What are the other Names for this Condition? (Also known as/Synonyms)

• D2HA (D-2-Hydroxyglutaric Acidemia)
• D-2-HGA (D-2-Hydroxyglutaric Acidemia)
• D-2-Hydroxyglutaric Acidemia (D-2-HGA)

What is D-2-Alpha Hydroxyglutaric Aciduria? (Definition/Background Information)

• D-2-Alpha Hydroxyglutaric Aciduria (or D-2-HGA) is an inherited metabolic condition that is associated with progressive brain damage
• Signs and symptoms of this condition include developmental delay, seizures, hypotonia, and abnormalities in the largest part of the brain (the cerebrum), which controls many important functions such as muscle movement, speech, vision, thinking, emotion, and memory
• D-2-Alpha Hydroxyglutaric Aciduria is caused by changes (mutations) in the D2HGDH gene and is inherited in an autosomal recessive manner
• Treatment is focused on alleviating the signs and symptoms of the condition, such as medications to control seizures

(Source: D-2-Alpha Hydroxyglutaric Aciduria; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets D-2-Alpha Hydroxyglutaric Aciduria? (Age and Sex Distribution)

• D-2-Alpha Hydroxyglutaric Aciduria is a rare inherited disorder, with less than 100 cases being reported in the medical literature
• The onset of symptoms may occur at birth, in infancy, or during childhood
• The condition can affect both genders
• Worldwide, individuals of all races and ethnicities may be affected

What are the Risk Factors for D-2-Alpha Hydroxyglutaric Aciduria? (Predisposing Factors)

• A positive family history may be an important risk factor, since D-2-Alpha Hydroxyglutaric Aciduria can be inherited
• A child of consanguineous parents may bear an increased risk of being born with this disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of D-2-Alpha Hydroxyglutaric Aciduria? (Etiology)

• D-2-Alpha Hydroxyglutaric Aciduria is caused by mutation(s) in the D2HGDH gene in approximately 50% of affected individuals
  • This gene codes for the mitochondrial D-2-hydroxyglutarate dehydrogenase enzyme have been identified in approximately 50% of patients with D-2-Alpha Hydroxyglutaric Aciduria
  • The causative D2HGDH gene mutations are inherited in a n autosomal recessive manner
• In addition, mutation(s) in the IDH2 gene have also been reported to cause D-2-Alpha Hydroxyglutaric Aciduria 
  • The IDH2 gene codes for the mitochondrial enzyme isocitrate dehydrogenase
  • IDH2 gene mutations that cause this condition are inherited in an autosomal dominant manner

Autosomal recessive inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

Autosomal dominant inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of D-2-Alpha Hydroxyglutaric Aciduria?

The signs and symptoms of D-2-Alpha Hydroxyglutaric Aciduria may vary in type and severity among affected individuals, and include:

• Neonatal or infantile onset epileptic encephalopathy
• Low muscle tone
• Involuntary movements
• Cerebral visual failure
• Developmental delay 
• Seizures
• Cardiomyopathy 
• Facial dysmorphic features 
  • A flat face
  • Broad nasal bridge
  • External ear anomalies

In general, the signs and symptoms associated with causative IDH2 gene mutation(s) are more severe when compared to D2HDGH mutation(s).

(Source: D-2-Alpha Hydroxyglutaric Aciduria; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

How is D-2-Alpha Hydroxyglutaric Aciduria Diagnosed?

D-2-Alpha Hydroxyglutaric Aciduria is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests, including checking for excess levels of D-2-hydroxyglutaric acid in urine
• Imaging studies
• Biopsy studies, if necessary
• Prenatal measurement of D-2-hydroxyglutaric acid in amniotic fluid
• Molecular genetic testing to check for or confirm causative gene mutation(s)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of D-2-Alpha Hydroxyglutaric Aciduria?

The complications of D-2-Alpha Hydroxyglutaric Aciduria may include:

• Blindness
• Abnormalities in heart function, which may lead to heart attack or cardiac arrest

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is D-2-Alpha Hydroxyglutaric Aciduria Treated?

There is no cure for D-2-Alpha Hydroxyglutaric Aciduria, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops.

How can D-2-Alpha Hydroxyglutaric Aciduria be Prevented?

Currently, D-2-Alpha Hydroxyglutaric Aciduria may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of D-2-Alpha Hydroxyglutaric Aciduria? (Outcomes/Resolutions)

• The prognosis of D-2-Alpha Hydroxyglutaric Aciduria is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• The prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for D-2-Alpha Hydroxyglutaric Aciduria:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/