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Hyperinsulinism-hyperammonemia syndrome(HHF6)

MedGen UID:
376153
Concept ID:
C1847555
Disease or Syndrome
Synonyms: GLUD1-Related Hyperinsulinism; HA/HI syndrome; HHF6; Hyperinsulinemic hypoglycemia familial 6
SNOMED CT: Hyperinsulinism and hyperammonemia syndrome (718106009); Glutamate dehydrogenase 1 related hyperinsulinism and hyperammonemia syndrome (718106009); GLUD1 related hyperinsulinism and hyperammonemia syndrome (718106009)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): GLUD1 (10q23.2)
 
Monarch Initiative: MONDO:0011717
OMIM®: 606762
Orphanet: ORPHA35878

Definition

Congenital hyperinsulinism is a condition that causes individuals to have abnormally high levels of insulin. Insulin is a hormone that helps control levels of blood glucose, also called blood sugar. People with this condition have frequent episodes of low blood glucose (hypoglycemia). In infants and young children, these episodes are characterized by a lack of energy (lethargy), irritability, or difficulty feeding. Repeated episodes of low blood glucose increase the risk for serious complications such as breathing difficulties, seizures, intellectual disability, vision loss, brain damage, and coma.

The severity of congenital hyperinsulinism varies widely among affected individuals, even among members of the same family. About 60 percent of infants with this condition experience a hypoglycemic episode within the first month of life. Other affected children develop hypoglycemia by early childhood. Unlike typical episodes of hypoglycemia, which occur most often after periods without food (fasting) or after exercising, episodes of hypoglycemia in people with congenital hyperinsulinism can also occur after eating. [from MedlinePlus Genetics]

Clinical features

From HPO
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Abnormality of the pancreatic islet cells
MedGen UID:
870594
Concept ID:
C4025043
Anatomical Abnormality
An abnormality of the islet of Langerhans, i.e., of the regions of the pancreas that contain its endocrine cells. These are the alpha cells, which produce glucagon, the beta cells, which produce insulin and amylin, the delta cells, which produce somatostatin, the PP cells, which produce pancreatic polypeptide, and the epsilon cells, which produce ghrelin.
Hypoglycemic coma
MedGen UID:
5710
Concept ID:
C0020617
Disease or Syndrome
Coma induced by low blood sugar.
Hypoglycemic seizures
MedGen UID:
164079
Concept ID:
C0877056
Disease or Syndrome
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Asymptomatic hyperammonemia
MedGen UID:
867194
Concept ID:
C4021552
Finding
An increased concentration of ammonia in the blood not associated with symptoms such as encephalopathy.
Hyperinsulinemic hypoglycemia
MedGen UID:
351247
Concept ID:
C1864903
Disease or Syndrome
An increased concentration of insulin combined with a decreased concentration of glucose in the blood.

Term Hierarchy

Follow this link to review classifications for Hyperinsulinism-hyperammonemia syndrome in Orphanet.

Recent clinical studies

Etiology

Sarajlija A, Milenkovic T, Djordjevic M, Mitrovic K, Todorovic S, Kecman B, Hussain K
J Clin Res Pediatr Endocrinol 2016 Jun 5;8(2):228-31. Epub 2015 Dec 18 doi: 10.4274/jcrpe.2436. PMID: 26759084Free PMC Article
Stanley CA
Neurochem Int 2011 Sep;59(4):465-72. Epub 2010 Dec 2 doi: 10.1016/j.neuint.2010.11.017. PMID: 21130127Free PMC Article
de Lonlay P, Touati G, Robert JJ, Saudubray JM
Semin Neonatol 2002 Feb;7(1):95-100. doi: 10.1053/siny.2001.0090. PMID: 12069542
Kelly A, Ng D, Ferry RJ Jr, Grimberg A, Koo-McCoy S, Thornton PS, Stanley CA
J Clin Endocrinol Metab 2001 Aug;86(8):3724-8. doi: 10.1210/jcem.86.8.7755. PMID: 11502802Free PMC Article
Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, Perlman K, Rich BH, Zammarchi E, Poncz M
N Engl J Med 1998 May 7;338(19):1352-7. doi: 10.1056/NEJM199805073381904. PMID: 9571255

Diagnosis

Safran A, Proskorovski-Ohayon R, Eskin-Schwartz M, Yogev Y, Drabkin M, Eremenko E, Aharoni S, Freund O, Jean MM, Agam N, Hadar N, Loewenthal N, Staretz-Chacham O, Birk OS
J Inherit Metab Dis 2023 Jul;46(4):744-755. Epub 2023 Feb 9 doi: 10.1002/jimd.12594. PMID: 36695547
Aka S, Alanay Y, Boodhansingh KE, Stanley CA, Semiz S
Turk J Pediatr 2016;58(5):541-544. doi: 10.24953/turkjped.2016.05.014. PMID: 28621098
Palladino AA, Stanley CA
Rev Endocr Metab Disord 2010 Sep;11(3):171-8. doi: 10.1007/s11154-010-9146-0. PMID: 20936362
de Lonlay P, Touati G, Robert JJ, Saudubray JM
Semin Neonatol 2002 Feb;7(1):95-100. doi: 10.1053/siny.2001.0090. PMID: 12069542
Hsu BY, Kelly A, Thornton PS, Greenberg CR, Dilling LA, Stanley CA
J Pediatr 2001 Mar;138(3):383-9. doi: 10.1067/mpd.2001.111818. PMID: 11241047

Therapy

De Los Santos-La Torre MA, Del Águila-Villar CM, Lu-de Lama LR, Nuñez-Almache O, Chávez-Tejada EM, Espinoza-Robles OA, Pinto-Ibárcena PM, Calagua-Quispe MR, Azabache-Tafur PM, Tucto-Manchego RM
J Pediatr Endocrinol Metab 2023 Feb 23;36(2):207-211. Epub 2022 Dec 8 doi: 10.1515/jpem-2022-0490. PMID: 36476334
Bera S, Lamba S, Rashid M, Sharma AK, Medvinsky AB, Acquisti C, Chakraborty A, Li BL
Integr Biol (Camb) 2016 Nov 7;8(11):1126-1132. doi: 10.1039/c6ib00158k. PMID: 27747338
de las Heras J, Garin I, de Nanclares GP, Aguayo A, Rica I, Castaño L, Vela A
J Pediatr Endocrinol Metab 2010 Aug;23(8):827-30. doi: 10.1515/jpem.2010.132. PMID: 21073125
de Lonlay P, Touati G, Robert JJ, Saudubray JM
Semin Neonatol 2002 Feb;7(1):95-100. doi: 10.1053/siny.2001.0090. PMID: 12069542
Hsu BY, Kelly A, Thornton PS, Greenberg CR, Dilling LA, Stanley CA
J Pediatr 2001 Mar;138(3):383-9. doi: 10.1067/mpd.2001.111818. PMID: 11241047

Prognosis

Ninković D, Sarnavka V, Bašnec A, Ćuk M, Ramadža DP, Fumić K, Kušec V, Santer R, Barić I
J Pediatr Endocrinol Metab 2016 Sep 1;29(9):1083-8. doi: 10.1515/jpem-2016-0086. PMID: 27383869
Odom J, Gieron-Korthals M, Shulman D, Newkirk P, Prijoles E, Sanchez-Valle A
J Med Case Rep 2016 Feb 2;10:25. doi: 10.1186/s13256-016-0811-0. PMID: 26839063Free PMC Article
Tran C, Konstantopoulou V, Mecjia M, Perlman K, Mercimek-Mahmutoglu S, Kronick JB
J Pediatr Endocrinol Metab 2015 Jul;28(7-8):873-6. doi: 10.1515/jpem-2014-0441. PMID: 25781533
de Lonlay P, Touati G, Robert JJ, Saudubray JM
Semin Neonatol 2002 Feb;7(1):95-100. doi: 10.1053/siny.2001.0090. PMID: 12069542
Santer R, Kinner M, Passarge M, Superti-Furga A, Mayatepek E, Meissner T, Schneppenheim R, Schaub J
Hum Genet 2001 Jan;108(1):66-71. doi: 10.1007/s004390000432. PMID: 11214910

Clinical prediction guides

De Los Santos-La Torre MA, Del Águila-Villar CM, Lu-de Lama LR, Nuñez-Almache O, Chávez-Tejada EM, Espinoza-Robles OA, Pinto-Ibárcena PM, Calagua-Quispe MR, Azabache-Tafur PM, Tucto-Manchego RM
J Pediatr Endocrinol Metab 2023 Feb 23;36(2):207-211. Epub 2022 Dec 8 doi: 10.1515/jpem-2022-0490. PMID: 36476334
Rosenfeld E, Nanga RPR, Lucas A, Revell AY, Thomas A, Thomas NH, Roalf DR, Shinohara RT, Reddy R, Davis KA, De León DD
Orphanet J Rare Dis 2022 Jun 25;17(1):248. doi: 10.1186/s13023-022-02398-3. PMID: 35752848Free PMC Article
Bera S, Lamba S, Rashid M, Sharma AK, Medvinsky AB, Acquisti C, Chakraborty A, Li BL
Integr Biol (Camb) 2016 Nov 7;8(11):1126-1132. doi: 10.1039/c6ib00158k. PMID: 27747338
Plaitakis A, Zaganas I, Spanaki C
J Neurosci Res 2013 Aug;91(8):1007-17. Epub 2013 Mar 6 doi: 10.1002/jnr.23176. PMID: 23463419
Santer R, Kinner M, Passarge M, Superti-Furga A, Mayatepek E, Meissner T, Schneppenheim R, Schaub J
Hum Genet 2001 Jan;108(1):66-71. doi: 10.1007/s004390000432. PMID: 11214910

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