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

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

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.
Original languageEnglish
Title of host publicationJIMD Reports
PublisherSpringer
Pages63-70
Volume43
DOIs
Publication statusPublished - 2019

Publication series

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

Cite this

Stutterd, C. A., Lake, N. J., Peters, H., Lockhart, P. J., Taft, R. J., van der Knaap, M. S., ... Leventer, R. J. (2019). Severe leukoencephalopathy with clinical recovery caused by recessive BOLA3 mutations. In JIMD Reports (Vol. 43, pp. 63-70). (JIMD Reports). Springer. https://doi.org/10.1007/8904_2018_100
Stutterd, C. A. ; Lake, N. J. ; Peters, H. ; Lockhart, P. J. ; Taft, R. J. ; van der Knaap, M. S. ; Vanderver, A. ; Thorburn, D. R. ; Simons, C. ; Leventer, R. J. / Severe leukoencephalopathy with clinical recovery caused by recessive BOLA3 mutations. JIMD Reports. Vol. 43 Springer, 2019. pp. 63-70 (JIMD Reports).
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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.",
author = "Stutterd, {C. A.} and Lake, {N. J.} and H. Peters and Lockhart, {P. J.} and Taft, {R. J.} and {van der Knaap}, {M. S.} and A. Vanderver and Thorburn, {D. R.} and C. Simons and Leventer, {R. J.}",
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Stutterd, CA, Lake, NJ, Peters, H, Lockhart, PJ, Taft, RJ, van der Knaap, MS, Vanderver, A, Thorburn, DR, Simons, C & Leventer, RJ 2019, Severe leukoencephalopathy with clinical recovery caused by recessive BOLA3 mutations. in JIMD Reports. vol. 43, JIMD Reports, Springer, pp. 63-70. https://doi.org/10.1007/8904_2018_100

Severe leukoencephalopathy with clinical recovery caused by recessive BOLA3 mutations. / Stutterd, C. A.; Lake, N. J.; Peters, H.; Lockhart, P. J.; Taft, R. J.; van der Knaap, M. S.; Vanderver, A.; Thorburn, D. R.; Simons, C.; Leventer, R. J.

JIMD Reports. Vol. 43 Springer, 2019. p. 63-70 (JIMD Reports).

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

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T1 - Severe leukoencephalopathy with clinical recovery caused by recessive BOLA3 mutations

AU - Stutterd, C. A.

AU - Lake, N. J.

AU - Peters, H.

AU - Lockhart, P. J.

AU - Taft, R. J.

AU - van der Knaap, M. S.

AU - Vanderver, A.

AU - Thorburn, D. R.

AU - Simons, C.

AU - Leventer, R. J.

PY - 2019

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N2 - 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.

AB - 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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Stutterd CA, Lake NJ, Peters H, Lockhart PJ, Taft RJ, van der Knaap MS et al. Severe leukoencephalopathy with clinical recovery caused by recessive BOLA3 mutations. In JIMD Reports. Vol. 43. Springer. 2019. p. 63-70. (JIMD Reports). https://doi.org/10.1007/8904_2018_100