Early onset or syndromic epilepsy

Gene: PPOX

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 11 Mar 2026, 3:39 p.m. | Last Modified: 11 Mar 2026, 3:39 p.m.

Panel Version: 8.134

Green List (high evidence)

Comment on list classification: There are at least 4 unrelated individuals with biallelic variants in PPOX that presented with early onset (2-6 months after birth), syndromic epilepsy. Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.

Created: 21 Oct 2025, 5:52 p.m. | Last Modified: 21 Oct 2025, 5:52 p.m.

Panel Version: 8.53

Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Created: 21 Oct 2025, 4:57 p.m. | Last Modified: 21 Oct 2025, 5:52 p.m.

Panel Version: 8.53

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, childhood-onset, MONDO:0957577

Publications

• 8290408
• 9811936
• 2004012
• 30861571
• 35164799
• 37879139
• 40114189