MinireviewWhite matter involvement in mitochondrial diseases
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
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Affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.