Further Delineation of Pyridoxine-Responsive Pyridoxine Phosphate Oxidase Deficiency Epilepsy: Report of a New Case and Review of the Literature With Genotype-Phenotype Correlation

Lugli, Licia; Bariola, Maria Carolina; Ori, Luca; Lucaccioni, Laura; Berardi, Alberto; Ferrari, Fabrizio

doi:10.1177/0883073819863992

Cited by 7 publications

(4 citation statements)

References 15 publications

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“…There were no specific imaging features identified in the brains of the reviewed patients. Different radiological findings were described; however, 34 patients (61.8%) had normal brain imaging 7‐9,11‐13,16,21,26‐33 . Di Salvo et al reported three patients with a c.347G > A (p. Arg116Gln) mutation in the PNPO gene who had normal brain imaging.…”

Section: Resultsmentioning

confidence: 99%

“…had normal brain imaging. [7][8][9][11][12][13]16,21,[26][27][28][29][30][31][32][33] The most common abnormality revealed on brain imaging was diffuse atrophy, which was observed in eight patients (14.5%), 8,9,16,20 followed by ischemic changes and encephalomalacia in five patients (5.5%), 1,13,16,17 and delayed myelination and atrophy in another three patients. 18,34,35 An additional two patients (2.5%) had diffuse or focal edema.…”

Section: Brain Imagingmentioning

confidence: 99%

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Phenotypic and molecular spectrum of pyridoxamine‐5′‐phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine‐5′‐phosphate oxidase deficiency

et al. 2020

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Pyridoxamine-5 0-phosphate oxidase (PNPO) deficiency is an autosomal recessive pyridoxal 5 0-phosphate (PLP)-vitamin-responsive epileptic encephalopathy. The emerging feature of PNPO deficiency is the occurrence of refractory seizures in the first year of life. Pre-maturity and fetal distress, combined with neonatal seizures, are other associated key characteristics. The phenotype results from a dependency of PLP which regulates several enzymes in the body. We present the phenotypic and genotypic spectrum of (PNPO) deficiency based on a literature review (2002-2020) of reports (n = 33) of patients with confirmed PNPO deficiency (n = 87). All patients who received PLP (n = 36) showed a clinical response, with a complete dramatic PLP response with seizure cessation observed in 61% of patients. In spite of effective seizure control with PLP, approximately 56% of patients affected with PLP-dependent epilepsy suffer developmental delay/intellectual disability. There is no diagnostic biomarker, and molecular testing required for diagnosis. However, we noted that cerebrospinal fluid (CSF) PLP was low in 81%, CSF glycine was high in 80% and urinary vanillactic acid was high in 91% of the cases. We observed only a weak correlation

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Section: Resultsmentioning

confidence: 99%

Section: Brain Imagingmentioning

confidence: 99%

Phenotypic and molecular spectrum of pyridoxamine‐5′‐phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine‐5′‐phosphate oxidase deficiency

et al. 2020

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“…Developmental delay is one common symptom manifested by PNPO-deficient patients ( 3 , 17 , 19 , 53 ), raising the question of whether specific developmental impairments lead to seizures. By providing flies with PLP during either the larval or adult stages, we have demonstrated that developmental impairments and seizures in adults are dissociable ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Drosophila carrying epilepsy-associated variants in the vitamin B6 metabolism gene PNPO display allele- and diet-dependent phenotypes

Chi

Iyengar

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Pyridox(am)ine 5′-phosphate oxidase (PNPO) catalyzes the rate-limiting step in the synthesis of pyridoxal 5′-phosphate (PLP), the active form of vitamin B6 required for the synthesis of neurotransmitters gamma-aminobutyric acid (GABA) and the monoamines. Pathogenic variants in PNPO have been increasingly identified in patients with neonatal epileptic encephalopathy and early-onset epilepsy. These patients often exhibit different types of seizures and variable comorbidities. Recently, the PNPO gene has also been implicated in epilepsy in adults. It is unclear how these phenotypic variations are linked to specific PNPO alleles and to what degree diet can modify their expression. Using CRISPR-Cas9, we generated four knock-in Drosophila alleles, hWT, hR116Q, hD33V , and hR95H, in which the endogenous Drosophila PNPO was replaced by wild-type human PNPO complementary DNA (cDNA) and three epilepsy-associated variants. We found that these knock-in flies exhibited a wide range of phenotypes, including developmental impairments, abnormal locomotor activities, spontaneous seizures, and shortened life span. These phenotypes are allele dependent, varying with the known biochemical severity of these mutations and our characterized molecular defects. We also showed that diet treatments further diversified the phenotypes among alleles, and PLP supplementation at larval and adult stages prevented developmental impairments and seizures in adult flies, respectively. Furthermore, we found that hR95H had a significant dominant-negative effect, rendering heterozygous flies susceptible to seizures and premature death. Together, these results provide biological bases for the various phenotypes resulting from multifunction of PNPO, specific molecular and/or genetic properties of each PNPO variant, and differential allele–diet interactions.

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“…Developmental delay is one common symptom manifested by PNPO deficient patients [3,18,20,53], raising the ques- tion of whether specific developmental impairments lead to seizures. By providing flies with PLP during either the developmental or adult stage, we demonstrate that developmental impairments and seizures in adults are dissociable (Fig.…”

Section: Discussionmentioning

confidence: 99%

Diet modifies allele-specific phenotypes inDrosophilacarrying epilepsy-associatedPNPOvariants

Chi

Iyengar

et al. 2021

Preprint

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Pyridox(am)ine 5'-phosphate oxidase (PNPO) catalyzes the rate-limiting step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6 required for the synthesis of neurotransmitters GABA and monoamines. Pathogenic variants in PNPO have been repeatedly identified in patients with neonatal epileptic encephalopathy and early-onset epilepsy. These patients often exhibit different types of seizures and variable comorbidities, including developmental impairment and intellectual disability. It is unclear how seizure types and associated comorbidities are linked to specific PNPO alleles and to what degree diet can modify their expression. Furthermore, the molecular characteristics of PNPO variants have not been examined in model systems. Using CRISPR/Cas9, we generated four knock-in Drosophila alleles, hWT, hR116Q, hD33V, and hR95H, in which the endogenous Drosophila PNPO (sugarlethal) was replaced by wild-type human PNPO cDNA and epilepsy-associated variants corresponding to R116Q, D33V, and R95H, respectively. We examined these knock-in flies at the molecular, circuitry, and behavioral levels. Collectively, we found a wide range of phenotypes in an allele- and diet-dependent manner. Specifically, the D33V mutation reduces the mRNA level, R95H reduces the protein stability, and R116Q alters the protein localization of PNPO in the brain. D33V and R95H mutations lead to partial and complete lethality during development, respectively and R116Q and D33V mutations shorten lifespan. At the behavioral level, hD33V/hR95H trans-heterozygous flies are hypoactive on all tested diets whereas hR116Q flies show diet-dependent locomotor activities. At the circuitry level, hD33V homozygotes show rhythmic burst firing and hD33V/hR95H trans-heterozygotes exhibit spontaneous seizure discharges. In hR95H homozygotes rescued with PLP supplementation, we uncovered that PLP deficiency abolishes development and causes extreme seizures in adults. Lastly, genetic and electrophysiological analyses demonstrate that hWT/hR95H heterozygous flies are prone to seizures due to a dominant-negative effect of hR95H on hWT, highlighting the possibility that human R95H carriers may also be susceptible to epilepsy. Together, this study demonstrates that human PNPO variants interact with diet to contribute to phenotypic variations; and that the knock-in Drosophila model offers a powerful approach to systematically examine clinical manifestations and the underlying mechanisms of human PNPO deficiency.

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Further Delineation of Pyridoxine-Responsive Pyridoxine Phosphate Oxidase Deficiency Epilepsy: Report of a New Case and Review of the Literature With Genotype-Phenotype Correlation

Cited by 7 publications

References 15 publications

Phenotypic and molecular spectrum of pyridoxamine‐5′‐phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine‐5′‐phosphate oxidase deficiency

Phenotypic and molecular spectrum of pyridoxamine‐5′‐phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine‐5′‐phosphate oxidase deficiency

Drosophila carrying epilepsy-associated variants in the vitamin B6 metabolism gene PNPO display allele- and diet-dependent phenotypes

Diet modifies allele-specific phenotypes inDrosophilacarrying epilepsy-associatedPNPOvariants

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