Novel Single Nucleotide Polymorphism (9678G→A) for Linkage Analysis of Acute Intermittent Porphyria

Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of metabolism caused by a partial deficiency of the third enzyme of the heme biosynthetic pathway, hydroxymethylbilane synthase (EC 4.3.1.8.; HMBS). This enzyme catalyzes the condensation of four molecules of porphobilinogen to a tetrapyrrole hydroxymethylbilane. Clinically, AIP is characterized by acute attacks of neurological disorders manifesting as abdominal pain, hypertension, tachycardia, peripheral neuropathy, and mental dysfunction. Biochemical diagnosis of AIP relies on increased urinary porphobilinogen and fecal porphyrin excretion within the health-related reference interval. The definitive diagnosis requires the assay of red blood cell (RBC) HMBS activity (1).AIP is a genetic disease characterized by poor penetrance; therefore, identification of presymptomatic AIP carriers in families with manifesting individuals is of utmost clinical importance because avoidance of precipitating agents, e.g., drugs and alcohol, can prevent the occurrence of the first porphyric attacks, which may be life-threatening. However, the identification of AIP carriers by assaying the RBC HMBS activity is problematic because there is substantial overlap between the enzyme activities of healthy individuals and patients with AIP (2). In addition, in one variant of AIP, the decreased enzyme activity is confined to …