Mitochondrial disorders

Gene: PPOX

Green List (high evidence)

Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease 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).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Mitochondrial disorders.

Created: 13 Oct 2025, 3:08 p.m. | Last Modified: 14 Oct 2025, 8:19 a.m.

Panel Version: 9.32

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297; variegate porphyria, childhood-onset, MONDO:0957577

Publications

• 10486317
• 33159949
• 35584894
• 37879139
• 38940544
• 40114189

Green List (high evidence)

Relevant metabolic investigation: urine porphobilinogen and plasma porphyrin fluorescence emission
PMID: 33159949 Cho reports that PPOX is an intrinsic protein of the inner mitochondrial membrane that oxidizes protoporphyrinogen IX to protoporphyrin as a penultimate enzyme in haem biosynthetic pathway. Although the enzyme is located in the mitochondria, the gene that codes for it is located in the nucleus, not in the mitochondrial DNA.
PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.
PMID: 10486317 Whatley found that skin lesions were the only manifestation of VP in 59% of patients whereas 21% of patients had acute attacks and skin lesions. The remainder having only acute attacks.
PMID: 8290408 Hift reports that cutaneous VP presents with photosensitivity which may result in blistering, erosions, a fragile skin with chronic scarring and pigmentary changes.
PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma fluoresecence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence) as the penetrance is so low.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (PMID: 40114189 Kaiser, 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.

Created: 8 Sep 2025, 4:57 p.m. | Last Modified: 8 Sep 2025, 4:57 p.m.

Panel Version: 9.26

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
176200; 620483

Publications

• 33159949
• 38940544
• 10486317
• 8290408
• 38940544
• 37879139
• 40114189

Green List (high evidence)

Comment on list classification: There are more than three unrelated cases each with both monoallelic and biallelic variants in PPOX gene. Hence, this gene should be promoted to Green at the next GMS update and the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'.

Created: 27 Jul 2023, 12:30 p.m. | Last Modified: 27 Jul 2023, 12:30 p.m.

Panel Version: 4.60

As reviewed by Zornitza Stark and suggested in PMID:25778941, Variegate porphyria (VP) should be included in this panel.

Autosomal dominat variegate porphyria (VP):

VP is usually caused by autosomal dominant variants in PPOX gene in the majority of the cases.

PMID:30476629 - Eight unrelated individuals with seven different variants in heterozygous state were reported with VP.

Autosomal dominant variants in this gene have also been associated with VP in OMIM (MIM #176200).

Autosomal recessive variegate porphyria (VP):

PMID:9540991 - A severely affected female proband with recessive VP was identified with two missense compound heterozygous variants in PPOX gene (p.Gly169Glu & p.Gly358Arg), as detected by heteroduplex analysis, automated sequencing, and allele specific oligonucleotide hybridization.

PMID:10870850 - Two unrelated South African cases with variegate porphyria were reported with onset of the disease usually in infancy and with severe skin manifestations. The variant detection included combined SSCP-heteroduplex analysis followed by direct sequencing and both had the common p.Arg59Trp variant, while the other variant was p.Tyr348Cys in one and p.Arg138Pro in the other.

PMID:32247286 - A case of VP was reported from a family with only cutaneous manifestations and was identified with two heterozygous missense variants in PPOX gene (p.Gly41Cys and p.Trp42Arg). The same variants were identified in patient's mother who had skin lesions, whereas father had no clinical involvement and did not have any of these variants. The familly study showed that the two variants occur in cis on the same allele.

PMID:33159949 - A novel homozygous variant in PPOX gene (c.808G>T) was identified in a patient with autosomal recessive form of VP.

Overall, the autosomal recessive form of VP usually occurs early in in fancy and have markedly reduced levels of protoporphyrinogen oxidase than autosomal dominant form. Autosomal recessive VP has not yet been reported in OMIM.

Created: 27 Jul 2023, 10:23 a.m. | Last Modified: 27 Jul 2023, 12:25 p.m.

Panel Version: 4.59

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Porphyria variegata, OMIM:176200

Publications

• 9540991
• 10870850
• 25778941
• 30476629
• 32247286
• 33159949

Green List (high evidence)

Variegate porphyria is a disorder of heme metabolism resulting from a deficiency in protoporphyrinogen oxidase, an enzyme located on the inner mitochondrial membrane. A defect in a relevant mitochondrial cofactor, we have included it in our mitochondrial panel in line with the groupings suggested in PMID: 25778941. >3 cases reported.

Created: 23 Mar 2020, 12:43 a.m. | Last Modified: 23 Mar 2020, 12:43 a.m.

Panel Version: 2.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Porphyria variegata MIM#176200

Publications

• 25778941
• 9811936
• 12859407
• 30476629

Green List (high evidence)

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

Created: 2 May 2024, 10:34 a.m. | Last Modified: 2 May 2024, 10:34 a.m.

Panel Version: 6.3

Initial gene list and info collated by Carl Fratter (Oxford University Hospitals NHS Trust) January 2019 on behalf of the GMS Mitochondrial specialist test group.

Created: 23 Jul 2019, 10:13 a.m. | Last Modified: 23 Jul 2019, 10:13 a.m.

Panel Version: 1.412

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal