Page 99 - BH-2-3

Brain & Heart L2-hydroxyglutaric aciduria

Figure 1. Schematic representation of the action of L-2-hydroxyglutarate dehydrogenase (L2HGDH). Taken from Canda et al. 4

determined that he had a moderate to severe learning
disability, having the intelligence equivalent to a 5 – 6-year-
old school-aged child.
2.1. Examination of the external appearance and
biochemical findings
Figure 2 shows the external appearance of the patient, who
showed relative macrocephaly.
The results of his general biochemical and hematological
investigations were mostly normal, except for a mild
elevation of creatine phosphokinase (Table 1) (237 U/L;
reference range: 30 - 350 U/L).

2.2. Brain MRI examination
Brain MRI revealed T2/FLAIR hyperintensities in bilateral Figure 2. External appearance of the patient showing relative
symmetrical subcortical white matter involving the macrocephaly
cerebellum and bilateral basal ganglia (Figure 3). On the
other hand, a spine MRI yielded normal results. phase of the variants in the index patient and their status as
carriers for a pathogenic L2HGDH variant. The pathogenic
2.3. Urine organic acid chromatogram nonsense variant was maternally inherited, whereas the
The urine organic acid chromatogram based on an analysis pathogenic missense variant was inherited from the
by GC/MS revealed a massive peak of 2HG (Figure 4). paternal side (Sanger sequencing was performed to verify
in this regard).
2.4. Genetic testing
2.5. Management and treatment
To confirm the diagnosis, the entire codon region and
highly conserved exon-intron splice junctions of L2HGDH, The patient was managed through a multidisciplinary
D2HGDH, IDH2, and SLC25A1 genes were analyzed using approach that also encompasses periodic follow-up,
next-generation sequencing (NGS). Two heterozygous rehabilitation, and genetic counseling. The patient was
pathogenic variants (class 1) were identified in the L2HGDH treated with riboflavin, carnitine, FAD, and coenzyme Q
gene: a missense variant in exon 3, c.293A>G p. (His98arg), for improving his motor and intellectual disability. UOA
and a nonsense variant in exon 7, c.829c>T p.(Arg277٭), analyses (GC-MS) performed 1 month before and after the
confirming the diagnosis of autosomal recessive L2HGA treatment with riboflavin similarly revealed the distinct
due to compound heterozygosity. No clinically relevant peak of 2HG on the chromatogram. However, the patient
variants were identified in other genes. The classification was less compliant with the treatment and defaulted to
was done according to the recommendations of Centogene follow-up. At the time of writing this paper, the patient was
and ACMG and the latest ACMG/AMP and ClinGen studying at grade eight in school, with very poor academic
guidelines. Parental genetic testing confirmed the trans performance. He was also unable to do daily living

Volume 2 Issue 3 (2024) 3 doi: 10.36922/bh.2145