Download PDF
Neuropediatrics 2005; 36(5): 290-301
DOI: 10.1055/s-2005-872807
Original Article

Georg Thieme Verlag KG Stuttgart · New York

Brain MRI and Proton MRS Findings in Infants and Children with Respiratory Chain Defects

A. Dinopoulos1 , K. M. Cecil2 , M. B. Schapiro1 , A. Papadimitriou3 , G. M. Hadjigeorgiou3 , B. Wong1 , T. deGrauw1 , J. C. Egelhoff2
  • 1Cincinnati Children's Hospital Medical Center, Division of Neurology, Cincinnati, Ohio, USA
  • 2Cincinnati Children's Hospital Medical Center, Department of Radiology, Cincinnati, Ohio, USA
  • 3University of Thessaly, Department of Neurology, Larissa, Greece
Further Information

Publication History

Received: February 18, 2005

Accepted after Revision: July 7, 2005

Publication Date:
26 September 2005 (online)

Also available at
    Permissions and Reprints

Abstract

Objective: The aim of this study is to describe neuroimaging patterns in children with respiratory chain (RC) defects using magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) and to assess their role in the diagnostic evaluation. Method: Neuroimaging studies of 49 children (newborn to 15 years old) with biochemical evidence of RC defect were reviewed. Patients were divided in 3 groups (“definite” = 24, “probable” = 14, “possible” = 11) according to Modified Adult Criteria for the diagnosis of RC defect. Eighty-one MRI studies were reviewed for deep gray and white matter changes, degree of myelination, cerebral and cerebellar atrophy, and 67 proton MRS studies were assessed for the presence or absence of lactate elevation, as well as NAA/Cr ratio. The findings were compared among the 3 groups with chi-square test. Results: All patients with “pure” myopathy had normal imaging studies. In patients with CNS involvement, significant differences in the frequency of imaging abnormalities among groups were found for deep gray matter (43 %/8 %/0 %; p = 0.01) and for the presence of lactate elevation on proton MRS (81 %/31 %/0 %; p = 0.001). Conclusion: Brain MRI and proton MRS abnormalities were observed only in association with clinical CNS involvement. Deep gray matter signal abnormalities on structural imaging and lactate elevation on proton MRS were more frequently observed in the “definite” group and represent neuroimaging markers for RC mitochondriopathy.

Key words

Mitochondrial encephalomyopathy - respiratory chain defect - childhood - MRI - MRS

References

  • 1 Barkovich A J, Good W V, Koch T K, Berg B O. Mitochondrial disorders: analysis of their clinical and imaging characteristics.  AJNR Am J Neuroradiol. 1993;  14 1119-1137
    PubMedSearch in Google Scholar
  • 2 Berkovic S F, Carpenter S, Evans A, Karpati G, Shoubridge E A, Andermann F, Meyer E, Tyler J L, Diksic M, Arnold D, Wolfe L S, Andermann E, Hakim A M. Myoclonus epilepsy and ragged-red fibres (MERRF). 1. A clinical, pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study.  Brain. 1989;  112 (Pt 5) 1231-1260
    PubMedSearch in Google Scholar
  • 3 Bernier F P, Boneh A, Dennett X, Chow C W, Cleary M A, Thorburn D R. Diagnostic criteria for respiratory chain disorders in adults and children.  Neurology. 2002;  59 1406-1411
    CrossrefPubMedSearch in Google Scholar
  • 4 Bianchi C M, Tossetti M, Battini R, Manca L M, Mancuso M, Cioni G, Canapicchi R, Siciliano G. Proton MRS of mitochondrial diseases: Analysis of brain metabolic abnormalities and their possible diagnostic relevance.  AJNR Am J Neuroradiol. 2003;  24 1958-1966
    PubMedSearch in Google Scholar
  • 5 Brockmann K, Dechent P, Meins M, Haupt M, Sperner J, Stephanie U, Frahm J, Hanafeld F. Cerebral proton MRS in infantile Alexander disease.  J Neurol. 2003;  250 300-306
    PubMedSearch in Google Scholar
  • 6 Castillo M, Kwock L, Green C. MELAS syndrome: Imaging and proton MR spectroscopic findings.  Am J Neuroradiol. 1995;  16 233-239
    PubMedSearch in Google Scholar
  • 7 Cavanagh B J, Harding N B. Pathogenic factors underlying the lesions in Leigh's disease.  Brain. 1994;  117 1357-1376
    CrossrefPubMedSearch in Google Scholar
  • 8 de Lonlay-Debeney P, von Kleist-Retzow J C, Hertz-Pannier L, Peudenier S, Cormier-Daire V, Berquin P, Chretien D, Rotig A, Saudubray J M, Baraton J, Brunelle F, Rustin P, Van Der Knaap M, Munnich A. Cerebral white matter disease in children may be caused by mitochondrial respiratory chain deficiency.  J Pediatr. 2000;  136 209-214
    PubMedSearch in Google Scholar
  • 9 DiMauro S. Mitochondrial diseases.  Biochim Biophys Acta. 2004;  1658 80-88
    PubMedSearch in Google Scholar
  • 10 Farina L, Chiapparini L, Uziel G, Bugiani M, Zeviani M, Savoiardo M. MR findings in Leigh Syndrome with COX deficiency and SURF‐1 mutation.  Am J Neuroradiol. 2002;  23 1095-1100
    PubMedSearch in Google Scholar
  • 11 Kang P B, Hunter J V, Kaye E M. Lactic acid elevation in extramitochondrial childhood neurodegenerative diseases.  J Child Neurol. 2001;  16 657-660
    PubMedSearch in Google Scholar
  • 12 Kapeller P, Fazekas F, Offenbacher H, Stollberger R, Schmidt R, Bergloff J, Radner H, Fazekas G, Schafhalter-Zoppoth I. Magnetic resonance imaging and spectroscopy of progressive cerebral involvement in Kearns Sayre syndrome.  J Neurol Sci. 1996;  135 126-130
    CrossrefPubMedSearch in Google Scholar
  • 13 Kaufmann P, Shungu D C, Sano M C, Jhung S, Engelstad K, Mitsis E, Mao X, Shanske S, Hirano M, DiMauro S, De Vivo D C. Cerebral lactic acidosis correlates with neurological impairment in MELAS.  Neurology. 2004;  62 1297-1302
    PubMedSearch in Google Scholar
  • 14 Kirby D M, Crawford M, Cleary M A, Dahl H HM, Dennet X, Thorburn D R. Respiratory chain complex I deficiency. An underdiagnosed energy generation disorder.  Neurology. 1999;  52 1255-1264
    PubMedSearch in Google Scholar
  • 15 Krageloh-Mann I, Grodd W, Schoning M, Marquard K, Nagele T, Ruitenbeek W. Proton spectroscopy in five patients with Leigh's disease and mitochondrial enzyme deficiency.  Dev Med Child Neurol. 1993;  35 769-776
    PubMedSearch in Google Scholar
  • 16 Krahenbuhl S, Talco C, Wiesmann U, Hoppel C L. Development and evaluation of a spectrophotometric assay for complex III in isolated mitochondria, tissues and fibroblasts from rats and humans.  Clin Chim Acta. 1994;  230 177-187
    CrossrefPubMedSearch in Google Scholar
  • 17 Lammont P J, Surtees R, Woodward C E, Leonard J V, Wood N W, Harding A E. Clinical and laboratory findings in referral for mitochondrial DNA analysis.  Arch Dis Child. 1998;  79 22-27
    PubMedSearch in Google Scholar
  • 18 Lin D D, Crawford T O, Barker P B. Proton MR spectroscopy in the diagnostic evaluation of mitochondrial disease.  AJNR Am J Neuroradiol. 2003;  24 33-44
    PubMedSearch in Google Scholar
  • 19 Lindner A, Hofmann E, Naumann M, Becker G, Reichmann H. Clinical, morphological, biochemical, and neuroradiological features of mitochondrial encephalomyopathies. Presentation of 19 patients.  Mol Cell Biochem. 1997;  174 297-303
    CrossrefPubMedSearch in Google Scholar
  • 20 Mathews P M, Andermann F, Silver K, Karpati G, Arnold D L. Proton MR spectroscopic characterization of differences in regional brain metabolic abnormalities in mitochondrial encephalomyopathies.  Neurology. 1993;  43 2484-2490
    PubMedSearch in Google Scholar
  • 21 Moroni I, Bugiani M, Bizzi A, Castelli G, Lamantea E, Uziel G. Cerebral white matter involvement in children with mitochondrial encephalopathies.  Neuropediatrics. 2002;  33 79-85
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Munoz A, Mateos F, Simon R, Garcia-Silva M T, Cabello S, Arenas J. Mitochondrial diseases in children: neuroradiological and clinical features in 17 patients.  Neuroradiology. 1999;  41 920-928
    CrossrefPubMedSearch in Google Scholar
  • 23 Nishino I, Spinazzola A, Papadimitriou A, Hammans S, Steiner I, Hahn C D, Connolly A M, Verloes A, Guimaraes J, Maillard I, Hamano H, Donati M A, Semrad C E, Russell J A, Andreu A L, Hadjigeorgiou G M, Vu T H, Tadesse S, Nygaard T G, Nonaka I, Hirano I, Bonilla E, Rowland L P, DiMauro S, Hirano M. Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.  Ann Neurol. 2000;  47 792-800
    CrossrefPubMedSearch in Google Scholar
  • 24 Papadimitriou A, Comi G P, Hadjigeorgiou G M, Bordoni A, Sciacco M, Napoli L, Prelle A, Moggio M, Fagiolari G, Bresolin N, Salani S, Anastasopoulos I, Giassakis G, Divari R, Scarlato G. Partial depletion and multiple deletions of muscle mtDNA in familial MNGIE syndrome.  Neurology. 1998;  51 1086-1092
    CrossrefPubMedSearch in Google Scholar
  • 25 Powers J M, DeVivo D C. Peroxisomal and mitochondrial disorders. Graham DI, Lantos PL Greenfield's Neuropathology. London; Arnold 2002: 758-797
    Search in Google Scholar
  • 26 Scaglia F, Towbin J A, Craigen W J, Belmont J W, Smith E O, Neish S R, Ware S M, Hunter J V, Fernbach S D, Vladutiu G D, Wong L J, Vogel H. Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease.  Pediatrics. 2004;  114 925-931
    CrossrefPubMedSearch in Google Scholar
  • 27 Shoubridge E A. Nuclear genetic defects of oxidative phosphorylation.  Hum Mol Genet. 2001;  10 2277-2284
    CrossrefPubMedSearch in Google Scholar
  • 28 Sparaco M, Bonilla E, DiMauro S, Powers J M. Neuropathology of mitochondrial encephalomyopathies due to mitochondrial DNA defects.  J Neuropathl Exp Neurol. 1993;  52 1-10
    PubMedSearch in Google Scholar
  • 29 Szigeti K, Sule N, Adesina A M, Armstrong D L, Saifi G M, Bonilla E, Hirano M, Lupski J R. Increased blood-brain barrier permeability with thymidine phosphorylase deficiency.  Ann Neurol. 2004;  56 881-886
    CrossrefPubMedSearch in Google Scholar
  • 30 Thorburn D R, Smeitink J. Diagnosis of mitochodrial disorders: Clinical and biochemical approach.  J Inherit Metab Dis. 2001;  24 312-316
    CrossrefPubMedSearch in Google Scholar
  • 31 Valanne L, Ketonen L, Majander A, Suomalainen A, Pihko H. Neuroradiologic findings in children with mitochondrial disorders.  AJNR Am J Neuroradiol. 1998;  19 369-377
    PubMedSearch in Google Scholar
  • 32 van der Knaap M S, Kamphorst W, Barth P G, Kraaijeveld C L, Gut E, Valk J. Phenotypic variation in leukoencephalopathy with vanishing white matter.  Neurology. 1998;  51 540-547
    CrossrefPubMedSearch in Google Scholar
  • 33 van der Knaap M S, van der Voorn P, Barkhof F, Van Coster R, Krageloh-Mann I, Feigenbaum A, Blaser S, Vles J S, Rieckmann P, Pouwels P J. A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate.  Ann Neurol. 2003;  53 252-258
    CrossrefPubMedSearch in Google Scholar
  • 34 Wolf N I, Smeitink J A. Mitochondrial disorders: a proposal for consensus diagnostic criteria in infants and children.  Neurology. 2002;  59 1402-1405
    CrossrefPubMedSearch in Google Scholar
  • 35 Wray S H, Provenzale J M, Johns D R, Thulborn K R. MR of the brain in mitochondrial myopathy.  Am J Neuroradiol. 1995;  16 1167-1173
    PubMedSearch in Google Scholar
  • 36 Zafeiriou D I, Koletzko B, Mueller-Felber W, Paetzke I, Kueffer G, Jensen M. Deficiency in complex IV (cytochrome c oxidase) of the respiratory chain, presenting as a leukodystrophy in two siblings with Leigh syndrome.  Brain Dev. 1995;  17 117-121
    CrossrefPubMedSearch in Google Scholar

MD Agirios Dinopoulos

Cincinnati Children's Hospital Medical Center
Division of Neurology

3333 Burnet Avenue

Cincinnati

OH 45229-3039

USA

Email: Agirios.Dinopoulos@cchmc.org