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Open Access 01-12-2018 | Case report

Identification of novel L2HGDH mutation in a large consanguineous Pakistani family- a case report

Authors: Muhammad Ikram Ullah, Abdul Nasir, Arsalan Ahmad, Gaurav Vijay Harlalka, Wasim Ahmad, Muhammad Jawad Hassan, Emma L. Baple, Andrew H. Crosby, Barry A. Chioza

Published in: BMC Medical Genetics | Issue 1/2018

Abstract

Background

L-2-hydroxyglutaric aciduria (L2HGA) is a progressive neurometabolic disease of brain caused by mutations of in L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. Cardinal clinical features include cerebellar ataxia, epilepsy, neurodevelopmental delay, intellectual disability, and other clinical neurological deficits.

Case presentation

We describe an index case of the family presented with generalised tonic-clonic seizure, developmental delay, intellectual disability, and ataxia. Initially, the differential diagnosis was difficult to be established and a SNP genome wide scan identified the candidate region on chromosome 14q22.1. DNA sequencing showed a novel homozygous mutation in the candidate gene L2HGDH (NM_024884.2: c.178G > A; p.Gly60Arg). The mutation p.Gly60Arg lies in the highly conserved FAD/NAD(P)-binding domain of this mitochondrial enzyme, predicted to disturb enzymatic function.

Conclusions

The combination of homozygosity mapping and DNA sequencing identified a novel mutation in Pakistani family with variable clinical features. This is second report of a mutation in L2HGDH gene from Pakistan and the largest family with L2HGA reported to date.

Duran M, Kamerling JP, Bakker HD, van Gennip AH, Wadman SK. L-2-Hydroxyglutaric aciduria: an inborn error of metabolism? J Inherit Metab Dis. 1980;3:109–12.CrossRefPubMed

Chen E, Nyhan WL, Jakobs C, Greco CM, Barkovich AJ, Cox VA, Packman S. L-2-Hydroxyglutaric aciduria: neuropathological correlations and first report of severe neurodegenerative disease and neonatal death. J Inherit Metab Dis. 1996;19:335–43.CrossRefPubMed

Barth PG, Hoffmann GF, Jaeken J, Lehnert W, Hanefeld F, van Gennip AH, Duran M, Valk J, Schutgens RB, Trefz FK, et al. L-2-hydroxyglutaric acidemia: a novel inherited neurometabolic disease. Ann Neurol. 1992;32:66–71.CrossRefPubMed

Barth PG, Wanders RJ, Scholte HR, Abeling N, Jakobs C, Schutgens RB, Vreken P. L-2-hydroxyglutaric aciduria and lactic acidosis. J Inherit Metab Dis. 1998;21:251–4.CrossRefPubMed

Hanefeld F, Kruse B, Bruhn H, Frahm J. In vivo proton magnetic resonance spectroscopy of the brain in a patient with L-2-hydroxyglutaric acidemia. Pediatr Res. 1994;35:614–6.CrossRefPubMed

Steenweg ME, Jakobs C, Errami A, van Dooren SJ, Adeva Bartolome MT, Aerssens P, Augoustides-Savvapoulou P, Baric I, Baumann M, Bonafe L, et al. An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study. Hum Mutat. 2010;31:380–90.CrossRefPubMed

Aghili M, Zahedi F, Rafiee E. Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. J Neuro-Oncol. 2009;91:233–6.CrossRef

Haliloglu G, Jobard F, Oguz KK, Anlar B, Akalan N, Coskun T, Sass JO, Fischer J, Topcu M. L-2-hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene: neuroimaging findings. Neuropediatrics. 2008;39:119–22.CrossRefPubMed

Moroni I, Bugiani M, D'Incerti L, Maccagnano C, Rimoldi M, Bissola L, Pollo B, Finocchiaro G, Uziel G. L-2-hydroxyglutaric aciduria and brain malignant tumors: a predisposing condition? Neurology. 2004;62:1882–4.CrossRefPubMed

10.

Seijo-Martinez M, Navarro C, Castro del Rio M, Vila O, Puig M, Ribes A, Butron M. L-2-hydroxyglutaric aciduria: clinical, neuroimaging, and neuropathological findings. Arch Neurol. 2005;62:666–70.CrossRefPubMed

11.

Topcu M, Aydin OF, Yalcinkaya C, Haliloglu G, Aysun S, Anlar B, Topaloglu H, Turanli G, Yalnizoglu D, Kesimer M, Coskun T. L-2-hydroxyglutaric aciduria: a report of 29 patients. Turk J Pediatr. 2005;47:1–7.PubMed

12.

Steenweg ME, Salomons GS, Yapici Z, Uziel G, Scalais E, Zafeiriou DI, Ruiz-Falco ML, Mejaski-Bosnjak V, Augoustides-Savvopoulou P, Wajner M, et al. L-2-Hydroxyglutaric aciduria: pattern of MR imaging abnormalities in 56 patients. Radiology. 2009;251:856–65.CrossRefPubMed

13.

Vilarinho L, Cardoso ML, Gaspar P, Barbot C, Azevedo L, Diogo L, Santos M, Carrilho I, Fineza I, Kok F, et al. Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin. Hum Mutat. 2005;26:395–6.CrossRefPubMed

14.

Goffette SM, Duprez TP, Nassogne MC, Vincent MF, Jakobs C, Sindic CJ. L-2-Hydroxyglutaric aciduria: clinical, genetic, and brain MRI characteristics in two adult sisters. Eur J Neurol. 2006;13:499–504.CrossRefPubMed

15.

Topcu M, Jobard F, Halliez S, Coskun T, Yalcinkayal C, Gerceker FO, Wanders RJ, Prud'homme JF, Lathrop M, Ozguc M, Fischer J. L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum Mol Genet. 2004;13:2803–11.CrossRefPubMed

16.

Vilarinho L, Tafulo S, Sibilio M, Kok F, Fontana F, Diogo L, Venancio M, Ferreira M, Nogueira C, Valongo C, et al. Identification of novel L2HGDH gene mutations and update of the pathological spectrum. J Hum Genet. 2010;55:55–8.CrossRefPubMed

17.

Jellouli NK, Hadj Salem I, Ellouz E, Kamoun Z, kamoun F, tlili A, Kaabachi N, Triki C, Fakhfakh F, Tunisian Network on Mental Retardation s. 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. 2014;59:216–22.CrossRefPubMed

18.

Larnaout A, Amouri R, Kefi M, Hentati F. 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. 2008;31(Suppl 2):S375–9.CrossRefPubMed

19.

O'Connor G, King M, Salomons G, Jakobs C, Hardiman O. A novel mutation as a cause of L-2-hydroxyglutaric aciduria. J Neurol. 2009;256:672–3.CrossRefPubMed

20.

Puffenberger EG, Hu-Lince D, Parod JM, Craig DW, Dobrin SE, Conway AR, Donarum EA, Strauss KA, Dunckley T, Cardenas JF, et al. Mapping of sudden infant death with dysgenesis of the testes syndrome (SIDDT) by a SNP genome scan and identification of TSPYL loss of function. Proc Natl Acad Sci U S A. 2004;101:11689–94.CrossRefPubMedPubMedCentral

21.

Faiyaz-Ul-Haque M, Al-Sayed MD, Faqeih E, Jamil M, Saeed A, Amoudi MS, Kaya N, Abalkhail H, Al-Abdullatif A, Rashed M, et al. Clinical, neuroimaging, and genetic features of L-2-hydroxyglutaric aciduria in Arab kindreds. Ann Saudi Med. 2014;34:107–14.CrossRefPubMed

22.

Ramachandran G, Kumar M, Selvi Rani D, Annanthapur V, Calambur N, Nallari P, Kaur P. An in silico analysis of troponin I mutations in hypertrophic cardiomyopathy of Indian origin. PLoS One. 2013;8:e70704.CrossRefPubMedPubMedCentral

Title: Identification of novel L2HGDH mutation in a large consanguineous Pakistani family- a case report
Authors: Muhammad Ikram Ullah
Abdul Nasir
Arsalan Ahmad
Gaurav Vijay Harlalka
Wasim Ahmad
Muhammad Jawad Hassan
Emma L. Baple
Andrew H. Crosby
Barry A. Chioza
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2018
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-018-0532-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Identification of novel L2HGDH mutation in a large consanguineous Pakistani family- a case report

Abstract

Background

Case presentation

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Case presentation

Conclusions

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