Use this URL to cite or link to this record in EThOS:
Title: Elucidation of the molecular mechanisms responsible for the central folate deficiency associated with mitochondrial disease
Author: Aylett, S.-B.
ISNI:       0000 0004 5362 495X
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Please try the link below.
Access from Institution:
5-Methyltetrahydrofolate (5-MTHF) is involved in over 100 metabolic reactions. Potentially treatable cerebral folate deficiency (CFD) of 5-MTHF in cerebrospinal fluid (CSF) is associated in mitochondrial disease. The prevalence and significance of CSF 5-MTHF deficiency in mitochondrial disease was initially investigated. Prevalence of CSF 5-MTHF deficiency in skeletal muscle mitochondrial respiratory chain enzyme (RCE) defects was 15% and the minimum population prevalence of mitochondrial disease with CSF 5-MTHF deficiency was at least one in 30,000. This suggests under-diagnosis of the condition. The most common RCE defect in CSF 5-MTHF deficient patients was isolated complex IV deficiency. Severe CSF 5-MTHF deficiencies (<10 nmol/L) were confined to Kearns-Sayre syndrome or FOLR1 mutations. A novel homozygous missense mutation in FOLR1 exon 5 was observed. Oral folinic acid supplementation restored CSF 5-MTHF levels to within the age-related reference range in the majority of cases. Measurement of CSF 5-MTHF and, where appropriate, FOLR1 mutation analysis, in suspected mitochondrial disease patients is recommended. The mechanisms responsible for CFD in mitochondrial disease are unclear. The potential role of oxidative stress as a contributing mechanism was also investigated. CSF conveyed antioxidant properties towards 5-MTHF, which were overcome by hydroxyl radicals. CSF antioxidants may include ascorbic acid (AA). A CSF AA reference range was established and a significant positive correlation between CSF 5-MTHF and AA demonstrated. In SH-SY5Y cells, inhibition of mitochondrial complex I caused increased mitochondrial superoxide generation and significantly increased loss of 5-MTHF from the extracellular medium. Selenium has been reported to be elevated in CFD. The latter observation was also seen following treatment of cells with the selenium compound selenite; selenite has previously been implicated in ROS generation. Addition of AA prevented 5-MTHF degradation. Oxidative stress may be a factor in the development of CFD. Co-supplementation of folinic acid and AA may be of therapeutic benefit.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available