Mitochondrial Complex I Encephalomyopathy and Cerebral 5-Methyltetrahydrofolate Deficiency

Cerebral folate deficiency and CNS inflammatory markers in Alpers disease

“…The low CSF levels of 5MTHF in our patient can be explained by blocked transport across the blood-brain barrier due to the presence of FR autoantibodies as well as by increased utilization and catabolism of 5MTHF due to oxidative stress [16]. Another explanation may be a defective transport due to ATP depletion in the choroid plexus, as seen in Kearns-Sayre syndrome.…”

“…However, the presence of folate receptor autoantibodies, oxidative stress and secondary inflammatory responses are able to block folate transfer across the choroid plexus to the CNS. Such primary and secondary forms of cerebral folate deficiency (CFD) with an encephalopathic symptomatology have extensively been described in the infantile-onset CFD syndrome [14], mitochondrial encephalopathies [15], Kearns-Sayre syndrome [16], Rett syndrome [17,18], and Aicardi-Goutières syndrome [19]. The use of antifolate drugs in rare inborn errors of metabolism like deficiency of dihydropteridine reductase, methylenetetrahydrofolate reductase, aromatic aminoacid decarboxylase and 3-phosphoglycerate dehydrogenase should be excluded [14].…”

Disorders of mitochondrial function

“…Dichloroacetate can lower lactate level nonspecifically in mitochondrial disease [114] and may be useful for short treatment of severe acidotic episodes. Recent observations in a small number of patients have suggested that defective ATP-dependent cerebral folate transport may result in reduced CSF 5-methyltetrahydrofolate levels in some patients with mitochondrial disease, with detectable clinical improvement with oral folinic acid supplementation [115,116]. Potential future approaches to mitochondrial disease treatment have recently been reviewed [10 ,33 ].…”

Can folic acid have a role in mitochondrial disorders?

“…However, profound 5-MTHF deficiency was only detected in KSS. By contrast, CFD was less marked in those patients with clinically heterogeneous respiratory chain enzyme deficiencies, including one further reported patient with severe mitochondrial complex I deficiency presenting with low CSF folate values [37].…”