Novel A219P Mutation of Hydroxymethylbilane Synthase Identified in a Chinese Woman with Acute Intermittent Porphyria and Syndrome of Inappropriate Antidiuretic Hormone

Abstract

SummaryAcute intermittent porphyria (AIP) is an autosomal dominant metabolic disorder caused by deficiency of the heme biosynthetic enzyme hydroxymethylbilane synthase (approved gene symbol HMBS), also known as porphobilinogen deaminase (PBGD). AIP is characterised by intermittent attacks of abdominal pain, vomiting, and neurological complaints. The highly variable symptomatic presentation of AIP causes confusion with other diseases and results in a high misdiagnosis rate (68% in China) and delayed effective treatments. Based on biochemical and genetic analysis of two Chinese families, a new and a previously reported HMBS mutation were identified in patients with AIP and syndrome of inappropriate antidiuretic hormone (SIADH). The novel HMBS mutation is the 655G>C point mutation (A219P). In addition, the 973C>T point mutation (R325X), which had been previously reported in two Danish families, was identified.

Clinical and Laboratory Features of Acute Porphyria: A Study of 36 Subjects in a Chinese Tertiary Referral Center

“…It could also help to screen asymptomatic family members of patients with acute porphyria. The natural history and clinical and biochemical and genetic features of acute porphyrias have been described in Western countries [3, 4], but, to our knowledge, it has been described in the Chinese population only in case reports [5–12]. In this retrospective study, we analyzed the characteristics of 36 cases of acute porphyria from the Peking Union Medical College Hospital.…”

Novel mutation of PPOX gene in a patient with abdominal pain and syndrome of inappropriate antidiuresis

“…We have detected a novel mutation associated with VP that is family-specific, as most VP mutations are [13] and we have provided evidence that this novel mutation is likely to be pathogenetic. Moreover the identification of asymptomatic carriers of the mutation is very important because they could receive counseling on methods to minimize the risk of acute porphyric attacks, such as avoidance of certain drugs or other environmental factors [7]. The present case is an archetype of the challenges encountered in recognizing VP and underlines the importance of a genetic screening in affected patients and their family members.…”

“…Thus, in our patient valproic acid is likely to have played a role in promoting both VP attacks and SIADH. SIADH associated with AP is responsive to fluid restriction and high-carbohydrate loading [7,12], or hematin administration [6], but in our patient fluid restriction coupled with valproic acid withdrawal was sufficient to restore normality. The presence of a Cys459Tyr variant in both our proband and her affected cousin, the absence of this variant in 100 healthy controls, the location of the residue located in the highly conserved FAD-binding domain and the results of different in silico tools used to predict pathogenicity, all give to the c.1376 G>A (p.Cys459Tyr) variant a very likely pathogenetic role.…”

“…The mechanism underling the AP-induced SIADH is unclear but it may be due to hypothalamic damage by ALA accumulation that is neurotoxic. [1,6,7]. It is known that valproic acid may display a porphyrinogenic effect inducing ALA synthase enzyme [1] and the drug has also the potential for causing SIADH increasing hypothalamic antidiuretic hormone secretion [11].…”

“…Delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) are almost always elevated in urine during acute attacks. Mild to severe hyponatremia may be found during an attack [5], resulting from SIADH due to the neurotoxicity of ALA [6,7].…”