Abstract
Aim: To identify the genetic aetiology of a distinct leukoencephalopathy causing acute neurological regression in infancy with apparently complete clinical recovery. Methods: We performed trio whole genome sequencing (WGS) to determine the genetic basis of the disorder. Mitochondrial function analysis in cultured patient fibroblasts was undertaken to confirm the pathogenicity of candidate variants. Results: The patient presented at 18 months with acute hemiplegia and cognitive regression without obvious trigger. This was followed by clinical recovery over 4 years. MRI at disease onset revealed bilateral T2 hyperintensity involving the periventricular and deep white matter and MR spectroscopy of frontal white matter demonstrated a lactate doublet. Lactate levels and mitochondrial respiratory chain enzyme activity in muscle, liver and fibroblasts were normal. Plasma glycine was elevated. The MRI abnormalities improved. WGS identified compound heterozygous variants in BOLA3: one previously reported (c.136C>T, p.Arg46*) and one novel variant (c.176G>A, p.Cys59Tyr). Analysis of cultured patient fibroblasts demonstrated deficient pyruvate dehydrogenase (PDH) activity and reduced quantity of protein subunits of mitochondrial complexes I and II, consistent with BOLA3 dysfunction. Previously reported cases of multiple mitochondrial dysfunctions syndrome 2 (MMDS2) with hyperglycinaemia caused by BOLA3 mutations have leukodystrophy with severe, progressive neurological and multisystem disease. Conclusions: We report a novel phenotype for MMDS2 associated with apparently complete clinical recovery and partial resolution of MRI abnormalities. We have identified a novel disease-causing variant in BOLA3 validated by functional cellular studies. Our patient’s clinical course broadens the phenotypic spectrum of MMDS2 and highlights the potential for some genetic leukoencephalopathies to spontaneously improve.
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Acknowledgements
We thank the family for participating in this study.
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Communicated by: Jerry Vockley, M.D., Ph.D.
Electronic Supplementary Material
Supplementary Fig. 1
Chromatograms showing sequence variants in our patient and his parents (TIFF 88 kb)
Supplementary Fig. 2
Protein sequence alignment of human BOLA3 with its homologs in nine other vertebrate species showing the conservation of the p.Cys59 residue mutated in our patient. Asterisks (*) depict conserved amino acids (TIFF 93 kb)
Supplementary Fig. 3
Magnetic resonance spectroscopy A) At presentation at 18 months of age: Single voxel spectrum of the left frontal white matter demonstrates a massive lactate doublet (arrow) with decreased N-acetylaspartate (NAA). B) At 4 years of age demonstrates a significant reduction in the degree of lactate peak (arrow) in the frontal region with associated increase in the NAA (TIFF 1309 kb)
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Synopsis
We report a novel phenotype for MMDS2 associated with apparent clinical recovery and partial resolution of MRI abnormalities, highlighting the potential for some genetic leukoencephalopathies to spontaneously improve.
Conflict of Interest
Chloe Stutterd, Nicole Lake, Heidi Peters, Paul Lockhart, Ryan Taft, Marjo van der Knaap, David Thorburn, Cas Simons and Richard Leventer declare that they have no conflict of interest. Adeline Vanderver receives in kind and research support from Illumina, Shire, Gilead, Eli Lilly and Ionis.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.
Author Contributions
Conception and design of the study: RL, CAS, NL, DT and PL.
Acquisition and analysis of data: CAS, NL, HP, RT, MV, AV and CS.
Drafting a significant portion of the manuscript or figures: CAS, NL, DT and RL.
Details of Funding
CAS was supported by NHMRC Postgraduate Scholarship (ID: APP1133266) and the Royal Children’s Hospital/Murdoch Children’s Research Institute Flora Suttie Neurogenetics Fellowship made possible by the Thyne-Reid Foundation and the Macquarie Foundation. RJL is supported by a Melbourne Children’s Clinician Scientist Fellowship. This work was supported by the Victorian Government’s Operational Infrastructure Support Program and Australian Government National Health and Medical Research Council Independent Research Institute Infrastructure Support Scheme (NHMRC IRIISS) and NHMRC Project Grant 1068278. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.
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Dr. Chloe Stutterd.
Murdoch Children’s Research Institute.
50 Flemington Road.
Parkville, Victoria, 3052, Australia.
Email: chloe.stutterd@mcri.edu.au.
Phone: +61383416201, Fax: +61383416390.
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Stutterd, C.A. et al. (2018). Severe Leukoencephalopathy with Clinical Recovery Caused by Recessive BOLA3 Mutations. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 43. JIMD Reports, vol 43. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2018_100
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DOI: https://doi.org/10.1007/8904_2018_100
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