Undiagnosed metabolic disorders

Gene: PPOX

Green List (high evidence)

Relevant metabolic investigation: urine porphobilinogen and plasma porphyrin fluorescence emission
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 the 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 porphyrin fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence emission) as the penetrance of VP 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, 10:54 a.m. | Last Modified: 8 Sep 2025, 10:55 a.m.

Panel Version: 1.631

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

Phenotypes
176200; 620483

Publications

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

Green List (high evidence)

Associated with variegate porphyria in many cases (PMID: 19460837). Homozygous for has more severe phenotype

Created: 23 Feb 2017, 5:15 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Porphyria variegata 176200

Publications

• 19460837
• 9811936