A novel heterozygous mutation in the HMBS gene in a patient with acute intermittent porphyria and posterior reversible encephalopathy syndrome

Acute intermittent porphyria (AIP) is a rare inherited disorder, which is caused by the partial deficiency of hydroxymethylbilane synthase (HMBS), an enzyme of the heme biosynthetic pathway. Abdominal pain, neuropsychiatric disturbance and neuropathy are the typical manifestations of the disease. Complications such as posterior reversible encephalopathy syndrome (PRES), a rare type of brain lesion present on MRI, are also observed in patients with AIP. The present study reports on the case of a 36-year-old Chinese female patient with AIP and PRES. Genomic DNA were obtained from peripheral blood leukocytes and genomic regions of the HMBS gene were amplified as 2 fragments, which together contained all the exons and flanking intronic regions. Sanger sequencing of the amplified DNA fragments from the patient and the patient's family revealed a novel frameshift deletion (c.405-406delAA) in exon 8 of the HMBS gene. This mutation leads to a subsequent truncated protein (p.Glu135AspfsX74). The recombinant mutant protein had 62% activity relative to the wild-type protein but similar thermostability. It was confirmed that this novel mutation was the cause of AIP. Accumulation of D-aminolevulinic acid (ALA) due to HMBS dysfunction is a potential mechanism of PRES. The manifestation of PRES may be associated with ALA-induced cytotoxicity and the destruction of the blood-brain barrier. In summary, in the present study, a novel pathogenic HMBS mutation was identified, expanding on the molecular heterogeneity of AIP.