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Disease Profile

Hyperinsulinism-hyperammonemia syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Infancy

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ICD-10

E72.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Hyperinsulinism hyperammonemia syndrome; HA/HI syndrome; Hyperinsulinemic hypoglycemia familial 6

Categories

Congenital and Genetic Diseases; Endocrine Diseases; Metabolic disorders

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
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Orpha Number: 35878

Definition
Hyperinsulinism-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.

Epidemiology
Prevalence is estimated at 1 in 200,000.

Clinical description
Clinical 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.

Etiology
Glutamate 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 betacells. 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 counseling
Most activating mutations of the gene GLUD1 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.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Asymptomatic hyperammonemia
0008162
Reactive hypoglycemia
Low blood sugar after a meal
0012051
30%-79% of people have these symptoms
Attention deficit hyperactivity disorder
Attention deficit
Attention deficit disorder
Attention deficit-hyperactivity disorder
Attention deficits
Childhood attention deficit/hyperactivity disorder

[ more ]

0007018
EEG with generalized epileptiform discharges
0011198
Fasting hyperinsulinemia
High blood insulin levels while fasting
0008283
Generalized non-motor (absence) seizure
Brief seizures with staring spells
0002121
Global developmental delay
0001263
Hyperinsulinemic hypoglycemia
0000825
Increased urine alpha-ketoglutarate concentration
0012402
Intellectual disability, moderate
IQ between 34 and 49
0002342
Specific learning disability
0001328
Percent of people who have these symptoms is not available through HPO
Autosomal dominant inheritance
0000006
Hypoglycemic coma
Coma caused by low blood sugar
0001325
Hypoglycemic seizures
0002173
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249

Diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

In-Depth Information

  • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Hyperinsulinism-hyperammonemia syndrome. Click on the link to view a sample search on this topic.