L-2 Hydroxyglutaric Aciduria (L2HGA)
https://www.mdpi.com/2073-4425/17/7/735
L-2-hydroxyglutaric aciduria (L2HGA) is a rare inherited neurometabolic disorder that primarily affects the brain. It is caused by changes in the L2HGDH gene, which provides instructions for an enzyme involved in breaking down L-2-hydroxyglutarate. When this enzyme is not working correctly, L-2-hydroxyglutaric acid accumulates in the body and can damage brain cells over time. People with L2HGA can develop developmental delay, intellectual disability, low muscle tone (hypotonia), seizures, movement difficulties and problems with balance and coordination. This study investigated a patient with a complex combination of neurological and muscle-related symptoms. Clinical assessments included brain magnetic resonance imaging (MRI), biochemical testing and electromyography (evaluates health and function of muscles and nerves), alongside whole-exome sequencing (WES) to search for disease-causing genetic variants. The patient had markedly increased levels of 2-hydroxyglutaric acid in urine, supporting a diagnosis of L2HGA. Genetic analysis identified a previously unreported homozygous L2HGDH variant (c.589_590insGGC, p.Q197insG), which was classified as likely pathogenic and provided a genetic explanation for the patient’s neurometabolic features. Likely pathogenic means there’s strong evidence the variant causes a genetic condition, but not sufficient evidence for it to be classified as pathogenic. The researchers also identified a heterozygous variant (two different versions of a gene) in RYR1, a gene associated with inherited muscle disorders. However, this variant was classified as a variant of uncertain significance, meaning there is currently insufficient evidence to determine whether it contributed to the patient’s symptoms. It was also noted that it was inherited from the patient’s mildly affected father. Overall, this case expands the known genetic spectrum of L2HGA and demonstrates the value of combining biochemical, clinical and genomic testing when diagnosing rare and complex neurological disorders. These findings may also support improved genetic counselling and future research into L2HGA.