimulates insulin secretion in the pancreatic beta cells, while they impair detoxification of ammonium in the liver.

Wikipedia : 72 Hyperinsulinism hyperammonemia syndrome (HI/HA or HHS), is an autosomal dominant disorder that results... more...

Description from OMIM: 606762

Related Diseases for Hyperinsulinism-Hyperammonemia Syndrome

Diseases related to Hyperinsulinism-Hyperammonemia Syndrome via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 59)
id Related Disease Score Top Affiliating Genes
1 acute insulin response 29.7 INS KCNJ5
2 hypotrichosis 1 11.5
3 tumoral calcinosis, hyperphosphatemic, familial 11.4
4 dyskeratosis congenita, x-linked 11.4
5 hypogonadotropic hypogonadism 7 without anosmia 11.3
6 heart-hand syndrome, slovenian type 11.3
7 hemochromatosis 11.2
8 glud1-related hyperinsulinism 11.1
9 hypogonadotropic hypogonadism 11.0
10 hypothalamic hamartomas, somatic 10.9
11 dyskeratosis congenita, autosomal dominant 1 10.8
12 kallmann syndrome 10.8
13 dyskeratosis congenita, autosomal recessive 5 10.8
14 hypogonadotropic hypogonadism 2 with or without anosmia 10.8
15 hypotrichosis simplex 10.7
16 hyperinsulinism 10.6
17 hyperammonemia 10.6
18 hypogonadotropic hypogonadism 6 with or without anosmia 10.6
19 hypogonadotropic hypogonadism 14 with or without anosmia 10.6
20 hypogonadotropic hypogonadism 4 with or without anosmia 10.6
21 hypogonadotropic hypogonadism 10 with or without anosmia 10.6
22 hypogonadotropic hypogonadism 18 with or without anosmia 10.6
23 hypogonadotropic hypogonadism 19 with or without anosmia 10.6
24 hypogonadotropic hypogonadism 11 with or without anosmia 10.6
25 hypogonadotropic hypogonadism 8 with or without anosmia 10.6
26 hypogonadotropic hypogonadism 17 with or without anosmia 10.6
27 hypogonadotropic hypogonadism 3 with or without anosmia 10.6
28 hypogonadotropic hypogonadism 21 with anosmia 10.6
29 hypogonadotropic hypogonadism 16 with or without anosmia 10.6
30 hypogonadotropic hypogonadism 22, with or without anosmia 10.6
31 hypogonadotropic hypogonadism 20 with or without anosmia 10.6
32 hypogonadotropic hypogonadism 12 with or without anosmia 10.6
33 hypogonadotropic hypogonadism 13 with or without anosmia 10.6
34 hypogonadotropic hypogonadism 5 with or without anosmia 10.6
35 hypogonadotropic hypogonadism 15 with or without anosmia 10.6
36 hypogonadotropic hypogonadism 9 with or without anosmia 10.6
37 hypoglycemia 10.1
38 pancreatitis 10.0
39 fasting hypoglycemia 10.0
40 hepatitis 10.0
41 monocarboxylate transporter 1 deficiency 9.9 GLUD1 INS
42 hyperinsulinemic hypoglycemia, familial, 4 9.8 GLUD1 INS
43 breast cancer 9.8
44 hypogonadism 9.8
45 hyperostosis 9.8
46 hypogonadotropism 9.8
47 hyperphosphatemia 9.8
48 diabetic cataract 9.8 GLUD1 INS
49 triple x syndrome 9.8 GLUD1 INS
50 pancreatic cancer 9.7

Graphical network of the top 20 diseases related to Hyperinsulinism-Hyperammonemia Syndrome:



Diseases related to Hyperinsulinism-Hyperammonemia Syndrome

Symptoms & Phenotypes for Hyperinsulinism-Hyperammonemia Syndrome

Symptoms via clinical synopsis from OMIM:

54

Neurologic- Central Nervous System:
seizures, hypoglycemic
loss of consciousness due to hypoglycemia
mental retardation due to repeated episodes of hypoglycemia

Laboratory- Abnormalities:
hypoglycemia
hyperinsulinemia
hyperammonemia, asymptomatic (2-5 times normal)

Endocrine Features:
hyperinsulinemic hypoglycemia


Clinical features from OMIM:

606762

Human phenotypes related to Hyperinsulinism-Hyperammonemia Syndrome:

32
id Description HPO Frequency HPO Source Accession
1 intellectual disability 32 HP:0001249
2 hyperinsulinemic hypoglycemia 32 HP:0000825
3 hypoglycemic coma 32 HP:0001325
4 hypoglycemic seizures 32 HP:0002173
5 asymptomatic hyperammonemia 32 HP:0008162

Drugs & Therapeutics for Hyperinsulinism-Hyperammonemia Syndrome

Search Clinical Trials , NIH Clinical Center for Hyperinsulinism-Hyperammonemia Syndrome

Genetic Tests for Hyperinsulinism-Hyperammonemia Syndrome

Genetic tests related to Hyperinsulinism-Hyperammonemia Syndrome:

id Genetic test Affiliating Genes
1 Hyperinsulinism-Hyperammonemia Syndrome 29

Anatomical Context for Hyperinsulinism-Hyperammonemia Syndrome

MalaCards organs/tissues related to Hyperinsulinism-Hyperammonemia Syndrome:

39
Liver, Testes

Publications for Hyperinsulinism-Hyperammonemia Syndrome

Articles related to Hyperinsulinism-Hyperammonemia Syndrome:

(show all 24)
id Title Authors Year
1
Hyperinsulinism-hyperammonemia syndrome: a de novo mutation of the GLUD1 gene in twins and a review of the literature. ( 27383869 )
2016
2
Hyperinsulinism Hyperammonemia Syndrome, a Rare Clinical Constellation. ( 26962538 )
2016
3
Seizures and diagnostic difficulties in hyperinsulinism-hyperammonemia syndrome. ( 28621098 )
2016
4
Early Presentation of Hyperinsulinism/Hyperammonemia Syndrome in Three Serbian Patients. ( 26759084 )
2015
5
Intractable absence seizures in hyperinsulinism-hyperammonemia syndrome. ( 22759688 )
2012
6
Biochemical evaluation of an infant with hypoglycemia resulting from a novel de novo mutation of the GLUD1 gene and hyperinsulinism-hyperammonemia syndrome. ( 21932603 )
2011
7
Familial hyperinsulinism-hyperammonemia syndrome in a family with seizures: case report. ( 21073125 )
2010
8
On the reversibility of glutamate dehydrogenase and the source of hyperammonemia in the hyperinsulinism/hyperammonemia syndrome. ( 19895831 )
2010
9
The hyperinsulinism/hyperammonemia syndrome. ( 20936362 )
2010
10
Systemic activation of glutamate dehydrogenase increases renal ammoniagenesis: implications for the hyperinsulinism/hyperammonemia syndrome. ( 20332361 )
2010
11
Hyperammonemia and positive allopurinol test in hyperinsulinism-hyperammonemia syndrome: Taiwanese case report. ( 19379266 )
2009
12
Unregulated insulin secretion by pancreatic beta cells in hyperinsulinism/hyperammonemia syndrome: role of glutamate dehydrogenase, ATP-sensitive potassium channel, and nonselective cation channel. ( 16492972 )
2006
13
Hyperinsulinism/Hyperammonemia Syndrome: a synopsis. ( 15773041 )
2005
14
[Hyperinsulinism-hyperammonemia syndrome due to a de novo mutation in exon 7 (G979A) of the glutamate dehydrogenase gene with excellent response to diazoxide]. ( 15530324 )
2004
15
Urinary alpha-ketoglutarate is elevated in patients with hyperinsulinism-hyperammonemia syndrome. ( 14967154 )
2004
16
Hyperinsulinism/hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism. ( 15050973 )
2004
17
Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome. ( 11214910 )
2001
18
Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/hyperammonemia syndrome. ( 11241047 )
2001
19
Acute insulin responses to leucine in children with the hyperinsulinism/hyperammonemia syndrome. ( 11502802 )
2001
20
Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. ( 11297618 )
2001
21
Functional hyperactivity of hepatic glutamate dehydrogenase as a cause of the hyperinsulinism/hyperammonemia syndrome: effect of treatment. ( 10969108 )
2000
22
Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. HI/HA Contributing Investigators. ( 10871207 )
2000
23
Novel missense mutations in the glutamate dehydrogenase gene in the congenital hyperinsulinism-hyperammonemia syndrome. ( 10636977 )
2000
24
Hyperinsulinism-hyperammonemia syndrome caused by mutant glutamate dehydrogenase accompanied by novel enzyme kinetics. ( 10453735 )
1999

Variations for Hyperinsulinism-Hyperammonemia Syndrome

UniProtKB/Swiss-Prot genetic disease variations for Hyperinsulinism-Hyperammonemia Syndrome:

71 (show all 13)
id Symbol AA change Variation ID SNP ID
1 GLUD1 p.Ser498Leu VAR_008666 rs121909731
2 GLUD1 p.Gly499Asp VAR_008667 rs121909734
3 GLUD1 p.Gly499Ser VAR_008668 rs121909733
4 GLUD1 p.Ser501Pro VAR_008669 rs121909732
5 GLUD1 p.His507Tyr VAR_008670 rs121909730
6 GLUD1 p.Arg318Lys VAR_009270 rs121909736
7 GLUD1 p.Glu349Ala VAR_009271 rs121909735
8 GLUD1 p.Ser270Cys VAR_016760
9 GLUD1 p.Arg274Cys VAR_016761 rs56275071
10 GLUD1 p.Arg318Thr VAR_016762
11 GLUD1 p.Tyr319Cys VAR_016763
12 GLUD1 p.Arg322Cys VAR_016764
13 GLUD1 p.Arg322His VAR_016765 rs121909737

ClinVar genetic disease variations for Hyperinsulinism-Hyperammonemia Syndrome:

6 (show all 11)
id Gene Variation Type Significance SNP ID Assembly Location
1 GLUD1 NM_005271.4(GLUD1): c.1519C> T (p.His507Tyr) single nucleotide variant Pathogenic rs121909730 GRCh37 Chromosome 10, 88813137: 88813137
2 GLUD1 NM_005271.4(GLUD1): c.1493C> T (p.Ser498Leu) single nucleotide variant Pathogenic rs121909731 GRCh37 Chromosome 10, 88817449: 88817449
3 GLUD1 NM_005271.4(GLUD1): c.1501T> C (p.Ser501Pro) single nucleotide variant Pathogenic rs121909732 GRCh37 Chromosome 10, 88813155: 88813155
4 GLUD1 NM_005271.4(GLUD1): c.1495G> A (p.Gly499Ser) single nucleotide variant Pathogenic rs121909733 GRCh37 Chromosome 10, 88813161: 88813161
5 GLUD1 NM_005271.4(GLUD1): c.1496G> A (p.Gly499Asp) single nucleotide variant Pathogenic rs121909734 GRCh37 Chromosome 10, 88813160: 88813160
6 GLUD1 NM_005271.4(GLUD1): c.1046A> C (p.Glu349Ala) single nucleotide variant Pathogenic rs121909735 GRCh37 Chromosome 10, 88820685: 88820685
7 GLUD1 NM_005271.4(GLUD1): c.953G> A (p.Arg318Lys) single nucleotide variant Pathogenic rs121909736 GRCh37 Chromosome 10, 88820778: 88820778
8 GLUD1 NM_005271.4(GLUD1): c.820C> T (p.Arg274Cys) single nucleotide variant Pathogenic rs56275071 GRCh37 Chromosome 10, 88822514: 88822514
9 GLUD1 NM_005271.4(GLUD1): c.965G> A (p.Arg322His) single nucleotide variant Pathogenic rs121909737 GRCh37 Chromosome 10, 88820766: 88820766
10 GLUD1 NM_005271.4(GLUD1): c.1498G> A (p.Ala500Thr) single nucleotide variant Likely pathogenic rs797045597 GRCh38 Chromosome 10, 87053401: 87053401
11 GLUD1 NM_005271.4(GLUD1): c.1496G> T (p.Gly499Val) single nucleotide variant Pathogenic rs121909734 GRCh38 Chromosome 10, 87053403: 87053403

Expression for Hyperinsulinism-Hyperammonemia Syndrome

Search GEO for disease gene expression data for Hyperinsulinism-Hyperammonemia Syndrome.

Pathways for Hyperinsulinism-Hyperammonemia Syndrome

GO Terms for Hyperinsulinism-Hyperammonemia Syndrome

Biological processes related to Hyperinsulinism-Hyperammonemia Syndrome according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 cellular amino acid biosynthetic process GO:0008652 9.16 GLUD1 GLUL
2 positive regulation of insulin secretion GO:0032024 8.96 GLUD1 GLUL
3 glutamate catabolic process GO:0006538 8.62 GLUD1 GLUL

Molecular functions related to Hyperinsulinism-Hyperammonemia Syndrome according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 identical protein binding GO:0042802 8.8 GLUD1 GLUL INS

Sources for Hyperinsulinism-Hyperammonemia Syndrome

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9 Cosmic
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70 UMLS via Orphanet
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