Recent advances in the mechanism of pyridoxine‐responsive disorders

Abstract

Pyridoxine metabolism is summarised and speculation on possible defects leading to disease is made. Inherited deficiencies of PLP enzymes, which are known to respond in vivo to pharmacologic doses of pyridoxine are listed. The mechanism of pyridoxine responsiveness in homocystinuria due to cystathionine beta-synthase deficiency is discussed. There is a correlation in most (but not all) cases between the presence of residual CS activity, which is often stimulated by pyridoxal phosphate much more than control enzyme, in cultured fibroblasts and pyridoxine responsiveness in vivo. Exceptional patients have been found and are discussed in the light of more detailed studies on their cell lines. Clearly defined abnormalities of pyridoxal phosphate binding to mutant enzyme have been demonstrated and evidence of reduced intracellular stability of mutant CS and possible modulation by pyridoxal phosphate is presented. Preliminary findings suggest that the tissue level of pyridoxal phosphate achieved following pyridoxine treatment could be one other factor in determining pyridoxine responsiveness.

Non-nutritional uses of vitamin B6

“…A number of (rare) genetic conditions are known in which a PLP-dependent enzyme has a defect in the coenzyme binding site, and only has significant activity when the tissue concentration of PLP is very much higher than normal. For such conditions (listed in Table 2), supplements of 200-1000 mg/d are required for life (Frimpter et al 1969;Mudd, 1971;Fowler, 1985).…”

Effects of a single dose of N-carbamylglutamate on the rate of ureagenesis

“…Similarly, it is possible that a subset of patients with mutations of CPS1 could benefit from treatment, especially if the mutation affected the binding of NAG. It also may be that binding of NCG to CPS1 could help to stabilize an otherwise labile enzyme, as may occur with regard to the binding of pyridoxine to cystathionine synthase (EC 4.2.1.22) [36] or reduced biopterin to phenylalanine hydroxylase (EC 1.5.1.34) [37]. …”

New therapeutic approach to Tourette Syndrome in children based on a randomized placebo-controlled double-blind phase IV study of the effectiveness and safety of magnesium and vitamin B6

“…It can be administered to children, and has been authorized for use to treat children with alterations in character, language and behaviour; learning difficulties; delayed learning to walk; convulsive illnesses; intoxication of the central nervous system; trembling; and Parkinson's disease. The dosage provided may vary widely, as renal elimination ensures its toxicity is minimal [ 52 ].…”