Abstract
Acute intermittent porphyria (AIP) is a rare hereditary metabolic disease with an autosomal dominant mode of inheritance. Germline mutations of HMBS gene causes AIP. Mutation of HMBS gene results into the partial deficiency of the heme biosynthetic enzyme hydroxymethylbilane synthase. AIP is clinically manifested with abdominal pain, vomiting, and neurological complaints. Additionally, an extreme phenotypic heterogeneity has been reported in AIP patients with mutations in HMBS gene. Here, we investigated a Chinese patient with AIP. The proband is a 28-year-old Chinese male manifested with severe stomach ache, constipation, nausea and depression. Proband’s father and mother is normal. Proband’s blood sample was collected and genomic DNA was extracted. Whole exome sequencing and Sanger sequencing identified a heterozygous novel single nucleotide deletion (c.809delC) in exon 12 of HMBS gene in the proband. This mutation leads to frameshift followed by formation of a truncated (p.Ala270Valfs∗2) HMBS protein with 272 amino acids comparing with the wild type HMBS protein of 361 amino acids. This mutation has not been found in proband’s unaffected parents as well as in 100 healthy normal control. According to the variant interpretation guidelines of American College of Medical Genetics and Genomics (ACMG), this variant is classified as “likely pathogenic” variant. Our findings expand the mutational spectra of HMBS gene related AIP which are significant for screening and genetic diagnosis for AIP.
Highlights
Acute intermittent porphyria (AIP) [MIM# 176000] is a rare hereditary metabolic disorder with an autosomal dominant mode of inheritance
Patients with AIP are characterized by the partial deficiency of the hydroxymethylbilane synthase
We report a clinical case of rare AIP in a Chinese family
Summary
Acute intermittent porphyria (AIP) [MIM# 176000] is a rare hereditary metabolic disorder with an autosomal dominant mode of inheritance. AIP is caused by the germline mutation of HMBS gene encoding the heme biosynthetic enzyme hydroxymethylbilane synthase which is the is the third enzyme in the heme biosynthetic pathway (Puy et al, 2010). Novel HMBS Mutation Causes AIP by eight evolutionarily highly conserved enzymes by a complex cellular machinery (Hrdinka et al, 2006). The clinical diagnosis of AIP has been made according to the clinical symptoms of the patient and biochemical examination. Whole exome sequencing is reported to be the best way to unveil the molecular genetic screening of the AIP patients (Hrdinka et al, 2006). Whole exome sequencing is essential for clinical diagnosis for AIP (Yang et al, 2015). Patients with AIP are presented with several behavioral changes such as irritability, insomnia, and depression (Hrdinka et al, 2006)
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