L-2-Hydroxyglutaric Aciduria Type I via the L2HGDH Gene

L-2-Hydroxyglutaric Aciduria (L2HGA) is a rare inborn error of metabolism caused by a defect in the processing of L-2-hydroxyglutaric acid (L2HG). Affected individuals typically present before the age of 7 years with mild developmental or intellectual delays, epilepsy, and/or cerebellar ataxia (Topçu et al. 2004; Steenweg et al. 2010; Struys et al. 2016). The disease shows a slowly progressive course, with worsening cerebellar ataxia, dysarthria, mild to moderate intellectual disability, and characteristic brain abnormalities that can be differentiated from other leukodystrophies via MRI. The MRI results will typically show a pattern of signal abnormalities of the subcortical cerebral white matter, putamen, caudate nucleus, globus pallidus and dentate nucleus (Steenweg et al. 2010; Struys et al. 2016). Additional features that may be observed in these patients are seizures, variable macrocephaly, and pyramidal and extrapyramidal signs (Topçu et al. 2004). Due to the progressive nature of the disease, patients may lose skills, such as walking, over time (Steenweg et al. 2010). In addition, it has been reported that L2HGA patients have an increased tendency to develop malignant tumors of the central nervous system (Haliloglu et al. 2008; Struys et al. 2016). Biochemically, these patients are found to have elevated levels of L2HG in the urine, plasma, and cerebrospinal fluid. They may also show a decrease in N-acetylaspartate and choline and an increase in myo-inositol peaks via MR spectroscopy (Topçu et al. 2004).

Pathogenic variants in the SLC25A1 gene cause combined D-2- and L-2-hydroxyglutaric aciduria, leading to increased levels of both L2HG and D-2-hydroxyglutaric acid (D2HG) in body fluids (Struys et al. 2016). As enantiomeric separation is required to distinguish L2HG from D2HG, it is possible that initial biochemical test results may look similar for L2HGDH and SLC25A1 patients. Additional metabolic or molecular genetic investigations should be able to distinguish these disorders.

L2HGA is an autosomal recessive disorder caused by pathogenic variants in the L2HGDH gene. Over 70 pathogenic variants have been described in this gene. Approximately half of the reported variants are missense variants and in-frame amino acid deletions. Nonsense and splice variants, small frameshift deletions, duplications and indels, and multi-exonic deletions have also been reported (Human Gene Mutation Database). There is no apparent genotype-phenotype correlation (Steenweg et al. 2010). The only two variants commonly reported in different populations are c.905C>T (p.Pro302Leu) and the frameshift variant c.530_533delinsATT (p.Pro177Hisfs*6). In addition, the variant c.241A>G (p.Lys81Glu) has been reported to be a founder mutation in the Tunisian population (Jellouli et al. 2014).

The L2HGDH gene encodes the L-2-hydroxyglutarate dehydrogenase enzyme, which converts the metabolite L-2-hydroxyglutaric acid to 2-ketoglutarate, an intermediate in the citric acid cycle (Struys et al. 2016).

Based on a collective total of patients with elevated L2HG levels reported in several studies, the clinical sensitivity of this test is expected to range from approximately 83% to nearly 100% (Topçu et al. 2004; Vilarinho et al. 2005; Sass et al. 2008; Vilarinho et al. 2010). Several patients were reported to carry large deletions, which would not be detectable via sequencing (Steenweg et al. 2010).

This test provides full coverage of all coding exons of the L2HGDH gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

This test also includes coverage for the c.906+354G>A intronic variant, as well as ~10 bp of adjacent sequence.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).