Cerebral White Matter Involvement in Children with Mitochondrial Encephalopathies

Abstract

In childhood mitochondrial encephalopathies the common MRI features are bilateral symmetric abnormalities in basal nuclei and brainstem. The presence of diffuse white matter abnormality has been described only in a few cases. Among a series of 110 children with mitochondrial encephalopathies, 8 patients with MR imaging consistent with a leukoencephalopathy were retrospectively evaluated. Diagnosis was based on the recognition of the biochemical defect in muscle homogenate. H-MR spectroscopic imaging was performed in six of them. Biochemical analysis demonstrated a defect of respiratory chain complexes in six patients: complex I in two cases, complex II in two, complex IV in one, multiple complexes defect in one. Pyruvate dehydrogenase deficiency was demonstrated in two patients. MRI showed severe involvement of the brain white matter without significant basal nuclei or brainstem abnormalities. Two patients developed large cystic areas since onset; in two others progressive vacuolisation of affected white matter was seen later in the course of the disease. One patient with pyruvate dehydrogenase deficiency also presented with a diffuse cortical polymicrogyria. H-MR spectroscopic imaging showed a decrease of N-acetylaspartate, choline and creatine with lactate accumulation in five patients, and was normal in one. These findings suggest that mitochondrial disorders should be included in the differential diagnosis of white matter disorders.

Mitochondrial Encephalopathy - Leukoencephalopathies - H-MR Spectroscopic Imaging

References

• 1 Barker P B, Gillard J H, van Zijl P C, Soher B J, Hanley D F, Agildere A M. et al . Acute stroke: evaluation with serial proton MR spectroscopic imaging.  Radiology. 1994;  192 723-732
• 2 Barkovich L, Good W V, Koch T K, Berg B O. Mitochondrial disorders: analysis of their clinical and imaging characteristics.  AJNR. 1993;  14 1119-1137
• 3 Bitsch A, Bruhn H, Vougioukas V, Stringaris A, Lassmann H, Frahm J. et al . Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy.  AJNR. 1999;  20 1619-1627
• 4 Bourgeois M, Goutières F, Chretien D, Roustin P, Munnich A, Aicardi J. Deficiency in complex II of the respiratory chain, presenting as a leukodystrophy in two sisters with Leigh syndrome.  Brain Dev. 1992;  14 404-408
• 5 Brown G K, Squier M V. Neuropathology and pathogenesis of mitochondrial diseases.  J Inher Metab Dis. 1996;  19 553-572
• 6 De Lonlay-Debeney P, von Kleist-Retzow J-C, Hertz-Pannier L, Peudenier S, Cormier-Daire V, Berquin P. et al . Cerebral white matter disease in children may be caused by mitochondrial respiratory chain deficiency.  J Pediatr. 2000;  136 209-214
• 7 Detre J A, Wang Z Y, Bogdan A R, Gusnard D A, Bay C A, Bingham P M. et al . Regional variation in brain lactate in Leigh syndrome by localized 1-H magnetic resonance spectroscopy.  Ann Neurol. 1991;  29 218-221
• 8 Dionisi-Vici C, Ruitenbeek W, Fariello G, Bentlage H, Wanders R JA, Schagger H. et al . New familial mitochondrial encephalopathy with macrocephaly, cardiomyopathy and complex I deficiency.  Ann Neurol. 1997;  42 661-665
• 9 Dubowitz V. Histological and histochemical stains and reactions. Dubowitz V et al. Muscle Biopsy A Practical Approach. 2nd ed. London; Bailliere Tindall 1985: 19-40
• 10 Duncan D B, Herholz K, Kugel H, Roth B, Ruitenbeek W, Heindel W. et al . Positron emission tomography and magnetic resonance spectroscopy of cerebral glycolysis in children with congenital lactic acidosis.  Ann Neurol. 1995;  37 351-358
• 11 Feillet F, Mousson B, Grignon Y, Leonard J V, Vilailhet M. Necrotizing encephalopathy and macrocephaly with mitochondrial complex I deficiency.  Pedatr Neurol. 1999;  20 305-308
• 12 Frahm J, Hanefeld F. Localized proton magnetic resonance spectroscopy of brain disorders in childhood. Bachelard HS Advances in Neurochemistry. Vol. 8. Magnetic Resonance Spectroscopy and Imaging in Neurochemistry. New York; Plenum Press 1997
• 13 Harpey J P, Heron D, Prudent M, Charpentier C, Rustin P, Ponsot G. et al . Diffuse leukodystrophy in an infant with cytochrome-c oxidase deficiency.  J Inher Metab Dis. 1998;  21 748-752
• 14 Samsom J F, Barth P G, de Vries J IP, Menko F H, Ruitenbeek W, van Oost B A. et al . Familial mitochondrial encephalopathy with fetal ultrasonographic ventriculomegaly and intracerebral calcifications.  Eur J Pediatr. 1994;  153 510-516
• 15 Sandhu F S, Dillon W P. MR demonstration of leukoencephalopathy associated with mitochondrial encephalomyopathy: case report.  AJNR. 1991;  12 375-379
• 16 Savoiardo M, Ciceri E, Uziel G, Scotti G. Symmetric lesions of the subthalamic nuclei in mitochondrial encephalopathies: an almost distinctive mark of Leigh disease with COX deficiency.  AJNR. 1995;  16 1746
• 17 Schuelke M, Smeitink J, Mariman E, Loeffen J, Plecko B, Trijbels F. et al . Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy.  Nat Genet. 1999;  21 260-261
• 18 Soher B J, van Zijl P CM, Duyn J H, Barker P B. Quantitative proton spectroscopic imaging of the human brain.  Magn Reson Med. 1996;  35 356-363
• 19 Tiranti V, Hoertnagel K, Carrozzo R, Galimberti C, Munaro M, Granatiero M. et al . Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency.  Am J Hum Genet. 1998;  63 1609-1621
• 20 Topçu M, Saatci I, Apak A, Soylemezoglu F, Akçoren Z. Leigh syndrome in a 3-year-old boy with unusual brain MR imaging and pathologic findings.  AJNR. 2000;  21 224-227
• 21 Uziel G, Garavaglia B, Di Donato S. Carnitine stimulation of pyruvate dehydrogenase complex (PDHC) in isolated human skeletal muscle mitochondria.  Muscle & Nerve. 1988;  11 720-724
• 22 Uziel G, Moroni I, Lamantea E, Fratta G M, Ciceri E, Carrara F. et al . Mitochondrial diseases associated with the T8993 G mutation of the mitochondrial ATPase 6 gene: a clinical, biochemical and molecular study in six families.  J Neurol Neurosurg Psychiatr. 1997;  63 16-22
• 23 Valanne L, Ketonen L, Majander A, Suomalainen A, Pihko H. Neuroradiological findings in children with mitochondrial disorders.  AJNR. 1998;  19 369-377
• 24 Van der Knaap M S, Barth P G, Stroink H, van Nieuwenhuizen O, Arts W FM, Hoogenraad F. et al . Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children.  Ann Neurol. 1995;  37 324-334
• 25 Van der Knaap M S, Jakobs C, Valk J. Magnetic resonance imaging in lactic acidosis.  J Inher Metab Dis. 1996;  19 535-547
• 26 Van der Knaap M S, Barth P G, Gabreëls F JM, Franzoni E, Begeer J H, Stroink H, Rotteveel J J, Valk J. A new leukoencephalopathy with vanishing white matter.  Neurology. 1997;  48 845-855
• 27 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
• 28 Van der Knaap M S, Naidu S, Breiter S N, Blaser S, Stroink H, Springer S. et al . Alexander disease: diagnosis with MR imaging.  AJNR. 2001;  22 541-552
• 29 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
• 30 Zheng X, Shoffner J M, Voljavec A S, Wallace D C. Evaluation of procedures for assaying oxidative phosphorylation enzyme activities in mitochondrial myopathy muscle biopsies.  Biochim Biophys Acta. 1990;  1019 1-10
• 31 Zeviani M, Moraes C T, DiMauro S, Nakase H, Bonilla E, Schon E A. et al . Deletions of mitochondrial DNA in Kearns-Sayre syndrome.  Neurology. 1988;  38 1339-1346
• 32 Zeviani M, Bertagnolio B, Uziel G. Neurological presentation of mitochondrial diseases.  J Inherit Metab Dis. 1996;  19 504-520