Genetic basis of Acute Intermittent Porphyria Variant 4 - in Siamese cats is an autosomal dominant inherited disorder caused by mutations in the hydroxymethylbilane synthase (HMBS) gene, which encodes a key enzyme in the heme biosynthesis pathway. In this variant, a specific mutation leads to deficient enzyme activity. This mutation results in reduced hydroxymethylbilane synthase activity to roughly half of normal, impairing heme synthesis. Because of the dominant inheritance, cats with one copy of the mutation develop the disease. Genetic testing for this variant is available to identify affected cats and guide breeding decisions.
Pathophysiology - The HMBS gene mutation reduces the enzyme's function essential for heme synthesis. This disruption causes accumulation of porphyrin precursors such as 5-aminolevulinic acid (ALA), porphobilinogen (PBG), and uroporphyrins (URO) in the blood, urine, teeth, and bones. Affected cats exhibit characteristic erythrodontia—a brown to reddish discoloration of the teeth—and yellow to brown urine due to porphyrin excretion. Bones and tissues fluoresce under UV light due to porphyrin accumulation. Unlike human AIP, acute neurological crises are not observed in cats, but biochemical markers and phenotypic signs are similar.
Complications - Distinctive brown or reddish teeth discoloration (erythrodontia). Yellow-brown urine with elevated porphyrins. Fluorescent bones under UV light due to porphyrin deposition. Mild hematological abnormalities may occur but severe anemia or acute attacks typical in humans have not been reported in cats. Chronic porphyrin accumulation can cause lifelong pigmentation changes but not severe systemic disease in cats.
Why This Matters to Breeders and Vets - Breeders should use available genetic testing to identify Siamese cats carrying the AIP Variant 4 mutation to avoid breeding affected animals and reduce disease incidence. Veterinarians need awareness of the classic signs such as erythrodontia and dark urine to suspect porphyria and recommend confirmatory biochemical or genetic tests. Since this is a dominant trait, every kitten of an affected cat has a 50% chance of inheriting the mutation. Genetic counseling is crucial. Early diagnosis allows better management, avoidance of misdiagnosis, and informed breeding decisions to prevent propagation of the disorder.
Summary - Acute Intermittent Porphyria (Variant 4) in Siamese cats is an autosomal dominant inherited metabolic disorder caused by specific mutations in the HMBS gene leading to deficient hydroxymethylbilane synthase enzyme activity. This causes accumulation of porphyrin precursors and manifests with characteristic brownish teeth discoloration (erythrodontia), yellow-brown urine, and fluorescence of bones. Unlike human AIP, cats do not typically develop acute neurological symptoms. Genetic testing enables identification and responsible breeding to manage and reduce the disease in affected populations.
