This poster (#0302) will be presented at the ACMG Annual Clinical Genetics Meeting by Amy Knight Johnson, our genetic counselor, Friday March 22: 10:30am-11:30am.  Stop by and learn more

L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder with autosomal recessive inheritance, associated with accumulation of L-2-hydroxyglutaric acid (L-2-HG) in urine and mutations in the L2HGDH gene. We present a case of a 14 year old male with a history of developmental delays and 2-hydroxyglutaric aciduria.

The major clinical features of L2HGA are developmental delay, cerebellar ataxia and epilepsy. Approximately half of affected individuals also have macrocephaly, extrapyramidal symptoms, and spasticity. The average age of onset is 2 years of age, and the condition is typically slowly progressive, with some patients showing developmental regression. Affected patients have a characteristic pattern of brain abnormalities, which include abnormalities of the subcortical cerebral white matter dentate nucleus, globus pallidus, putamen and caudate nucleus.

At the time of evaluation at age 13 years, the patient was performing at a 2nd grade level, and showed continued developmental progression, with no periods of regression and no history of seizures. He was first noted to have developmental delays at age 2 years. On examination he had a normal head circumference and no notable dysmorphic features. The patient showed a mildly ataxic gait, with no evidence of extrapyramidal movement abnormalities, spasticity, or other neurological abnormalities. MRI imaging of the patient’s brain was performed at age 11 and 12 years, and revealed non-progressive extensive subcortical white matter signal abnormality, with involvement of the dentate nucleus, and faint signal abnormality of the globus pallidus.

Urine organic acid studies performed at age 11 and 13 years revealed significant and persistent elevation of 2-hydroxyglutaric acid. It is not possible to differentiate between the enantiomeric D- and L- forms of 2-hydroxyglutaric acid (2-HG) by conventional organic acid analysis. Elevated D-2-hydroxyglutaric acid is associated with D-2-hydroxyglutaric aciduria (D2HGA), which shares some key clinical features with L2HGA, but can be clinically differentiated to a certain degree by neuroimaging findings and severity of symptoms.

This case illustrates the importance of urine organic acid analysis in patients with mild developmental delay as their major or only clinical finding. The patient in this case lacked many of the clinical features typically associated with L2HGA and had a mild clinical course compared to the majority of reported cases, therefore based on clinical findings alone suspicion for this disorder was low. As disease onset and progression in L2HGA is insidious, mildly affected patients can remain undiagnosed until adolescence or adulthood. There have been case reports of individuals affected by L2HGA showing clinical improvement after treatment with FAD or riboflavin, therefore confirmation of a diagnosis of L2HGA is of particular importance as it may affect management.