Pyridoxine responsiveness in PNPO deficiency

Posted by & filed under Part 17: VITAMINS, Part 28: NEUROGENETICS.

Plecko B, Paul K, Mills P, et al. (2014) Pyridoxine responsiveness in novel mutations of the PNPO gene. Neurology 82(16): 1425-1433.

Pyridoxal 5’-phosphate dependent epilepsy due to pyridox(am)ine 5’-phosphate oxidase deficiency is a newly discovered treatable cause of neonatal epileptic encephalopathy, clinically resembling pyridoxine-dependent epilepsy due to antiquitin deficiency  (Mills, Surtees et al. 2005). PNPO converts pyridoxine 5’-phosphate and pyridoxamine 5’-phosphate into pyridoxal 5’-phosphate (PLP; the only active form of vitamin B6). In keeping with this mechanism, most of the initially described patients with PNPO deficiency did not respond to pyridoxine, but did respond to PLP. This has been thought to provide a clinical means of discriminating between antiquitin deficiency and PNPO deficiency.

Recent studies, however, have suggested a more complex picture. For instance, Plecko et al performed PNPO gene analysis on a cohort of 31 patients presenting with pyridoxine-responsive seizures, but in whom antiquitin deficiency has been ruled out, and identified deleterious PNPO mutations in 9 living patients from 7 unrelated families. Surprisingly, two of these patients reacted poorly (with status epilepticus) to being switched from pyridoxine to PLP treatment.

These findings suggest that pyridoxine responsiveness in PNPO deficiency may be more common than initially thought, perhaps due to residual enzyme function being maximised by increased substrate; further studies are also needed to gain a more nuanced view of the molecular pathophysiology of the disorder, and in particular to explain some pyridoxine-responsive patients’ deterioration when switched to PLP.

Posted by Alina Levtova, MD

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