2-hydroxyglutaric aciduria
2-hydroxyglutaric aciduria is a rare genetic metabolic disorder that causes progressive brain damage, resulting in developmental delays, seizures, and motor coordination issues.
Overview & Types
2-hydroxyglutaric aciduria is a condition characterized by progressive damage to the brain. The disorder is classified into three major types based on the specific chemical compounds that accumulate and the genetic causes:
- D-2-hydroxyglutaric aciduria (D-2-HGA): Divided into Type I and Type II. Type II typically begins earlier, causes more severe health problems, and can be associated with a weakened and enlarged heart (cardiomyopathy), which is not usually seen in Type I.
- L-2-hydroxyglutaric aciduria (L-2-HGA): Primarily affects the cerebellum, the region of the brain responsible for coordinating movement.
- Combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA): A severe form that causes profound brain abnormalities starting in early infancy.
Symptoms
The symptoms of 2-hydroxyglutaric aciduria vary depending on the specific type of the disorder:
D-2-HGA (Type I and Type II)
- Delayed development
- Seizures
- Weak muscle tone (hypotonia)
- Abnormalities in the cerebrum, which controls muscle movement, speech, vision, thinking, emotion, and memory
- Cardiomyopathy (specifically in Type II)
L-2-HGA
- Problems with balance and muscle coordination (ataxia)
- Delayed development
- Seizures
- Speech difficulties
- An unusually large head (macrocephaly)
- Progressive worsening of symptoms, usually leading to severe disability by early adulthood
Combined D,L-2-HGA
- Severe brain abnormalities apparent in early infancy
- Severe seizures
- Weak muscle tone (hypotonia)
- Breathing and feeding problems
- Shortened lifespan, with affected infants usually surviving only into infancy or early childhood
Frequency
2-hydroxyglutaric aciduria is a rare disorder. Fewer than 150 cases of D-2-HGA and fewer than 150 cases of L-2-HGA have been reported worldwide. Combined D,L-2-HGA is even rarer, with only about a dozen reported cases.
Causes
The different types of 2-hydroxyglutaric aciduria are caused by mutations in several genes that affect mitochondrial function:
- D-2-HGA Type I is caused by mutations in the D2HGDH gene. This gene provides instructions for an enzyme that breaks down D-2-hydroxyglutarate. A shortage of this enzyme leads to a toxic buildup of the compound, damaging brain cells.
- D-2-HGA Type II is caused by mutations in the IDH2 gene. This mutation causes the mitochondrial enzyme to take on an abnormal function, producing excess, toxic D-2-hydroxyglutarate that damages brain cells.
- L-2-HGA is caused by mutations in the L2HGDH gene, which leads to a shortage of the enzyme that breaks down L-2-hydroxyglutarate, resulting in toxic accumulation in the brain.
- Combined D,L-2-HGA is caused by mutations in the SLC25A1 gene. This gene provides instructions for a protein that transports molecules like citrate in and out of mitochondria. When this transport is disrupted, both D-2-hydroxyglutarate and L-2-hydroxyglutarate build up, damaging brain cells. An imbalance of citrate is also thought to contribute to the severe symptoms.
Inheritance
The inheritance pattern depends on the specific type of the condition:
- D-2-HGA Type I, L-2-HGA, and combined D,L-2-HGA are inherited in an autosomal recessive pattern. This means both copies of the gene in each cell must have mutations for the condition to develop. The parents of an affected individual typically carry one copy of the mutated gene but do not show symptoms.
- D-2-HGA Type II is considered an autosomal dominant disorder because a mutation in only one copy of the IDH2 gene is sufficient to cause the condition. It typically results from a new mutation and occurs in individuals with no family history of the disorder.
Other Names for This Condition
- 2-HGA