Severe Leukoencephalopathy with Clinical Recovery Caused by Recessive BOLA3 Mutations

  • C. A. StutterdEmail author
  • N. J. Lake
  • H. Peters
  • P. J. Lockhart
  • R. J. Taft
  • M. S. van der Knaap
  • A. Vanderver
  • D. R. Thorburn
  • C. Simons
  • R. J. Leventer
Research Report
Part of the JIMD Reports book series (JIMD, volume 43)


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.


BOLA3 Fe–S cluster Leukoencephalopathy Mitochondrial disease MMDS2 Next-generation sequencing 



We thank the family for participating in this study.

Supplementary material (45 kb)
Supplementary Fig. 1 Chromatograms showing sequence variants in our patient and his parents (TIFF 88 kb) (27 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) (939 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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Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018

Authors and Affiliations

  • C. A. Stutterd
    • 1
    • 2
    • 3
    • 4
    Email author
  • N. J. Lake
    • 4
    • 5
  • H. Peters
    • 4
    • 6
    • 7
  • P. J. Lockhart
    • 1
    • 4
  • R. J. Taft
    • 8
  • M. S. van der Knaap
    • 9
    • 10
  • A. Vanderver
    • 11
    • 12
  • D. R. Thorburn
    • 3
    • 4
    • 5
  • C. Simons
    • 13
    • 14
  • R. J. Leventer
    • 2
    • 4
    • 15
  1. 1.Bruce Lefroy Centre for Genetic Health ResearchMurdoch Children’s Research InstituteParkvilleAustralia
  2. 2.Department of NeurologyRoyal Children’s HospitalParkvilleAustralia
  3. 3.Victorian Clinical Genetics Services, Murdoch Children’s Research InstituteParkvilleAustralia
  4. 4.Department of PaediatricsUniversity of MelbourneParkvilleAustralia
  5. 5.Mitochondrial Research GroupMurdoch Children’s Research InstituteParkvilleAustralia
  6. 6.Department of Metabolic MedicineRoyal Children’s HospitalParkvilleAustralia
  7. 7.Metabolic Research GroupMurdoch Children’s Research InstituteParkvilleAustralia
  8. 8.Illumina IncSan DiegoUSA
  9. 9.Department of Child NeurologyVU University Medical CenterAmsterdamThe Netherlands
  10. 10.Department of Functional Genomics, Center for Neurogenomics and Cognitive ResearchVU University AmsterdamAmsterdamThe Netherlands
  11. 11.Division of NeurologyChildren’s Hospital of PhiladelphiaPhiladelphiaUSA
  12. 12.Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  13. 13.Institute for Molecular Bioscience, University of QueenslandSt LuciaAustralia
  14. 14.Translational Bioinformatics Research GroupMurdoch Children’s Research InstituteParkvilleAustralia
  15. 15.Neuroscience Research GroupMurdoch Children’s Research InstituteParkvilleAustralia

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