Severe leukoencephalopathy with clinical recovery caused by recessive BOLA3 mutations

C. A. Stutterd*, 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

*Corresponding author for this work

Research output: Chapter in Book / Report / Conference proceedingChapterAcademicpeer-review


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.

Original languageEnglish
Title of host publicationJIMD Reports
Subtitle of host publicationVolume 43
EditorsEva Morava
Number of pages8
ISBN (Electronic)9783662586143
ISBN (Print)783662586136
Publication statusPublished - 2019

Publication series

NameJIMD Reports
ISSN (Print)2192-8304
ISSN (Electronic)2192-8312


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.

FundersFunder number
Australian Government National Health and Medical Research Council
Macquarie Foundation
Melbourne Children’s
Murdoch Children’s Research Institute Flora Suttie Neurogenetics Fellowship
Royal Children’s Hospital
Thyne-Reid Foundation
National Health and Medical Research CouncilAPP1133266, 1068278
State Government of Victoria


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


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