Neurodevelopmental retardation and neurological symptoms in homozygous variegate porphyria: two new cases and a literature review.

Abstract

Background: Genetic porphyrias, namely in their homozygous form, may cause a neurodevelopmental disorder which may even be the clinically dominant feature. But few cases have been described so far. The majority of neurodevelopmental disorders has a genetic cause and there is a big overlap of the clinical presentations due to unspecific symptoms. Additional specific clinical symptoms may enable a phenotypically orientated biochemical and genetic diagnostic approach. Skin lesions occurring in the neonatal period or the first years of life in a child with developmental delay may hint at a genetic porphyria.

Methods: We describe the clinical features, biochemical and genetic findings in two new cases, sister and brother, of biallelic resp. homozygous variegate porphyria and review all case reports published until December 2023 after systematic searches in PubMed, MEDLINE, Cochrane and Web of Science.

Results: A total of 19 patients with biallelic, largely homozygous variegate porphyria have so far been reported of whom 16 were confirmed by genetic testing. In 11 patients, neurodevelopmental problems were reported in addition to skin lesions. Additional symptoms were nystagmus, epileptic seizures as well as sensory neuropathy. Only 2 patients received a brain MRI showing a severe deficit of myelination at the age of 2-3 years suggesting that neurodevelopmental delay in HVP may be associated to hypomyelination. This article adds two cases of a genetic porphyria with developmental delay and epilepsy as well as skin lesions. In our two cases biochemistry revealed a porphyria and consecutive molecular genetic testing showed in each case a homozygous variant in the PPOX gene, which corresponds to a variegate porphyria. Interestingly, magnetic resonance imaging of the brain revealed a severe myelin deficit suggesting hypomyelination in both children.

Conclusions: 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. Especially variegate porphyria with biallelic variants may present as neurodevelopmental disorder with hypomyelination.