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.
The original version of this chapter was revised. An erratum to this chapter can be found at DOI 10.1007/8904_2017_588.
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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).
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Communicated by: Bridget Wilcken
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All authors declare that they have no conflicts of interest.
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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.
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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.
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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
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DOI: https://doi.org/10.1007/8904_2016_559
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