Hereditary neuropathy

Gene: PPOX

Green List (high evidence)

Relevant metabolic investigation: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyric attack) plasma porphyrin fluorescence emission (homozygous VP).
PMID: 38940544 Aarsand reports that variegate porphyria (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 fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence) as the penetrance is so low.
PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.
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 (40114189 Kaiser 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. Three of these patients (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift) had sensory neuropathy, as reported by the previous reviewer.

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, 11:23 a.m. | Last Modified: 8 Sep 2025, 11:25 a.m.

Panel Version: 1.500

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

Publications

• 38940544
• 35584894
• 37879139
• 11286631
• 10870850
• 8290408

Green List (high evidence)

Comment on mode of inheritance: There are at least three cases of variegate porphyria reported with biallelic variants in PPOX gene and sensory neuropathy. Hence, the MOI should be updated from "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal".

Created: 27 Jul 2023, 2:44 p.m. | Last Modified: 27 Jul 2023, 4:11 p.m.

Panel Version: 1.469

PMID:8290408 - The first of the two cases from South Africa (female proband) with "homozygous" variegate porphyria had developed gross sensory neuropathy of the hands and feet.

PMID:10870850 - One of the two South African probands reported with variegate porphyria and biallelic variants (p.Arg59Trp & p.Tyr348Cys) had sensory neuropathy as one of the clinical presentations.

PMID:11286631 - The patient reported with biallelic variants (p.Ile12Thr & p.Pro256Arg) had mild sensory neuropathy.

Created: 27 Jul 2023, 2:41 p.m. | Last Modified: 27 Jul 2023, 2:41 p.m.

Panel Version: 1.466

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Porphyria variegata, OMIM:176200; Sensory neuropathy, HP:0000763

Publications

• 8290408
• 10870850
• 11286631

Green List (high evidence)

The Neurology Specialist Test Group agreed that this gene was recommended for the WGS panel based on a broader phenotype view to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP. This panel includes conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation. This panel as going to be used for R78, but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy and as a result a new panel was created https://panelapp.genomicsengland.co.uk/panels/846/ for this purpose.

Created: 7 Dec 2019, 6:08 p.m. | Last Modified: 7 Dec 2019, 6:08 p.m.

Panel Version: 1.352

Review and rating uploaded from file (Curation_Template_GMS_Neuro_AR_20190521.xlsx) submitted by Alex Rossor (UCL Institute of Neurology) on behalf of London North GLH for GMS Neurology specialist test group.

Created: 11 Jun 2019, 1:40 p.m.

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Skin photosensitivity. Acute episodes similar to AIP.