New variegate porphyrias show neurodevelopmental delay, lesions
Unusual 'homozygous form' may present as neurodevelopmental disorder
Two siblings with a rare form of variegate porphyria (VP) who had skin lesions caused by light or sun exposure and neurodevelopmental symptoms were described in a study from Germany that also reviewed all the other cases in the literature until 2023.
Both had epileptic seizures, developmental delays, and intellectual disability caused by a homozygous mutation in the PPOX gene, meaning the mutation was present in both copies. Also, an MRI revealed deficits in brain myelination, suggesting a loss of myelin, the protective coating around nerve fibers, may underlie neurodevelopment symptoms in homozygous VP, according to the scientists.
“We want to draw attention to the fact that genetic porphyrias, namely in their homozygous form, may present as a predominantly neurodevelopmental disorder, a fact which pediatric neurologists may not be aware of,” the researchers wrote. The study, “Neurodevelopmental retardation and neurological symptoms in homozygous variegate porphyria: two new cases and a literature review,” was published in Orphanet Journal of Rare Diseases.
Porphyria comprises a group of genetic disorders that occur when the process of producing heme, a molecule that helps transport oxygen throughout the body, is disrupted. VP is a type of acute porphyria thats’s marked by sudden and potentially severe attacks, and is caused by PPOX mutations, usually in one copy of the gene. In rare cases, patients have homozygous VP (HVP), with symptoms appearing in infancy.
Two new cases
Here, researchers reviewed all 19 HVP cases described in the literature until December 2023. A genetic and/or biochemical diagnosis was established in 15 patients, of whom seven had the same variant in both gene copies. A sibling of one patient was included whose clinical symptoms corresponded to his brother’s, but he hadn’t had genetic testing.
Along with skin symptoms, 11 patients had neurological symptoms, including developmental delays and intellectual disability, epileptic seizures, and/or involuntary eye movements, or nystagmus. Twelve had disease onset in the first two years of life, most in the first year. Two of the published cases showed no or severely delayed myelin at ages 2 to 3.
The researchers described two new HVP cases, a brother and sister. The girl, 7, had skin lesions on her first day of life caused by the light of a pulse oximeter, which measures blood oxygen levels. Nystagmus became apparent at 6 weeks of age and epileptic seizures at 3 months, which successfully responded to valproic acid and phenobarbital. The girl had a developmental delay and, at her last evaluation, was able to walk without assistance and speak in simple two-word combinations. She also had serious skin lesions in sun-exposed areas, with scars and contractures from scratching.
Her 14-year-old brother was born in Syria and showed developmental delay in multiple areas. He also had epileptic seizures before 6 months of age, nystagmus in the first years of life, and skin lesions when he was 3 years old. When he was seen by the researchers at age 6, he was seizure-free, and treated with valproic acid and had no evidence of nystagmus.
The boy was able to walk without aid, but showed deficits in motor skills.He could speak sentences in Arabic and German and count to 20. Before his sister was born, his skin fragility and neurodevelopmental symptoms were considered separate conditions. Both had short stature and their heads were smaller than expected for their age.
Laboratory analysis indicated they had high blood and urinary levels of porphyrins, while genetic analysis revealed the same homozygous variant in PPOX, called c.164>C (p.Glu55Ala). This variant hadn’t been previously reported and was rated as possibly disease-causing, the researchers said.
A brain MRI, obtained at the age of 5 months in the girl and 3 years in the boy, revealed abnormalities in myelin deposition.
According to the researchers, “in children with a developmental disorder of unknown cause and early childhood epilepsy, an abnormally light-sensitive or fragile skin may indicate a primary genetic porphyria.”
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