New PPOX Mutation in Each Gene Tied to Variegate Porphyria in Boy

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A boy in Iran was found to carry two copies of a previously unknown mutation in the PPOX gene that caused both skin and neurological symptoms of variegate porphyria (VP), according to a recent case report.

“To the best of our knowledge, around 15 cases with homozygous VP [both gene copies with mutations] have been reported worldwide,” the scientists wrote. “Here, we reported the first case of homozygous VP with novel mutation on PPOX gene.”

The report, “A boy with blistering of sun-exposed skin and finger shortening: the first case of variegate porphyria with a novel mutation in protoporphyrinogen oxidase (PPOX) gene in Iran: a case report and literature review,” was published in the Italian Journal of Pediatrics.

A form of acute porphyria, VP is caused by mutations in PPOX, a gene that carries instructions for making an enzyme called protoporphyrinogen oxidase. Lack of this enzyme can affect both the skin and the nervous system, but symptoms vary greatly from person to person.

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Disease-causing mutations are passed from parents to their children in an autosomal dominant way, meaning VP can occur when a child inherits only one mutated gene copy from a parent.

A research team in Iran detailed the rare case of a 7-year-old boy with a newly identified disease-causing mutation found in both gene copies.

The boy had been to the hospital three times in the previous six months for generalized tonic-clonic seizures, which are sudden, uncontrolled body movements that occur because of abnormal electrical activity in both sides of the brain. He was started on phenobarbital, an anti-seizure medication.

A physical exam revealed rough, hairy, and fragile skin with excessive pigmentation, scars, and blisters on areas exposed to the sun. Skin on his hands and feet was also unusually thick. He was short for his age, as were his fingers and toes, a condition known as brachydactyly. His limbs appeared weak, with a tremor while walking.

The second child of parents who were related by blood, he had a medical history of skin lesions starting at age 2, and of previous hospital admissions for generalized tonic-clonic seizures and anti-seizure treatment starting at age 3. The boy also had delayed development, beginning to walking by 3 years old.

An electroencephalogram (EEG) showed epileptiform discharges, or unusual patterns of electrical activity in the brain. A brain MRI scan revealed a severe delay in myelination, the process by which a layer of myelin, a fatty substance, forms around nerves to cover and protect them.

A skin biopsy showed large fluid-containing blisters, called bullae, which led doctors to a suspect porphyria.

A genetic test revealed a mutation, called c.1072G > A, in both copies of the PPOX gene. According to researchers, this mutation had not been reported previously. Based on this finding, a diagnosis of VP was made.

“Although no evidence of similar conditions was reported in our patient’s family, he was born from parents with consanguineous marriage. Therefore, elucidation of the genetic basis in this family is important for genetic counselling,” the researchers wrote.

Two years after starting the boy on phenobarbital, doctors tapered the medication’s dose. However, a new generalized tonic-clinic seizure episode followed and he was again hospitalized. As brain MRI scans were normal, the boy started on levetiracetam, another anti-seizure medication, instead of phenobarbital.

To protect his skin, the child was advised to stay away from the sun and use sunscreen regularly.

“Avoiding excess sun exposure can reduce the blisters and skin lesions,” the researchers wrote.

He began to show aggressive behavior, learning difficulties, and complain of pain in his abdomen, the scientists noted.

“The severity of VP symptoms feasibly depends on the type of PPOX mutations,” they wrote. “Early diagnosis and treatment [of] the clinical features of the disease are important to improve the quality of life.”

Findings in this report, they added, “emphasize the importance of molecular genetic testing to find any mutations in PPOX gene and their correlation to VP occurrence and disease severity.”