Abstract
L-2-hydroxyglutaric aciduria (L2HGA) is an autosomal recessive neurometabolic disorder characterized essentially by the presence of elevated levels of L-2-hydroxyglutaric acid (LGA) in plasma, cerebrospinal fluid and urine. L2HGA is caused by a deficiency in the L2-Hydroxyglutaric dehydrogenase (L2HGDH) enzyme involved in the oxidation of LGA to the alpha 2-ketoglutarate. LGA has been proposed as an endo- and exogenous cytotoxic organic acid that induces free radical formation and generation of reactive oxygen species (ROS). In this report, we analyzed 14 L2HGA patients belonging to six unrelated consanguineous families the south of Tunisia. The patients were diagnosed with L2HGA disease confirmed on the presence of high level of LGA in urine. We analyzed the L2HGDH gene in all probands and identified the same c.241A>G homozygous mutation, which was previously reported in Tunisia. We also used intragenic single nucleotide length polymorphisms (SNPs) and two extragenic microsatellites flanking the L2HGDH gene to confirm the founder effect of c.241A>G mutation in the 14 studied cases. In addition, we carried out the measurement of the oxidative stress parameters in the plasma of L2HGA patients which revealed a significant increase in the malondialdehyde levels (MDA), a biomarker of lipid peroxydation, and the reduced glutathione (GSH). A diminution of the antioxidant enzyme activities including superoxide dismutase (SOD), glutathione peroxidase (GPx), was also observed.
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Acknowledgements
We are indebted to the families for their invaluable cooperation and for providing the blood samples. This research was funded by the Tunisian Ministry of Higher Education and Scientific Research.
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Appendix The Tunisian Network on Mental Retardation study Marie Françoise Ben DRIDI, Néji TEBIB, Hatem Azouz, Hend Ben Khelifa, Amel Ben Chehida, Habiba Bouhamed Chaabouni, Ridha M’rad, Myriam Chaabouni, Lamia Ben Jemaa, Faouzi Maaloul, Naziha Kaabachi, Haifa Sanhaji, Fahmi Nasrallah, Ali Saad Hatem Elghezal, Moez Gribaa, Soumaya Mougou, Ines Ben Abdallah, Ramzi Zemni, Foued Haj Salama, Elyes Chabchoub, Amani Achour, Ahmed Sahloul Essoussi, Lamia Boughamoura, Najla Souayah, Jihene Bouguila, Abdelhedi Miled, Salima Ferchichi, Henda Chahed, Chahnez Charfi Triki, Houda Ben Othman, Emna Ellouz, Fatma Kamoun, Faiza Fakhfakh, Hassen Kamoun, Neila Belghuith, Nourhene Fendri, Nadege Kamoun, Fatma Makni Ayedi, Kamel Jamoussi, Mouna Turki, Meriam Messeddi.
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Jellouli, N., Hadj Salem, I., Ellouz, E. et al. Founder effect confirmation of c.241A>G mutation in the L2HGDH gene and characterization of oxidative stress parameters in six Tunisian families with L-2-hydroxyglutaric aciduria. J Hum Genet 59, 216–222 (2014). https://doi.org/10.1038/jhg.2014.4
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DOI: https://doi.org/10.1038/jhg.2014.4
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