L-2-hydroxyglutaric aciduria

L-2-hydroxyglutaric aciduria is a primarily neurological condition characterized by the accumulation of L-2-hydroxyglutaric acid due to pathogenic variants in the L2HGDH gene. Affected individuals typically present in childhood with psychomotor retardation, cerebellar ataxia, seizures, and, in some cases, macrocephaly. This autosomal recessive disorder is very rare, affecting fewer than 1 in 1,000,000 people. The condition involves both cognitive and motor challenges, underscoring the impact on neurological development.

Individuals with L-2-hydroxyglutaric aciduria present with a constellation of neurological features. Prominent signs include ataxia, seizures, and intellectual disability, accompanied by leukoencephalopathy evident on brain imaging. The clinical picture also comprises psychomotor retardation and may include macrocephaly in some patients. Not all individuals experience all features, and severity varies considerably, with cognitive challenges and other neurological symptoms impacting learning and daily functioning.

L-2-hydroxyglutaric aciduria is caused by pathogenic variants in the L2HGDH gene, which encodes an enzyme involved in the metabolism of L-2-hydroxyglutaric acid. Disruption of this enzyme’s function leads to the accumulation of the metabolite, particularly affecting brain tissue. The condition is inherited in an autosomal recessive pattern, meaning that an affected individual inherits two defective copies of the gene, one from each parent. This disorder is more common when parents share a common ancestor, and genetic counseling is recommended to help families understand the implications for future family planning.

Currently, management of L-2-hydroxyglutaric aciduria focuses on supportive care and symptom management, as there are no approved treatments specifically targeting this condition. Treatment is tailored to the individual's needs and typically involves a multidisciplinary team, including specialists in neurology, physical therapy, and educational support. Interventions may include therapies to improve motor function, strategies to manage seizures, and supportive educational programs to address cognitive challenges. Patients are encouraged to discuss treatment options with their healthcare team and to consider genetic counseling as part of their care plan.

The prognosis for individuals with L-2-hydroxyglutaric aciduria varies widely, with outcomes depending on the severity of neurological symptoms and access to supportive care. This lifelong condition is marked by significant neurodevelopmental challenges that may remain stable or evolve over time. With current standards of care, many individuals benefit from interventions that improve quality of life, although intellectual and neurological issues persist. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with genetic counselors and specialized healthcare teams to navigate treatment options and long-term planning.

Clinical trials are underway exploring new treatment approaches for L-2-hydroxyglutaric aciduria. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.