Neurodevelopmental disorder in a patient with HMBS and SCN3A variants—A possibly blended phenotype further delineating autosomal recessive HMBS related disease

Abstract Monoallelic pathogenic HMBS variants are a well‐established cause of acute intermittent porphyria (AIP), whereas biallelic pathogenic variants may cause HMBS ‐related leukoencephalopathy which remains a poorly characterized disorder. We describe an 8‐year‐old girl with hypotonia, hearing impairment, horizontal nystagmus, bilateral strabismus, impaired visual acuity, and optic nerve atrophy. She had no epilepsy but sleep electroencephalogram showed paroxysmal changes in the right hemisphere with secondary generalizations. Brain magnetic resonance imaging was unremarkable apart from a few small white matter hyperintensities. Exome sequencing (ES) initially prioritized a SCN3A c.3822G>A de novo variant whose sole causative role was eventually questioned as not fully compatible with symptoms. ES reanalysis revealed a homozygous c.674G>A HMBS variant. In the monoallelic form this variant is a known cause of AIP, whereas in trans with another HMBS pathogenic variant it was associated with the HMBS ‐related leukoencephalopathy in four individuals. Despite lack of signs/symptoms of porphyria, literature analysis suggested that HMBS c.674G>A likely contributed to the disease either as the sole cause or together with SCN3A c.3822G>A as a part of blended phenotype. Our report adds to the relatively small number of described cases of HMBS ‐related leukoencephalopathy and emphasizes that autosomal recessive form of HMBS disease can be present in the absence of porphyria symptoms.