The 2-hydroglutaric aciduria is characterized by the progression of damage to the brain. The various types of this condition are known as D-2 hydroxglutaric aciduria (D-2-HGA), L-2 hydroxyglutaric aciduria (L-2-HGA) and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA). The subtypes of D-2-HGA consist of type 1 and type 2 which are distinguished by their genetic cause and their inheritance pattern. This is a rare disorder with a report suggesting the prevalence of D-2-HGA and L-2-HGA affecting less than 150 affected individuals globally. The prognosis of these cases is based on the severity of the clinical conditions and the progression of the disease.
Causes
The type 2, D-2-HGA is assumed to be inherited in an autosomal dominant pattern meaning one copy of the defective gene is sufficient to cause this condition. The type 2 can also develop in individuals as a new genetic mutation with no history of its prevalence among the family.
The mutation in the gene IDH2 causes this type of disorder. This gene delivers the instruction for producing an enzyme in the mitochondria. As the result of the genetic mutation, this enzyme is impaired and carries an abnormal function resulting in the production of the toxic compound D-2-hydroxglutarate. This toxic compound creates damage to the brain cells causing the symptom characteristic of this disorder. Among the individuals affected with this type of condition, the association with cardiomyopathy remains unclear.
Symptoms
The primary symptoms include the delayed development, seizures and hypotonia (weak muscle). It also affects the part of the brain known as cerebrum that controls several functions such as speech, vision, memory and thinking. The type 2, D-2-HGA may initially begin earlier than type 1 and is associated with severe health problems. It may also include symptoms such as weakened and enlarged heart (cardiomyopathy).
Diagnosis
The prenatal diagnosis of this condition is possible with the measurement of D-2 Hydroxyglutaric acid present in the amniotic fluid of the fetus. This can be done after 16 weeks of pregnancy.
The diagnosis of D-2 HGA indicates the elevated level of D-2 hydroxyglutaric acid in the urine and hence can be diagnosed by a urinary organic acid screening. Other diagnostic methods can include the MRI findings such as delayed cerebral maturation and white-matter abnormalities in the severe cases.
In order to identify the type of HGA condition, the gas chromatography-mass spectrometry can be done to determine the type of metabolite problems. The genetic testing can also identify the gene responsible for the cause of this condition.
Treatment
There is no cure for D-2 hydroxyglutaric aciduria 2 and the treatment is usually focused on the management of the symptoms that are present. The seizures can be treated with medications when it occurs and the therapeutic strategy involves the inhibition with IDH2 mutant specific drugs that can cause the reduction in the 2HG production. However, decreasing the D-2HG in the body fluids is a consideration for future treatment options.
References
https://www.ncbi.nlm.nih.gov/gtr/conditions/C3150909/
http://pfond.cmmt.ubc.ca/d2hydroxyglutaricaciduria/about/treatment/
http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=79315