Balkan Journal of Medical Genetics

A 7-YEAR-OLD BOY WITH HAND TREMORS AND A NOVEL MUTATION FOR L-2-HYDROXYGLUTARIC ACIDURIA
Olgac A1,*, Tekin Orgun L2, Ezgü FS1, Biberoǧlu G1, Tümer L1
*Corresponding Author: Dr. Asburce Olgac, Department of Pediatric Metabolism and Nutrition, Gazi University Hospital, Mevlana Bulvarı, Ankara, Turkey. Tel: +90-533-962-7800. Fax: +90-312-202-6027. E-mail: mabolgac@yahoo.com
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DISCUSSION

The differential diagnosis of L2HGA begins with the clinical evaluation of a patient with unexplained developmental delay and neurological findings of unknown etiology. Urinary organic acid screening with GC-MS, performed as a part of metabolic screening, may reveal increased 2-hydroclutaric acid, but the chiral configuration (D or L form) has to be determined by GC-MS or liquid chromatography-tandem mass spectrometry (LC-MS/MS), as D-2-hydroxyglutaric aciduria (D2HGA) and L2HGA are different clinical entities. D- 2-hydroxyglutaric aciduria is a neurometabolic disorder characterized by epilepsy, hypotonia and psychomotor retardation, caused by the mutations in the D2HGDH (Type 1 D2HGA) and IDH2 (Type 2 D2HGA) genes. It is important to differentiate between the different forms of L2HGA in order to provide genetic counseling and future prenatal diagnosis [1]. Although the underlying mechanisms are largely unclear, in animal models, L2HG acid has been shown to impair the activities of the enzymes cytochrome C-oxidase and ATP-synthase that play a major role in the oxidative phosphorylation. To date, there are approximately 100 documented cases in the medical literature [1-3]. Varying levels of urine L2HG levels have been previously reported (ranging from 350.0 to 3357.0 mmol/mmol creatinine). Urine L2HG of our patient was found to be similar to the cases reported in the literature [1]. Affected individuals have neurological manifestations including mild-to-moderate psychomotor retardation, loss of milestones, intention tremor, cerebellar ataxia, pyramidal and extrapyramidal symptoms and epilepsy. Macrocephaly has been reported in some cases diagnosed with L2HGA in the literature [4,5]. The disease may lead to chronic encephalopathy, without any symptoms of acute metabolic attacks. The progression of L2HGA and the consequent disability may vary between patients, which is a factor that may cause a delay in diagnosis [1]. At the time of diagnosis, the complaints of our patient were mild, including only hand tremors. Although macrocephaly and a slight ataxic gait were also present, this was not noticed at his previous visits to the pediatric clinic for routine follow-up. Our patient carries the homozygous c.368A>G, p.(Tyr123 Cys) mutation, which has not been previously reported according to the Leiden Open Variation Database (http:// www.LOVD.nl/L2HGDH2011), where numerous mutations in the L2HGDH gene have now been reported worldwide [6]. We used the SIFT (https://sift.bii.a-star.edu. sg/) and Mutationtaster (http://www.mutationsater.org/) to predict the possible impact of the amino acid substitution on the structure and function of the protein L2HGDH. The test results indicated it was a missense mutation, probably damaging and disease-causing. This mutation also showed deleterious and highly pathogenic effects on evolutionary highly conserved amino acid according to the LRT (https://dmpi.duke.eud/combined-likelihood-ratio-testcandidate- gene-studies), and MutationAssessor (http:// mutationassessor.org) databases. The parents were shown to carry the same mutation in a heterozygous state. This suggests that the mutation is probably pathogenic. Further functional tests are needed. Cranial MRI findings are very specific and include subcortical white matter signal changes, with cerebellar cortical atrophy and signal abnormalities in the basal ganglia and dentate nuclei despite deep white matter protection [7]. Moroni et al. [8] observed a good correlation between the severity of the disease and the extent of lesions on MRI. Cerebral neoplasms may also occur [8- 10] and rapid deterioration in L2HGA would not suggest a metabolic derangement but rather complications of a cerebral malignancy [8]. Brain tumors have been related to the metabolite L2HG acid that have also been known to be an oncometabolite. Shim et al. [11] have identified elevated L2HG acid levels in renal cells affected with clear cell renal carcinoma (RCC), especially the L-enantiomer being the predominant form, and have shown L2HG acid levels to be inversely correlated with L2HGDH expression. Furthermore, they have shown L2HGDH reconstitution in RCC cell lines to suppress in vitro tumor phenotypes and have suggested that L2HGDH has metabolic tumor suppressor activity [11]. As the mutation c.368A>G, p.(Tyr 123Cys) in the L2HGDH gene has not been previously reported, we do not have information regarding the clinical consequences of L2HGA in our patient. Although there are no specific therapeutic approaches, supplementation of and flavin adenin dinucleotide (FAD) and riboflavin (precursor of FAD) have been reported to be effective in some patients, especially in the ones with mild mutations [1-3]. Unfortunately, these do not improve the leukoencephalopathy. Our patient’s symptoms have now been stabilized. Although he had an episode of a focal seizure, his neurological complaints including hand tremors and ataxic gait have not deteriorated within 4 years follow-up.

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