Skip to main content

Advertisement

SpringerLink
Log in

The many faces of paediatric mitochondrial disease on neuroimaging

  • Review Paper
  • Published:
Child's Nervous System Aims and scope Submit manuscript

Abstract

The knowledge about the genetic spectrum underlying paediatric mitochondrial diseases is rapidly growing. As a consequence, the range of neuroimaging findings associated with mitochondrial diseases became extremely broad. This has important implications for radiologists and clinicians involved in the care of these patients. Here, we provide a condensed overview of brain magnetic resonance imaging (MRI) findings in children with genetically confirmed mitochondrial diseases. The neuroimaging spectrum ranges from classical Leigh syndrome with symmetrical lesions in basal ganglia and/or brain stem to structural abnormalities including cerebellar hypoplasia and corpus callosum dysgenesis. We highlight that, although some imaging patterns can be suggestive of a genetically defined mitochondrial syndrome, brain MRI-based candidate gene prioritization is only successful in a subset of patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

ADC:

Apparent diffusion coefficient

CISS:

Constructive interference in steady state

CNS:

Central nervous system

FLAIR:

Fluid attenuation inversion recovery

MELAS:

Mitochondrial encephalopathy, lactic acidoses and stroke-like lesions

MRI:

Magnetic resonance imaging

MRS:

Magnetic resonance spectroscopy

NO:

Nitric oxide

OXPHOS:

Oxidative phosphorylation

PDHC:

Pyruvate dehydrogenase complex

References

  1. Bricout M, Grevent D, Lebre AS, Rio M, Desguerre I, De Lonlay P, Valayannopoulos V, Brunelle F, Rotig A, Munnich A, Boddaert N (2015) Brain imaging in mitochondrial respiratory chain deficiency: combination of brain MRI features as a useful tool for genotype/phenotype correlations. J Med Genet 51:429–435

    Article  Google Scholar 

  2. Kevelam SH, Rodenburg RJ, Wolf NI, Ferreira P, Lunsing RJ, Nijtmans LG, Mitchell A, Arroyo HA, Rating D, Vanderver A, van Berkel CG, Abbink TE, Heutink P, van der Knaap MS (2013) NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern. Neurology 80:1577–1583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lebre AS, Rio M, Faivre d’Arcier L, Vernerey D, Landrieu P, Slama A, Jardel C, Laforet P, Rodriguez D, Dorison N, Galanaud D, Chabrol B, Paquis-Flucklinger V, Grevent D, Edvardson S, Steffann J, Funalot B, Villeneuve N, Valayannopoulos V, de Lonlay P, Desguerre I, Brunelle F, Bonnefont JP, Rotig A, Munnich A, Boddaert N (2010) A common pattern of brain MRI imaging in mitochondrial diseases with complex I deficiency. J Med Genet 48:16–23

    Article  PubMed  Google Scholar 

  4. Lake NJ, Compton AG, Rahman S, Thorburn DR (2016) Leigh syndrome: one disorder, more than 75 monogenic causes. Ann Neurol 79:190–203

    Article  PubMed  Google Scholar 

  5. Baertling F, Rodenburg RJ, Schaper J, Smeitink JA, Koopman WJ, Mayatepek E, Morava E, Distelmaier F (2014) A guide to diagnosis and treatment of Leigh syndrome. J Neurol Neurosurg Psychiatry 85:257–265

    Article  PubMed  Google Scholar 

  6. Leigh D (1951) Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry 14:216–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lake NJ, Bird MJ, Isohanni P, Paetau A (2015) Leigh syndrome: neuropathology and pathogenesis. J Neuropathol Exp Neurol 74:482–492

    Article  CAS  PubMed  Google Scholar 

  8. Medina L, Chi TL, DeVivo DC, Hilal SK (1990) MR findings in patients with subacute necrotizing encephalomyelopathy (Leigh syndrome): correlation with biochemical defect. AJR Am J Roentgenol 154:1269–1274

    Article  CAS  PubMed  Google Scholar 

  9. Valanne L, Ketonen L, Majander A, Suomalainen A, Pihko H (1998) Neuroradiologic findings in children with mitochondrial disorders. AJNR Am J Neuroradiol 19:369–377

    CAS  PubMed  Google Scholar 

  10. Saneto RP, Friedman SD, Shaw DW (2008) Neuroimaging of mitochondrial disease. Mitochondrion 8:396–413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ross B, Bluml S (2001) Magnetic resonance spectroscopy of the human brain. Anat Rec 265:54–84

    Article  CAS  PubMed  Google Scholar 

  12. Lin DD, Crawford TO, Barker PB (2003) Proton MR spectroscopy in the diagnostic evaluation of suspected mitochondrial disease. AJNR Am J Neuroradiol 24:33–41

    PubMed  Google Scholar 

  13. Sijens PE, Smit GP, Rodiger LA, van Spronsen FJ, Oudkerk M, Rodenburg RJ, Lunsing RJ (2008) MR spectroscopy of the brain in Leigh syndrome. Brain Dev 30:579–583

    Article  CAS  PubMed  Google Scholar 

  14. Danhauser K, Haack TB, Alhaddad B, Melcher M, Seibt A, Strom TM, Meitinger T, Klee D, Mayatepek E, Prokisch H, Distelmaier F (2016) EARS2 mutations cause fatal neonatal lactic acidosis, recurrent hypoglycemia and agenesis of corpus callosum. Metab Brain Dis 31:717–721

    Article  CAS  PubMed  Google Scholar 

  15. Bonfante E, Koenig MK, Adejumo RB, Perinjelil V, Riascos RF (2015) The neuroimaging of Leigh syndrome: case series and review of the literature. Pediatr Radiol 46:443–451

    Article  Google Scholar 

  16. Giribaldi G, Doria-Lamba L, Biancheri R, Severino M, Rossi A, Santorelli FM, Schiaffino C, Caruso U, Piemonte F, Bruno C (2012) Intermittent-relapsing pyruvate dehydrogenase complex deficiency: a case with clinical, biochemical, and neuroradiological reversibility. Dev Med Child Neurol 54:472–476

    Article  PubMed  Google Scholar 

  17. El-Hattab AW, Adesina AM, Jones J, Scaglia F (2015) MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab 116:4–12

    Article  CAS  PubMed  Google Scholar 

  18. Yatsuga S, Povalko N, Nishioka J, Katayama K, Kakimoto N, Matsuishi T, Kakuma T, Koga Y (2012) MELAS: a nationwide prospective cohort study of 96 patients in Japan. Biochim Biophys Acta 1820:619–624

    Article  CAS  PubMed  Google Scholar 

  19. Pauli W, Zarzycki A, Krzysztalowski A, Walecka A (2013) CT and MRI imaging of the brain in MELAS syndrome. Pol J Radiol 78:61–65

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ito H, Mori K, Kagami S (2010) Neuroimaging of stroke-like episodes in MELAS. Brain Dev 33:283–288

    Article  PubMed  Google Scholar 

  21. Ohama E, Ohara S, Ikuta F, Tanaka K, Nishizawa M, Miyatake T (1987) Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy. Acta Neuropathol 74:226–233

    Article  CAS  PubMed  Google Scholar 

  22. Betts J, Jaros E, Perry RH, Schaefer AM, Taylor RW, Abdel-All Z, Lightowlers RN, Turnbull DM (2006) Molecular neuropathology of MELAS: level of heteroplasmy in individual neurones and evidence of extensive vascular involvement. Neuropathol Appl Neurobiol 32:359–373

    Article  CAS  PubMed  Google Scholar 

  23. Siddiq I, Widjaja E, Tein I (2015) Clinical and radiologic reversal of stroke-like episodes in MELAS with high-dose L-arginine. Neurology 85:197–198

    Article  PubMed  PubMed Central  Google Scholar 

  24. Iizuka T, Sakai F, Suzuki N, Hata T, Tsukahara S, Fukuda M, Takiyama Y (2002) Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome. Neurology 59:816–824

    Article  CAS  PubMed  Google Scholar 

  25. Scaglia F, Wong LJ, Vladutiu GD, Hunter JV (2005) Predominant cerebellar volume loss as a neuroradiologic feature of pediatric respiratory chain defects. AJNR Am J Neuroradiol 26:1675–1680

    PubMed  Google Scholar 

  26. Holzerova E, Danhauser K, Haack TB, Kremer LS, Melcher M, Ingold I, Kobayashi S, Terrile C, Wolf P, Schaper J, Mayatepek E, Baertling F, Friedmann Angeli JP, Conrad M, Strom TM, Meitinger T, Prokisch H, Distelmaier F (2016) Human thioredoxin 2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neurodegeneration. Brain 139:346–354

    Article  PubMed  Google Scholar 

  27. Naini A, Lewis VJ, Hirano M, DiMauro S (2003) Primary coenzyme Q10 deficiency and the brain. Biofactors 18:145–152

    Article  CAS  PubMed  Google Scholar 

  28. Baertling F, Haack TB, Rodenburg RJ, Schaper J, Seibt A, Strom TM, Meitinger T, Mayatepek E, Hadzik B, Selcan G, Prokisch H, Distelmaier F (2015) MRPS22 mutation causes fatal neonatal lactic acidosis with brain and heart abnormalities. Neurogenetics 16:237–240

    Article  CAS  PubMed  Google Scholar 

  29. Brito S, Thompson K, Campistol J, Colomer J, Hardy SA, He L, Fernandez-Marmiesse A, Palacios L, Jou C, Jimenez-Mallebrera C, Armstrong J, Montero R, Artuch R, Tischner C, Wenz T, McFarland R, Taylor RW (2015) Long-term survival in a child with severe encephalopathy, multiple respiratory chain deficiency and GFM1 mutations. Front Genet 6:102

    PubMed  PubMed Central  Google Scholar 

  30. Vanderver A, Prust M, Tonduti D, Mochel F, Hussey HM, Helman G, Garbern J, Eichler F, Labauge P, Aubourg P, Rodriguez D, Patterson MC, Van Hove JL, Schmidt J, Wolf NI, Boespflug-Tanguy O, Schiffmann R, van der Knaap MS (2014) Case definition and classification of leukodystrophies and leukoencephalopathies. Mol Genet Metab 114:494–500

    Article  Google Scholar 

  31. Baertling F, Schaper J, Mayatepek E, Distelmaier F (2013) Teaching neuroimages: rapidly progressive leukoencephalopathy in mitochondrial complex I deficiency. Neurology 81:e10–e11

    Article  PubMed  Google Scholar 

  32. Huemer M, Karall D, Schossig A, Abdenur JE, Al Jasmi F, Biagosch C, Distelmaier F, Freisinger P, Graham BH, Haack TB, Hauser N, Hertecant J, Ebrahimi-Fakhari D, Konstantopoulou V, Leydiker K, Lourenco CM, Scholl-Burgi S, Wilichowski E, Wolf NI, Wortmann SB, Taylor RW, Mayr JA, Bonnen PE, Sperl W, Prokisch H, McFarland R (2015) Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations. J Inherit Metab Dis 38:905–914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wortmann SB, Zietkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, Strom TM, Meitinger T, Rubio-Gozalbo ME, Chrusciel E, Distelmaier F, Golzio C, Jansen JH, van Karnebeek C, Lillquist Y, Lucke T, Ounap K, Zordania R, Yaplito-Lee J, van Bokhoven H, Spelbrink JN, Vaz FM, Pras-Raves M, Ploski R, Pronicka E, Klein C, Willemsen MA, de Brouwer AP, Prokisch H, Katsanis N, Wevers RA (2015) CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder. Am J Hum Genet 96:245–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany

    Fabian Baertling, Ertan Mayatepek & Felix Distelmaier

  2. Department of Diagnostic and Interventional Radiology, Medical Faculty, University Dusseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany

    Dirk Klee & Jörg Schaper

  3. Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675, Munich, Germany

    Tobias B. Haack, Holger Prokisch & Thomas Meitinger

  4. Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany

    Tobias B. Haack, Holger Prokisch & Thomas Meitinger

  5. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    Thomas Meitinger

Authors
  1. Fabian Baertling
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dirk Klee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tobias B. Haack
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Holger Prokisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas Meitinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ertan Mayatepek
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jörg Schaper
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Felix Distelmaier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Felix Distelmaier.

Ethics declarations

Funding

This project was supported by the BMBF-funded German Network for Mitochondrial Disorders (mitoNET #01GM1113C) and by the E-Rare project GENOMIT (01GM1207). TBH was supported by the BMBF through the Juniorverbund in der Systemmedizin “mitOmics” (FKZ 01ZX1405C). FD was supported by a grant of the Forschungskommission of the Medical Faculty of the Heinrich-Heine-University Düsseldorf. FB was supported by a grant of the German Research Foundation/Deutsche Forschungsgemeinschaft (BA 5758/1-1).

Conflict of interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baertling, F., Klee, D., Haack, T.B. et al. The many faces of paediatric mitochondrial disease on neuroimaging. Childs Nerv Syst 32, 2077–2083 (2016). https://doi.org/10.1007/s00381-016-3190-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00381-016-3190-3

Keywords

Search

Navigation