Acute Intermittent Porphyria via the HMBS Gene

Acute Intermittent porphyria (AIP) is a metabolic disorder due to impairment of the third enzyme, porphobilinogen (PBG) deaminase, in the heme biosynthetic pathway. AIP is the most common form of acute porphyria affecting about 1 in 10,000 Swedish, 3 in 100,000 Finnish, and 5-10 in 100,000 US individuals. It is characterized by intermittent attacks of neurological dysfunction including severe abdominal pain, neuropsychiatric symptoms, nausea, vomiting, tachycardia and hypertension. Acute, life-threatening, attacks may be provoked by certain drugs, stress, infections, alcohol, caloric restriction, or endocrine factors with bouts typically resolving within two weeks. Symptom onset primarily occurs during the third and fourth decades of life with women being more susceptible to attacks, although some individuals with AIP may remain asymptomatic throughout life (Whatley and Badminton 1993). Pre-symptomatic diagnosis of AIP is helpful in preventing acute attacks through avoidance of certain triggers highlighted above. Biochemical analysis showing elevated PBG and aminolevulinic acid (ALA) levels in urine are primary indicators for AIP but may appear normal during asymptomatic phases. Impaired erythrocyte PBGD activity is also a hallmark of AIP, but is also seen in patients with anemia, liver disease, uremia, chronic polyarthritis, and malignancies. Genetic testing has been shown helpful in diagnosis of AIP during asymptomatic phases and in differential diagnosis (Puy et al. 1997; Kauppinen and Fraunberg 2002).

AIP is primarily inherited in an autosomal dominant manner through mutations in the HMBS gene with incomplete penetrance. Individuals homozygous for HMBS mutations have also been reported in a few cases with severe AIP presenting before two years of age (Solis et al. 2004). Missense, splice site alterations, nonsense, and small insertions/deletions represent 45%, 18%, 15%, and 22% of causative variants for AIP with about half occurring within exons 10-14 (Puy et al. 1997; Kauppinen and Fraunberg 2002; Yang et al. 2008). Large deletions have been reported in a few cases (Whatley et al. 2009). The HMBS gene encodes porphobilinogen (PGB) deaminase which is the third enzyme involved in the heme biosynthetic pathway. Causative variants primarily lead to premature protein termination or destabilization leading to decreased PGB deaminase levels and activity (Whatley and Badminton 1993; Bustad et al. 2013).

In patients with decreased PBG deaminase activity indicative of AIP, underlying mutations in the HMBS gene were detected in 240 of 252 individuals (Puy et al. 1997). Analytical sensitivity for detection of causative mutations in the HMBS gene is >95% as large deletions are present in only a few cases (Whatley et al. 2009).

This test provides full coverage of all coding exons of the HMBS gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).