Abstract
Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, is a genetically heterogeneous, relentlessly progressive, devastating neurodegenerative disorder that usually presents in infancy or early childhood. A diagnosis of Leigh-like syndrome may be considered in individuals who do not fulfil the stringent diagnostic criteria but have features resembling Leigh syndrome.
We describe a unique presentation of Leigh-like syndrome in a 3-year-old boy with elevated 3-hydroxyisovalerylcarnitine (C5-OH) on newborn screening (NBS). Subsequent persistent plasma elevations of C5-OH and propionylcarnitine (C3) as well as fluctuating urinary markers were suggestive of multiple carboxylase deficiency (MCD). Normal enzymology and mutational analysis of genes encoding holocarboxylase synthetase (HLCS) and biotinidase (BTD) excluded MCD. Biotin uptake studies were normal excluding biotin transporter deficiency. His clinical features at 13 months of age comprised psychomotor delay, central hypotonia, myopathy, failure to thrive, hypocitrullinemia, recurrent episodes of decompensation with metabolic keto-lactic acidosis and an episode of hyperammonemia. Biotin treatment from 13 months of age was associated with increased patient activity, alertness, and attainment of new developmental milestones, despite lack of biochemical improvements. Whole exome sequencing (WES) analysis failed to identify any other variants which could likely contribute to the observed phenotype, apart from the homoplasmic (100%) m.8993T>G variant initially detected by mitochondrial DNA (mtDNA) sequencing.
Hypocitrullinemia has been reported in patients with the m.8993T>G variant and other mitochondrial disorders. However, persistent plasma elevations of C3 and C5-OH have previously only been reported in one other patient with this homoplasmic mutation. We suggest considering the m.8993T>G variant early in the diagnostic evaluation of MCD-like biochemical disturbances, particularly when associated with hypocitrullinemia on NBS and subsequent confirmatory tests. An oral biotin trial is also warranted.
Keywords
The original version of this chapter was revised. An erratum to this chapter can be found at DOI 10.1007/8904_2017_588.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Atkuri KR, Cowan TM, Kwan T, Ng A, Herzenberg LA, Enns GM (2009) Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia. Proc Natl Acad Sci U S A 106(10):3941–3945
Baertling F, Rodenburg RJ, Schaper J et al (2014) A guide to diagnosis and treatment of Leigh syndrome. J Neurol Neurosurg Psychiatry 85:257–265
Baumgartner MR, Hu CA, Almashanu S et al (2000) Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta (1)-pyrroline-5-carboxylate synthase. Hum Mol Genet 9(19):2853–2858
Bindoff L (2006) Mitochondrial gastroenterology. In: DiMauro S, Hirano M, Schon EA (eds) Mitochondrial medicine. Informa Healthcare, Abingdon, pp 143–159
Blijlevens NMA, Lutgens LCHW, Schattenberg AVMB, Donnelly JP (2004) Citrulline: a potentially simple quantitative marker of intestinal epithelial damage following myeloablative therapy. Bone Marrow Transplant 34:193–196
Blok RB, Gook DA, Thorburn DR, Dahl H-HM (1997) Skewed segregation of the mtDNA nt 8993 (T→G) mutation in human oocytes. Am J Hum Genet 60:1495–1501
Crenn P, Coudray-Lucas C, Thuillier F, Cynober L, Messing B (2000) Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans. Gastroenterology 119:1495–1505
Crenn P, Vahedi K, Lavergne-Slove A, Cynober L, Matuchansky C, Messing B (2003) Plasma citrulline: a marker of enterocyte mass in villous atrophy-associated small bowel disease. Gastroenterology 124:1210–1219
Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M (2001) The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA anbormalities. Ann Neurol 49(3):377–383
Debray FG, Lambert M, Allard P, Mitchell GA (2010) Low citrulline in Leigh disease: still a biomarker of maternally inherited Leigh syndrome. J Child Neurol 25(8):1000–1002
Degoul F, Francois D, Diry M et al (1997) A near homoplasmic T8993G mtDNA mutation in a patient with atypic Leigh syndrome not present in the mother’s tissues. J Inherit Metab Dis 20(1):49–53
Elliot KRF, Tipton KF (1974) Product inhibition studies on bovine liver carbamoyl phosphate synthetase. Biochem J 141:817–824
Enns GM, Bai RK, Beck AE, Wong LJ (2006) Molecular-clinical correlations in a family with variable tissue mitochondrial DNA T8993G mutant load. Mol Genet Metab 88(4):364–371
Hauser N (2014) Persistent elevations in C3 and C5OH, heralding signs for an underlying mitochondrial defect: neurogenic weakness with ataxia and retinitis pigmentosa (NARP). 64th Annual meeting of the American Society of Human Genetics, San Diego
Henriques M, Diogo L, Garcia P, Pratas J, Simoes M, Grazina M (2012) Mitochondrial DNA 8993T>G mutation in a child with ornithine transcarbamylase deficiency and Leigh syndrome: an unexpected association. J Child Neurol 27(8):1059–1061
Huntsman RJ, Sinclair DB, Bhargava R, Chan A (2005) Atypical presentations of Leigh syndrome: a case series and review. Pediatr Neurol 32(5):334–340
Ishigami A, Ohsawab T, Asagab H, Akiyama K, Kuramotoa M, Maruyamaa N (2002) Human peptidylarginine deiminase type II: molecular cloning, gene organization, and expression in human skin. Arch Biochem Biophys 407(1):25–31
Ishiyama N, Bates IR, Hill CM et al (2001) The effects of deimination of myelin basic protein on structures formed by its interaction with phosphoinositide-containing lipid monolayers. J Struct Biol 136(1):30–45
Kucharczyk R, Zick M, Bietenhader M et al (2009) Mitochondrial ATP synthase disorders: molecular mechanisms and the quest for curative therapeutic approaches. Biochim Biophys Acta 1793(1):186–199
Kumakura A, Asada J, Okumura R, Fujisawa I, Hata D (2009) Diffusion-weighted imaging in preclinical Leigh syndrome. Pediatr Neurol 41(4):309–311
Lake NJ, Compton AG, Rahman S, Thorburn DR (2015) Leigh syndrome: one disorder, more than 75 monogenic causes. Ann Neurol. doi:10.1002/ana.24551
Leigh D (1951) Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry 14:216–221
Lutgens LCHW, Deutz NEP, Gueulette J et al (2003) Citrulline: a physiologic marker enabling quantitation and monitoring of epithelial radiation-induced small bowel damage. Int J Radiat Oncol Biol Phys 57:1067–1074
Mock DM (1997) Determinations of biotin in biological fluids. In: McCormick DB, Suttie JW, Wagner C (eds) Methods in enzymology. Academic, New York, pp 265–275
Mori M, Mytingerm JR, Martin LC, Bartholomew D, Hickey S (2014) 8993T>G-Associated Leigh syndrome with hypocitrullinemia on newborn screening. JIMD Rep 17:47–51
Morin C, Mitchell G, Larochelle J et al (1993) Clinical, metabolic, and genetic aspects of cytochrome C oxidase deficiency in Saguenay-Lac-Saint-Jean. Am J Hum Genet 53:488–496
Naini A, Kaufmann P, Shanske S, Engelstad K, De Vivo DC, Schon EA (2005) Hypocitrullinemia in patients with MELAS: an insight into the “MELAS paradox”. J Neurol Sci 229–230:187–193
Ostergaard E, Hansen FJ, Sorensen N et al (2007) Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations. Brain 130:853–861
Parfait P, de Lonlay P, von Kleist-Retzow JC et al (1999) The neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome mtDNA mutation (T8993G) triggers muscle ATPase deficiency and hypocitrullinaemia. Eur J Pediatr 158:55–58
Rabier D, Diry C, Rotig A et al (1998) Persistent hypocitrullinaemia as a marker for mtDNA NARP T8993G mutation? J Inherit Metab Dis 21:216–219
Rahman S, Blok RB, Dahl HH et al (1996) Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol 39:343–351
Ribes A, Riudor E, Valcarel R et al (1993) Pearson syndrome: altered tricarboxylic acid and urea-cycle metabolites, adrenal insufficiency and corneal opacities. J Inherit Metab Dis 16(3):537–540
Said HM, Redah R (1988) Ontogenesis of the intestinal transport of biotin in the rat. Gastroenterology 94(1):68–72
Said HM, Ortiz A, McCloud E, Dyer D, Moyer MP, Rubin S (1998) Biotin uptake by human colonic epithelial NCM460 cells: a carrier-mediated process shared with pantothenic acid. Am J Physiol 275(5):C1365–C1371
Santorelli FM, Shanske S, Macaya A, DeVivo DC, DiMauro S (1993) The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh’s syndrome. Ann Neurol 34:827–834
Sofou K, De Coo IF, Isohanni P et al (2014) A multicenter study on Leigh syndrome: disease course and predictors of survival. Orphanet J Rare Dis 9:52
Spector R, Mock DM (1987) Biotin transport through the blood–brain barrier. J Neurochem 48:400–404
Spector R, Mock DM (1988) Biotin transport and metabolism in the central nervous system. Neurochem Res 13:213–219
Thorburn DR, Rahman S (2014) Mitochondrial DNA-associated Leigh syndrome and NARP. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP (eds) GeneReviews™[Internet]. University of Washington, Seattle, 1993–2013; (updated 2014 Apr 17, http://www.ncbi.nlm.nih.gov/books/NBK1173/)
van Karnebeek CDM, Sly WS, Ross CJ et al (2014) Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. Am J Hum Genet 94:453–461
White SL, Shanske S, McGill JJ et al (1999a) Mitochondrial DNA mutations at nucleotide 8993 show a lack of tissue or age-related variation. J Inherit Metab Dis 22:899–914
White SL, Collins VR, Wolfe R et al (1999b) Genetic counselling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am J Hum Genet 65:474–482
Acknowledgements
We are grateful to the patient and family for participation in this study; Dr Janice Fletcher (SA Pathology, Adelaide, South Australia) for advice on the diagnostic work-up; Mrs M Higginson for DNA extraction, sample handling and technical data; Dr W Wassermann for supervision of WES bio-informatics analyses; Dr CJ. Ross and Mrs X Han for Sanger sequencing (University of British Columbia, Vancouver, CA).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Bridget Wilcken
Appendices
Compliance with Ethics Guidelines
Conflict of Interest
All authors declare that they have no conflicts of interest.
Details of the Contributions of Individual Authors
SB was the physician in charge of the family. BL, DMM, HMS, MTG, AM, CDvK, DRT and RJR performed/supervised/interpreted laboratory investigations. JC advised on the overall diagnostic work-up and management of the proband. SB and JC drafted the original manuscript. All authors have read/critically revised the manuscript.
Sources of Support
NIH grants R37 DK 36823 (DMM), R37 DK36823-26S1 (DMM), RO1 DK79890, DK79890-01S1 (DMM); the UAMS CTSA Award UL1 TR000039. B.C. Children’s Hospital Foundation (www.tidebc.org) (CVK); Canadian Institutes of Health Research grant #301221 (CDvK); British Columbia Clinical Genomics Network grant BCCGN00031 (CDvK). CDvK is recipient of the Michael Smith Foundation for Health Research Scholar Award.
Rights and permissions
Copyright information
© 2016 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Balasubramaniam, S. et al. (2016). Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD). In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 33. JIMD Reports, vol 33. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_559
Download citation
DOI: https://doi.org/10.1007/8904_2016_559
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-55011-3
Online ISBN: 978-3-662-55012-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)