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

Abstract

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.

Recent advances in the epidemiology and genetics of acute intermittent porphyria

“…In recent years, this rare disorder has garnered attention from Chinese physicians, and small series of and case reports on AIP, and especially reports of novel mutations, have increased in China, indicating that AIP may not be as "rare" as was previously assumed (108)(109)(110)(111)(112)(113)(114). In addition, some studies have analyzed clinical features of Chinese patients with AIP, such as posterior reversible encephalopathy syndrome (110,(115)(116)(117)(118).…”

Identification and molecular analysis of 17 novel variants of hydroxymethylbilane synthase in Chinese patients with acute intermittent porphyria

“…To date, a total of 517 HMBS variants have been reported in the HGMD (version 2020.v2). Our study reports 17 novel variants to the existing literature, increasing the number of HMBS variants to 542 counting 8 novel variants not included in HGMD 14–16 …”

Identification and molecular analysis of 17 novel hydroxymethylbilane synthase mutations in 69 Chinese patients with acute intermittent porphyria

“…As of February 2020, a total of 517 HMBS gene mutations were reported, and 2 novel mutations were separately reported by Yang J in April 2020 and by Yang Y in July 2020 [7,8]. In addition, María-José Morán-Jiménez investigated the molecular defects in 55 unrelated Spanish patients with AIP, identifying 6 novel mutations [9].…”