Two Newly Identified Mutations Linked to Mild Form of Variegate Porphyria

Two previously unreported mutations were found in a man and his mother with variegate porphyria affecting the skin only, a new case study reports. 

This finding may help healthcare professionals better understand the connection between specific genetic mutations and disease development in those with variegate porphyria, investigators said.

The study, “Two new mutations in the PPOX gene in a patient with variegate porphyria,” was published in the Journal of the German Society of Dermatology.

Variegate porphyria is caused by mutations to the PPOX gene leading to the production of a faulty version of an enzyme called protoporphyrinogen oxidase. 

This enzyme is part of the pathway that generates heme, a component of iron-containing proteins such as hemoglobin, which transports oxygen throughout the body.

People with variegate porphyria have lower enzyme activity, causing a toxic build-up of porphyrin precursors being formed during normal heme production. Characteristic symptoms include blisters on sun-exposed skin (like the back of the hands); more variable systemwide complications include pain, seizures, and muscle weakness. 

So far, as many as 185 mutations have been reported in the PPOX gene. However, a connection between specific mutations (genotype) and related disease characteristics (phenotype) has not been established. 

Investigators in Spain described the case of a 25-year-old man who arrived at a dermatology department reporting a five-year history of skin blisters on the backs of his hands that became worse each spring and summer.

He also had dark skin spots on his hands, excessive hair growth, and evidence of skin thickening and scarring from a biopsy. 

He did not show any systemic symptoms, and his red blood cell count, iron levels, and kidney function were all normal. But urine and fecal tests found higher-than-usual levels of porphyrin precursors. 

Variegate porphyria was then suspected. Blood samples were collected from him and his parents for genetic testing. 

Results revealed two previously unreported mutations in one of the man’s two PPOX gene copies, as well as in his mother, who had also had a history of skin lesions without systemic symptoms. Each person inherits two copies of each gene, one from each parent.

The father did not carry the mutations and showed no signs of the condition. 

These mutations — known as G41C and W42R — changed two adjacent amino acids (the building blocks of proteins) in the protoporphyrinogen oxidase enzyme. Computer analysis predicted both mutations were pathogenic (disease-causing), as they are critical for proper enzyme function. 

“In conclusion, we report a double mutant allele [gene copy] … in the PPOX gene that is associated with a case of VP [variegate porphyria] with skin manifestations and slight biochemical abnormalities, but without associated systemic symptoms,” the researchers wrote.

“The importance of detailed clinical investigations in patients with genetic mutations are essential to establish a genotype-phenotype correlation that facilitates the clinical approach in this type of patient,” they added.