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

• 2-Hydroxyglutaric Acidemia

What is 2-Hydroxyglutaric Aciduria? (Definition/Background information)

• 2-Hydroxyglutaric Aciduria is a condition that causes progressive damage to the brain. The major types of this disorder are the following:
  • D-2-Hydroxyglutaric Aciduria (D-2-HGA)
  • L-2-Hydroxyglutaric Aciduria (L-2-HGA)
  • Combined D,L-2-Hydroxyglutaric Aciduria (D,L-2-HGA)
• The main features of D-2-HGA vary within the different types; but, in general, may include delayed development, seizures, weak muscle tone (hypotonia), and abnormalities in the largest part of the brain (the cerebrum)
• The cerebrum controls many important functions such as muscle movement, speech, vision, thinking, emotion, and memory
• The different types and subtypes of 2-Hydroxyglutaric Aciduria are caused by different gene mutations and are inherited in an autosomal recessive pattern, except for the D-2-HGA subtype, known as type II D-2-HGA, which is inherited in an autosomal dominant pattern
• There is no cure yet. The treatment depends on the symptoms and management mainly involves control of seizures when they are present

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

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

• 2-Hydroxyglutaric Aciduria is a rare congenital disorder, with fewer than 300 cases reported in the medical literature. The presentation of symptoms may occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

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

• A positive family history may be an important risk factor, since 2-Hydroxyglutaric Aciduria is an inherited condition
• Currently, no other risk factors have been clearly identified for the condition

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 2-Hydroxyglutaric Aciduria? (Etiology)

The three types of 2-Hydroxyglutaric Aciduria are caused by mutation(s) in different genes.

• Mutations in the D2HGDH and IDH2 genes are reported to cause D-2-Hydroxyglutaric Aciduria. The D2HGDH gene mutations are inherited in an autosomal recessive manner, whereas the IDH2 gene mutations are inherited in an autosomal dominant manner
• Mutations in the L2HGDH gene (14q22.1) gene have been implicated in L-2-Hydroxyglutaric Aciduria. L2HGDH gene mutations are inherited in an autosomal recessive manner
• The Combined D,L-2-Hydroxyglutaric Aciduria is caused by mutation(s) in the SLC25A1 gene, which is inherited in an autosomal recessive manner

Autosomal dominant: 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.

Autosomal recessive: 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).

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

The signs and symptoms of 2-Hydroxyglutaric Aciduria may include:

Very frequently present symptoms in 80-99% of the cases: 

• Encephalitis
• Intellectual disability, progressive and/or severe
• Seizures

Frequently present symptoms in 30-79% of the cases:

• Abnormality of extrapyramidal motor function
• Aplasia/hypoplasia of the cerebellum
• Behavioral abnormality
• Macrocephaly
• Muscular hypotonia
• Neoplasm (tumor) of the nervous system
• Spastic tetraparesis

Occasionally present symptoms in 5-29% of the cases: Dysphasia

In addition to the above, the following signs and symptoms may be present in some affected individuals:

• Abnormal pyramidal signs
• Cerebellar atrophy
• Corpus callosum atrophy
• Developmental regression
• Gliosis
• Global brain atrophy
• Hearing impairment
• Leukoencephalopathy
• Morphological abnormality of the pyramidal tract
• Nystagmus
• Optic atrophy
• Severe demyelination of the white matter
• Strabismus

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

How is 2-Hydroxyglutaric Aciduria Diagnosed?

2-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
• Imaging studies
• Biopsy studies, if necessary

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 2-Hydroxyglutaric Aciduria?

The complications of 2-Hydroxyglutaric Aciduria may include:

• Delay in achieving developmental milestones
• Problems with movement due to low muscle tone and lack of coordination
• Risk of falls and injury due to seizures
• Intellectual disability

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

How is 2-Hydroxyglutaric Aciduria Treated?

• There is still no established treatment for 2-Hydroxyglutaric Aciduria
• However, for the D,L-2HGA type (combined type), some researches had used either malate or citrate:
  • During malate treatment, urinary malate concentration increased, but beyond that, no effects were observed
  • In contrast, treatment with citrate led to some good results, but more studies are needed to confirm the effectiveness of this treatment

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

There is no cure for 2-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 2-Hydroxyglutaric Aciduria be Prevented?

2-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 2-Hydroxyglutaric Aciduria? (Outcomes/Resolutions)

• The prognosis of 2-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
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for 2-Hydroxyglutaric Aciduria:

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

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