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White matter involvement in mitochondrial diseases

https://doi.org/10.1016/j.ymgme.2004.09.008Get rights and content

Abstract

White matter involvement is recently being realized as a common finding in mitochondrial disorders. It is considered an inherent part of the classical mitochondrial syndromes which are usually associated with alterations in the mitochondrial DNA such as: Leigh disease, Kearns–Sayre syndrome, mitochondrial encephalomyopathy lactic acidosis, and stroke like episodes, mitochondrial neuro-gastro-intestinal encephalomyopathy and Leber’s hereditary optic neuropathy. White matter involvement is also described in mitochondrial disorders due to mutations in the nuclear DNA which are transmitted in an autosomal pattern. MRI findings suggestive of a mitochondrial disease are: small cyst-like lesions in abnormal white matter, involvement of both cerebral and cerebellar white matter, and a combination of a leukoencephalopathy with bilateral basal ganglia lesions. The clinical manifestations may be disproportionate to the extent of white matter involvement. Other organs may frequently be involved. The onset is often in infancy with a neurodegenerative course. The finding of a leukoencephalopathy in a patient with a complex neurologic picture and multisystem involvement should prompt a thorough mitochondrial evaluation.

Introduction

Leukoencephalopathies, include a wide spectrum of inherited neurodegenerative disorders affecting the integrity of myelin in the brain. In the past most were attributed to lysosomal storage diseases or peroxisomal disorders. However, in the last decade white matter involvement has been described in mitochondrial syndromes, mostly due to mutations or rearrangements in the mtDNA: Leigh disease, Kearns–Sayre syndrome, mitochondrial encephalomyopathy lactic acidosis and stroke like episodes (MELAS), mitochondrial neuro-gastro-intestinal encephalomyopathy (MNGIE), and Leber’s hereditary optic neuropathy (LHON).

A few small series have been described. In 1993, Barkovich et al. [1] reviewed the neuroimaging findings in children with mitochondrial syndromes. All patients showed the classical involvement of the deep gray matter early in the disease but in some patients with MELAS, MERRF, Kearns–Sayre, and Leigh syndromes, T2 prolongation was also seen in the white matter with the peripheral and retrotrigonal white matter showing early involvement. The authors concluded that the combination of deep gray matter and peripheral white matter involvement in young adults or children should suggest the diagnosis of a mitochondrial disorder. In 1995, Huang et al. [2] described white matter involvement in two patients with MELAS from a series of seven patients with mitochondrial encephalomyopathies: there were subcortical white matter lesions most prominent in the periventricular areas. Wray et al. [3] in 1995, described white matter abnormalities in patients with Kearns–Sayre syndrome and chronic progressive ophthalmoplegia: hyperintense signal abnormalities on T2-weighted images within the cerebral white matter in three out of eight patients. In two, the lesions were primarily peripheral and involved the arcuate fibers.

All three publications belong to the era where nuclear defects were not appreciated as a major cause of mitochondrial encephalomyopathies and therefore most of the patients reviewed had mtDNA mutations or deletions. Recently, mutations in nuclear encoded oxidative phosphorylation (OXPHOS) subunits and non-OXPHOS mitochondrial proteins associated with some aspect of the biogenesis of the respiratory chain are increasingly being recognized as the cause of encephalomyopathies [4]. It has become clear that in pediatric patients most mitochondrial disorders are transmitted in an autosomal recessive fashion and are due to nuclear genetic defects [5].

The first series of mitochondrial patients with white matter involvement that did not include only well classified mitochondrial syndromes was published in 1998 by Valanne et al. [6]. Diffuse supratentorial white matter T2 hyperintensity was seen in two patients with Leigh syndrome. One patient with combined complex I (EC1.6.5.3) and IV (EC1.9.3.1) deficiency had extensive white matter changes.

The occurrence of a severe leukoencephalopathy as the major manifestation of a genetic defect of oxidative phosphorylation has only recently been appreciated. The first series of patients presenting with cerebral white matter disease caused by mitochondrial disorders was described by de Lonlay-Debeney et al. [7]. The authors found respiratory enzyme deficiencies or mtDNA rearrangements in five patients with white matter involvement. In three, the leukoencephalopathy was the major manifestation. Kang et al. [8] reported infantile leukoencephalopathy owing to mitochondrial enzyme dysfunction in six infants from five families. The neurodegenerative process was characterized primarily by abnormalities in deep white-matter structures such as the periventricular region, internal capsule, and corpus callosum. The patients had impairments of mitochondrial enzymes, including a pre-electron transport chain defect and defects in respiratory chain complexes I, III (EC1.10.2.2), and IV. Moroni et al. [9] reviewed 110 MRI’s of children with mitochondrial disorders and identified eight patients with MR imaging consistent with a leukoencephalopathy. Biochemical analysis demonstrated a defect of respiratory chain complexes in six patients: complex I in two cases, complex II (1.3.5.1) in two, complex IV in one, multiple complexes defect in one. Pyruvate dehydrogenase (EC1.2.2.2) deficiency was demonstrated in two patients. A unique feature was the finding of cystic lesions in four of the patients. H-MR spectroscopic imaging showed a decrease of N-acetylaspartate, choline, and creatine with lactate accumulation in five patients, and was normal in one.

Section snippets

Leber’s hereditary optic neuropathy

LHON is a maternally inherited mitochondrial disease characterized by acute or subacute bilateral optic neuropathy. It is the most common mitochondrial disease affecting vision. Onset is during the 2nd and 3rd decades of life. The peak incidence is around age 20 years, but the presentation can be as early as 1 year of age and as late as 80 years. About 40% start in childhood. A male predominance of 80–90% is found in most pedigrees. The acute/subacute bilateral visual loss usually progresses

Complex I deficiency (NADH: ubiquinone oxidoreductase EC1.6.5.3)

Complex I is a multi-subunit protein structure at the inner mitochondrial membrane that transfers electrons from NADH to ubiquinone while pumping hydrogen ions out of the mitochondrial matrix into the inter-membrane space. It consists of 43 subunits of which 36 are encoded by nuclear genes. Isolated complex I deficiency is the most common enzyme defect among the group of OXPHOS disorders. There are many clinical presentations attributed to isolated complex I deficiency [24]. Leigh or Leigh-like

Conclusions

Genetic disorders of the mitochondrial respiratory chain should be regarded as possible and relatively frequent causes of diffuse leukoencephalopathy. The etiologies are multiple and the inheritance patterns vary. There is no typical course. Clinical involvement may be disproportionate to the extent of white matter involvement. New white matter lesions may be acquired during periods of clinical deterioration. Other organs are frequently involved (especially the eyes and heart). Many patients

References (77)

  • D.I. Zafeiriou et al.

    Deficiency in complex IV (cytochrome c oxidase) of the respiratory chain, presenting as leukodystrophy in two siblings with Leigh syndrome

    Brain Dev.

    (1995)
  • V. Carelli et al.

    Mitochondrial dysfunction as a cause of optic neuropathies

    Prog. Retin. Eye. Res.

    (2004)
  • A.J. Barkovich et al.

    Mitochondrial disorders: analysis of their clinical and imaging characteristics

    Am. J. Neuroradiol.

    (1993)
  • S.H. Wray et al.

    MR of the brain in mitochondrial myopathy

    Am. J. Neuroradiol.

    (1995)
  • E.A. Shoubridge

    Nuclear genetic defects of oxidative phosphorylation

    Hum. Mol. Genet.

    (2001)
  • L. Valanne et al.

    Neuroradiologic findings in children with mitochondrial disorders

    Am. J. Neuroradiol.

    (1998)
  • P.B. Kang et al.

    Infantile leukoencephalopathy owing to mitochondrial enzyme dysfunction

    J. Child Neurol.

    (2002)
  • I. Moroni et al.

    Cerebral white matter involvement in children with mitochondrial encephalopathies

    Neuropediatrics

    (2002)
  • P.Y. Man et al.

    Leber hereditary optic neuropathy

    J. Med. Genet.

    (2002)
  • K.M. Flanigan et al.

    Association of the 11,778 mitochondrial DNA mutation and demyelinating disease

    Neurology

    (1993)
  • E.K. Nikoskelainen et al.

    Leber’s “plus”: neurological abnormalities in patients with Leber’s hereditary optic neuropathy

    J. Neurol. Neurosurg. Psychiatry

    (1995)
  • M.T. Bhatti et al.

    A multiple sclerosis-like illness in a man harboring the mtDNA 14,484 mutation

    J. Neuroophthalmol.

    (1999)
  • B. Kalman et al.

    Is the mitochondrial DNA involved in determining susceptibility to multiple sclerosis?

    Acta Neurol. Scand.

    (1998)
  • I.O. Kim et al.

    Mitochondrial myopathy-encephalopathy-lactic acidosis-and stroke-like episodes (MELAS) syndrome: CT and MR findings in seven children

    Am. J. Roentgenol.

    (1996)
  • M. Castillo et al.

    MELAS syndrome: imaging and proton MR spectroscopic findings

    Am. J. Neuroradiol.

    (1995)
  • F. Degoul et al.

    Myo-leukoencephalopathy in twins: study of 3243-myopathy, encephalopathy, lactic acidosis, and stroke-like episodes mitochondrial DNA mutation

    Ann. Neurol.

    (1994)
  • D. Leigh

    Subacute necrotizing encephalomyelopathy in an infant

    J. Neurol. Neurosurg. Psychiatry

    (1951)
  • S. Rahman et al.

    Leigh syndrome: clinical features and biochemical and DNA abnormalities

    Ann. Neurol.

    (1996)
  • N. Darin et al.

    The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities

    Ann. Neurol.

    (2001)
  • A.A. Morris et al.

    Deficiency of respiratory chain complex I is a common cause of Leigh disease

    Ann. Neurol.

    (1996)
  • J.L. Loeffen et al.

    Isolated complex I deficiency in children: clinical, biochemical and genetic aspects

    Hum. Mutat.

    (2000)
  • I. Yamadori et al.

    Brain lesions of the Leigh-type distribution associated with a mitochondriopathy of Pearson’s syndrome: light and electron microscopic study

    Acta Neuropathol. (Berl.)

    (1992)
  • W. Lissens et al.

    Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency

    Hum. Mutat.

    (2000)
  • T. Bourgeron et al.

    Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency

    Nat. Genet.

    (1995)
  • M.O. Pequignot et al.

    Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome c oxidase deficiency

    Hum. Mutat.

    (2001)
  • H. Antonicka et al.

    Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early onset clinical phenotypes associated with isolated COX deficiency

    Hum. Mol. Genet.

    (2003)
  • D.D. De-Vries et al.

    A second missense mutation in the mitochondrial ATPase 6 gene in Leigh’s syndrome

    Ann. Neurol.

    (1993)
  • Y. Campos et al.

    Leigh syndrome associated with the T9176C mutation in the ATPase 6 gene of mitochondrial DNA

    Neurology

    (1997)
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    Affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

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