Summary
We report clinical and molecular studies in three unrelated Tunisian families containing seven patients with L2HGA. Although the age of onset is similar in all these patients at nearly 6 years, they progressively developed peculiar clinical phenotypes different from family to family. The three patients of family 1 showed mental retardation, epilepsy, cerebellar ataxia and pyramidal and pseudobulbar syndromes. The two patients of family 2 showed mental retardation and parkinsonism especially extrapyramidal stiffness, dystonia and myoclonus. The two patients of family 3 showed an intermediate phenotype; they share some clinical signs of the patients of family 1 (epilepsy, pyramidal and extrapyramidal syndromes) and some clinical signs of the patients of family 2 (extrapyramidal stiffness and dystonia). Molecular study identified a novel homozygous c.185C > A, p.A62D mutation on the L2HGDH gene in families 1 and 3 and the already known homozygous c.241A > G, p.K81E mutation in family 2. We suppose that the type of mutation in the L2HGDH gene does not play a complete role in the inter-familial phenotype variability. Disturbance of other unknown metabolic pathways related to L2HGA may contribute to this phenomenon.
References
Ben-zeev B, Gross V, Kushnir T, et al (2001) Vacuolating megalencephalic leukoencephalopathy in 12 Israeli patients. J Child Neurol 16(2): 93–99.
Clerc C, Bataillard M, Richard P, et al (2000) An adult form of l-2-hydroxyglutaric aciduria revealed by tremor. Eur Neurol 43(2): 119–120. doi:10.1159/000008149.
de Klerk JB, Hujmans JG, Stroink H, et al (1997) l-2-Hydroxyglutaric aciduria (1997) Clinical heterogeneity versus biochemical homogeneity in a sibship. Neuropediatrics 28(6): 314–317. doi:10.1055/s-2007-973722.
Hussmann O, Hass D, Neubauer BA, et al (2006) l-2-Hydroxyglutaric aciduria—a rare cause of macrocephaly. [In German]. Klin Padiatr 218(2): 72–73. doi:10.1055/s-2005-836848.
Larnaout A, Amouri R, Neji S, et al (2007) Osteoma of the calvaria in l-2-hydroxyglutaric aciduria. J Inherit Metab Dis 30: 980. doi:10.1007/s10545-007-0576-0.
Larnaout A, Hentati F, Belal S, et al (1994) Clinical and pathological study of three Tunisian siblings with l-2-hydroxyglutaric aciduria. Acta Neuropathol 88: 367–370. doi:10.1007/BF00310381.
Lee C, Born M, Salomons GS, Jacobs C, Woelfle J (2006) Hemiconvulsion-hemiplegia-epilepsy syndrome as a presenting feature of l-2-hydroxyglutaric aciduria. J Child Neurol 21(6): 538–540.
Moroni I, Bugiani M, D’Incerti I, et al (2004) l-2-Hydroxyglutaric aciduria and brain malignant tumors, a predisposing condition. Neurology 62: 1882–1884.
Ozişik PA, Akalan N, Palaoğlu S, Topçu M (2002) Medulloblastoma in a child with the metabolic disease l-2-hydroxyglutaric aciduria. Pediatr Neurosurg 37(1): 22–26. doi:10.1159/000065097.
Rzem R, Veiga-da-Cunha M, Noel G, et al (2004) A gene encoding a putative FAD-dependant l-2-hydroxyglutarate dehydrogenase is mutated in l-2-hydroxyglutaric aciduria. Proc Natl Acad Sci U S A 101(48): 16849–16854. doi:10.1073/pnas.0404840101.
Rzem R, Van Shaftingen E, Veiga-da-Cunha M (2006) The gene mutated in l-2-hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase. Biochimie 88(1): 113–116. doi:10.1016/j.biochi.2005.06.005.
Sass JO, Jobard F, Topçu M, et al (2008) l-2-Hydroxyglutaric aciduria: identification of ten novel mutations in the L2HGDH gene. J Inherit Metab Dis. doi:10.1007/s10545-008-0855-4.
Shafeghati Y, Vakili G, Entezari A (2006) l-2-Hydroxyglutaric aciduria: a report of six cases and review of the literature. Arch Iran Med 9(2): 165–169.
Topcu M, Jouhard F, Halliaz S, et al (2004) l-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum Mol Genet 13(22): 2803–2811.
Vilarinho L, Cardosso ML, Gaspar P, et al (2005) Novel L2HGDH mutations in 21 patients with l-2-hydroxyglutaric aciduria of Portuguese origin. Hum Mut 26(4): 395–396. doi:10.1002/humu.9373.
Yilmaz K (2008) Riboflavin treatment in a case with l-2-hydroxyglutaric aciduria. Eur J Paediatr Neurol 2008 Mar 14 [Epub ahead of print].
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicating editor: Cornelis Jakobs
Competing interests: None declared
References to electronic databases:
Rights and permissions
About this article
Cite this article
Larnaout, A., Amouri, R., Kefi, M. et al. l-2-Hydroxyglutaric aciduria: Clinical and molecular study in three Tunisian families. Identification of a new mutation and inter-familial phenotype variability. J Inherit Metab Dis 31 (Suppl 2), 375–379 (2008). https://doi.org/10.1007/s10545-008-0934-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-008-0934-6