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Title: S-adenosylmethionine deficiency and demyelination : a study of metabolites of the methyl-transfer pathway in cerebrospinal fluid
Author: Surtees, Robert Alexander Harrison
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1992
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Background. Subacute combined degeneration (SACD) of the spinal cord and brain has a characteristic pattern of demyelination. It is caused by deficiencies of methyl-cobalamin and methyltetrahydrofolate. A very similar pattern of demyelination is seen in acquired immunodeficiency syndrome and some histiocytic syndromes. The pathogenesis of SACD is not known, but the methyl-transfer pathway is implicated. Methods. New high-performance liquid chromatographic methods for the measurement of S-adenosylmethionine (SAM), methionine (MET) and 5-methyltetrahydrofolate (MTHF), critical metabolites in the methyl-transfer pathway, in cerebrospinal fluid (CSF) were devised and validated. Appropriate reference ranges were constructed. CSF concentrations of the metabolites were measured in children with abnormalities of the subcortical white matter due to 1) inborn errors of the methyl-transfer and transulphuration pathways, and 2) immunodeficiency and haemophagocytic syndromes. Infants with post-natal leukomalacia, who have central nervous system (CNS) macrophage activation, and children being treated with L-3,4-dihydroxyphenylalanine (L-DOPA), a compound known to require SAM for its breakdown, were also studied. Results. CSF SAM, but not MET or MTHF, was consistently reduced in those children with inborn errors and immunodeficiency or haemophagocytic syndromes at risk of developing abnormalities of subcortical white matter but not in those children with similar diseases without demyelination. When children with a low SAM and demonstrable demyelination were treated with standard therapy, previously shown to improve the neurological symptoms, SAM status was restored to normal and the white matter abnormalities were ameliorated or reversed. Infants developing leukomalacia and children treated with L-DOPA also proved to be associated with reduced CSF SAM but not MET nor MTHF. Conclusions. SAM deficiency is a critical event in the development of demyelination.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available