Disorders affecting vitamin B₆ metabolism

Abstract

Vitamin B6 is present in our diet in many forms, however, only pyridoxal 5′‐phosphate (PLP) can function as a cofactor for enzymes. The intestine absorbs nonphosphorylated B6 vitamers, which are converted by specific enzymes to the active PLP form. The role of PLP is enabled by its reactive aldehyde group. Pathways reliant on PLP include amino acid and neurotransmitter metabolism, folate and 1‐carbon metabolism, protein and polyamine synthesis, carbohydrate and lipid metabolism, mitochondrial function and erythropoiesis. Besides the role of PLP as a cofactor B6 vitamers also play other cellular roles, for example, as antioxidants, modifying expression and action of steroid hormone receptors, affecting immune function, as chaperones and as an antagonist of Adenosine‐5'‐triphosphate (ATP) at P2 purinoceptors. Because of the vital role of PLP in neurotransmitter metabolism, particularly synthesis of the inhibitory transmitter γ‐aminobutyric acid, it is not surprising that various inborn errors leading to PLP deficiency manifest as B6‐responsive epilepsy, usually of early onset. This includes pyridox(am)ine phosphate oxidase deficiency (a disorder affecting PLP synthesis and recycling), disorders affecting PLP import into the brain (hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects), a disorder of an intracellular PLP‐binding protein (PLPBP, previously named PROSC) and disorders where metabolites accumulate that inactivate PLP, for example, ALDH7A1 deficiency and hyperprolinaemia type II. Patients with these disorders can show rapid control of seizures in response to either pyridoxine and/or PLP with a lifelong dependency on supraphysiological vitamin B6 supply. The clinical and biochemical features of disorders leading to B6‐responsive seizures and the treatment of these disorders are described in this review.

Diagnostic pitfalls in vitamin B6‐dependent epilepsy caused by mutations in the PLPBP gene

“…CSF glycine was measured in five of these cases and glycine elevation was slightly more discrete than in patient 1 in this report, clearly below the values reached in patients with glycine encephalopathy, and persistent at 6 weeks and 17 months in two patients . In this regard, lactic acidemia as well as hyperglycinemia appear to be additional diagnostic pitfalls in patients with vitamin B6‐responsive epilepsies, possibly especially prominent in PLPHP deficiency . Increasing awareness toward these early secondary metabolic changes, may help to clarify whether elevated lactic acid and glycine are a more consistent biochemical feature in PLPHP deficient patients.…”

“…Pathogenicity of p.(Arg41Trp) is supported by the previous identification of the substitution of arginine 41 by glutamine in five patients with relatively mild clinical severity of vitamin B6‐dependent epilepsy due to PLPBP variants (four homozygous, one compound heterozygous) . Overall, 13 missense and 7 splice‐site and null (nonsense and frameshift) variants in PLPBP have been identified . Missense variants were shown to decrease the structural stability of the protein or interfere with PLP‐binding properties .…”

“…8,9 Overall, 13 missense and 7 splice-site and null (nonsense and frameshift) variants in PLPBP have been identified. 8,10,14 Missense variants were shown to decrease the structural stability of the protein or interfere with PLP-binding properties. 8,14 The splice-site and null variants were associated with the most severe phenotypic presentations.…”

“…8,10,14 Missense variants were shown to decrease the structural stability of the protein or interfere with PLP-binding properties. 8,14 The splice-site and null variants were associated with the most severe phenotypic presentations. 8 By applying an adapted clinical severity score 15 a genotype-phenotype correlation for this patient group was recently established.…”

B Vitamins: Small molecules, big effects

“…7 Finally, there is a comprehensive review of vitamin B12, folate and the methionine remethylation cycle, focussing on biochemical pathways and regulation 8 , accompanied by a clinical review of the cobalaminrelated disorders. 9 In conclusion, we anticipate that improved understanding of the complex relationships between the different biochemical pathways regulated in the brain by these vitamins will facilitate more prompt diagnosis and improved treatment of inborn errors and acquired B vitamin deficiencies in the future.…”