SNP Shot: Genomic Insights

2-hydroxyglutaric aciduria refers to a group of conditions that cause progressive brain damage. These disorders are primarily classified as D-2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA).

D-2-HGA is characterized by developmental delays, seizures, low muscle tone (hypotonia), and abnormalities of the cerebrum. The cerebrum is the largest part of the brain and is responsible for functions like movement, speech, vision, thinking, emotions, and memory. Two subtypes of D-2-HGA exist: type I and type II. They are differentiated by their underlying genetic causes and inheritance patterns, and also display variations in symptoms. Type II usually has an earlier onset and often results in more significant health problems than type I. Additionally, type II may involve cardiomyopathy (weakened and enlarged heart), a characteristic generally not seen in type I.

L-2-HGA primarily affects the cerebellum, a brain region critical for coordinating movement. Consequently, individuals with L-2-HGA commonly experience issues with balance and coordination (ataxia). Other symptoms associated with L-2-HGA can include developmental delays, seizures, speech impediments, and an abnormally large head size (macrocephaly). The signs and symptoms typically emerge during infancy or early childhood. This condition progresses over time, typically resulting in severe disability by early adulthood.

Combined D,L-2-HGA leads to significant brain abnormalities evident in early infancy. Affected infants display severe seizures, low muscle tone (hypotonia), and difficulties with breathing and feeding. Their survival is often limited to infancy or early childhood.

Inheritance:

D-2-HGA type I, L-2-HGA, and combined D,L-2-HGA are all inherited in an autosomal recessive manner. This means that both copies of the relevant gene in each cell must have mutations for the condition to develop. Individuals with an autosomal recessive condition inherit one mutated gene copy from each parent, who are typically carriers and do not exhibit symptoms of the disorder. D-2-HGA type II is considered an autosomal dominant disorder. In this case, only one copy of the altered gene in each cell is enough to cause the condition. It usually stems from a new mutation in the IDH2 gene, occurring in individuals without a family history of the disorder.