High-dose pyridoxine treatment for inherited glycosylphosphatidylinositol deficiency

Abstract

Objective: We aimed to assess the efficacy and safety of high-dose pyridoxine treatment for seizures and its effects on development in patients with inherited glycosylphosphatidylinositol deficiencies (IGDs).Methods:In this prospective open-label multicenter pilot study, we enrolled patients diagnosed with IGDs using flow cytometry and/or genetic tests. The patients received oral pyridoxine (20-30 mg/kg/day) for 1 year, in addition to previous treatment.Results: All nine enrolled patients (mean age: 66.3 ± 44.3 months) exhibited marked decreases in levels of CD16, a glycosylphosphatidylinositol-anchored protein, on blood granulocytes. The underlying genetic causes of IGDs were PIGO, PIGL, and unknown gene mutations in two, two, and five patients, respectively. Six patients experienced seizures, while all patients presented with developmental delay (mean developmental age: 11.1 ± 8.1 months). Seizure frequencies were markedly (>50%) and drastically (>90%) reduced in three and one patients who experienced seizures, respectively. None of the patients presented with seizure exacerbation. Eight of nine patients exhibited modest improvements in development (P = 0.14). No adverse events were observed except for mild transient diarrhea in one patient.Conclusion: One year of daily high-dose pyridoxine treatment was effective in the treatment of seizures in more than half of our patients with IGDs and modestly improved development in the majority of them. Moreover, such treatment was reasonably safe. These findings indicate that high-dose pyridoxine treatment may be effective against seizures in patients with IGDs, although further studies are required to confirm our findings.

Pyridoxine or pyridoxal‐5‐phosphate treatment for seizures in glycosylphosphatidylinositol deficiency: A cohort study

“…These studies also did not address whether other ASMs were added or changed alongside with pyridoxine treatment. Recently, a prospective study showed the efficacy and safety of pyridoxine in nine individuals 15 . Unfortunately, only 4 out of 9 individuals were genetically proven to have inherited GPI deficiency ( PIGL and PIGO ) 15 and it was unclear to what extent existing ASMs were altered during each study to document a reduced seizure burden and how seizure burden was monitored.…”

“…In neurons, pyridoxal is converted back to P5P and acts as a cofactor in the production of the inhibitory neurotransmitter γ‐aminobutyric acid 14 . In inherited GPI deficiency, there may be reduced neuronal TNSALP expression, which may in turn lead to intracellular P5P and γ‐aminobutyric acid deficiency 15 . This is the case in TNSALP‐deficient mice 16 and may underlie the intractable seizures observed in individuals with GPI anchoring disorders 15 .…”

PIGNencephalopathy: Characterizing the epileptology

“…Although TNSALP is not the only GPI‐anchored protein that leads to seizures in GPI‐anchoring disorders, 46 it is, at least in theory, possible that treatment with vitamin B6 could counteract the reduced availability of TNSALP in neurons of patients with GPI‐anchoring disorders to reduce seizures 41,47 . The beneficial effect of pyridoxine treatment has been documented in seven patients with a genetically proven GPI‐anchoring disorder; however, none had PIGN encephalopathy 43,48–50 . Four patients were prospectively treated with 20–30 mg/kg/day for 1 year, 50 and the remaining patients were reported in retrospective case reports 43,48,49 .…”

“…The beneficial effect of pyridoxine treatment has been documented in seven patients with a genetically proven GPI‐anchoring disorder; however, none had PIGN encephalopathy 43,48–50 . Four patients were prospectively treated with 20–30 mg/kg/day for 1 year, 50 and the remaining patients were reported in retrospective case reports 43,48,49 . In PIGN encephalopathy, four previously reported patients and eight of our 10 patients who were treated with pyridoxine did not derive any benefit in terms of seizure reduction.…”

Free GPI is the elusive Emm antigen

“…Supplementation with vitamin B6 to bypass the requirement for membrane-bound alkaline phosphatase and sodium benzoate to increase the transcription of PIGM have been partially helpful in some patients. [3][4][5][6] In 1980, at their Montreal congress, the International Society of Blood Transfusion established a working party for blood group terminology. 7 As of February 2021, they have identified 43 blood group systems.…”