Mitochondrial Complex I Encephalomyopathy and Cerebral 5-Methyltetrahydrofolate Deficiency

Abstract

Folate transport to the brain depends on ATP-driven folate receptor-mediated transport across choroid plexus epithelial cells. Failure of ATP production in Kearns-Sayre syndrome syndrome provides one explanation for the finding of low spinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF) levels in this condition. Therefore, we suspect the presence of reduced folate transport across the blood-spinal fluid barrier in other mitochondrial encephalopathies. In the present patient with mitochondrial complex I encephalomyopathy a low 5-methyltetrahydrofolate level was found in the CSF. Serum folate receptor autoantibodies were negative and could not explain the low spinal fluid folate levels. The epileptic seizures did not respond to primidone monotherapy, but addition of ubiquinone-10 and radical scavengers reduced seizure frequency. Add-on treatment with folinic acid led to partial clinical improvement including full control of epilepsy, followed by marked recovery from demyelination of the brainstem, thalamus, basal ganglia and white matter. Cerebral folate deficiency is not only present in Kearns-Sayre syndrome but may also be secondary to the failure of mitochondrial ATP production in other mitochondrial encephalopathies. Treatment with folinic acid in addition to supplementation with radical scavengers and cofactors of deficient respiratory enzymes can result in partial clinical improvement and reversal of abnormal myelination patterns on neuro-imaging.

Key words

mitochondrial disorder - folate - methyltetrahydrofolate - treatment

References

• 1 Allen RJ, DiMauro S, Coulter DL, Papadimitriou A, Rothenberg SP. Kearns-Sayre syndrome with reduced plasma and cerebrospinal fluid folate.  Ann Neurol. 1983;  13 679-682
• 2 Dougados M, Zittoun J, Laplane D, Castaigne P. Folate metabolism disorder in Kearns-Sayre syndrome.  Ann Neurol. 1983;  13 687
• 3 Fillano JJ, Goldenthal MJ, Rhodes CH, Marin-Garcia J. Mitochondrial dysfunction in patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome.  J Child Neurol. 2002;  17 435-439
• 4 Loeffen JL, Smeitink JA, Trijbels JM, Janssen AJ, Triepels RH, Sengers RC, Heuvel LP van den. Isolated complex I deficiency in children: clinical, biochemical and genetic aspects.  Hum Mutat. 2000;  15 123-134
• 5 Macron JM, Mizon JP, Rosa A. Disorders of folate metabolism in the Kearns-Sayre syndrome.  Rev Neurol (Paris). 1983;  139 673-677
• 6 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
• 7 Pineda M, Ormazabal A, López-Gallardo E, Nascimento A, Solano A, Herrero MD, Vilaseca MA, Briones P, Ibániez L, Montoya J, Artuch R. Cerebral folate deficiency and Leukoencephalopathy caused by mitochondrial DNA deletion.  Ann Neurol. 2006;  59 394-398
• 8 Ramaekers VT, Hausler M, Opladen T, Heimann G, Blau N. Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution.  Neuropediatrics. 2002;  33 301-308
• 9 Ramaekers VT, Rothenberg SP, Sequeira J, Opladen T, Blau N, Quadros EV, Selhub J. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome.  N Engl J Med. 2005;  352 1985-1991
• 10 Schapira AH. Mitochondrial disease.  Lancet. 2006;  368 70-82
• 11 Sheu SS, Nauduri D, Anders MW. Targeting antioxidants to mitochondria: a new therapeutic direction.  Biochim Biophys Acta. 2006;  1762 256-265
• 12 Tanji K, Schon EA, DiMauro S, Bonilla E. Kearns-Sayre syndrome: oncocytic transformation of choroid plexus epithelium.  J Neurol Sci. 2000;  178 29-36
• 13 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

Correspondence