Genetic basis of Acute Intermittent Porphyria Variant 5 - in Siamese cats is an autosomal recessive inherited metabolic disorder caused by mutations in the hydroxymethylbilane synthase (HMBS) gene. This mutation results in deficient activity of the HMBS enzyme, which is essential in the heme biosynthesis pathway. Unlike some other AIP variants inherited dominantly, Variant 5 follows a recessive pattern, requiring two copies of the mutated gene (one from each parent) for the disease to manifest. Genetic testing is available and important for identifying carriers and affected cats to guide responsible breeding.
Pathophysiology - The deficiency in HMBS activity reduces hydroxymethylbilane synthase enzyme function, disrupting heme synthesis. This leads to accumulation of porphyrin precursors such as 5-aminolevulinic acid (ALA), porphobilinogen (PBG), and porphyrins (uroporphyrin and coproporphyrin) in tissues, urine, and bones. These accumulated porphyrins cause the characteristic brown or reddish discoloration of the teeth (erythrodontia), yellow to brown urine, and fluorescence of bones and teeth under ultraviolet light. The clinical phenotype can resemble congenital erythropoietic porphyria (CEP) but is biochemically distinct by normal uroporphyrinogen-III-synthase activity and deficient HMBS activity.
Complications - Erythrodontia: brownish discoloration of the teeth with fluorescence under UV light. Dark yellow to brown urine due to porphyrin excretion. Fluorescence of bones and other tissues under UV light. Mild anemia and other hematological changes may be present. Unlike humans with AIP, cats generally do not show acute neurovisceral attacks or severe neurological symptoms. Chronic accumulation of porphyrins can cause progressive tissue pigmentation but limited systemic illness beyond hematological effects.
Why This Matters to Breeders and Vets - Breeders should utilize genetic testing to identify carriers and avoid breeding two carriers, which pose a 25% risk of producing affected kittens due to the recessive inheritance pattern. Responsible breeding can reduce disease incidence in the population. Veterinarians need to recognize clinical signs such as erythrodontia and discolored urine and confirm diagnosis via biochemical assays and genetic testing. This aids differentiation from other porphyrias and informs prognosis and care. Early diagnosis through testing enables better genetic counseling, improved disease management, and prevention of affected cats being produced.
Summary - Acute Intermittent Porphyria (Variant 5) (Siamese Type 2) is a rare autosomal recessive inherited disorder caused by HMBS gene mutations leading to deficient hydroxymethylbilane synthase activity and disrupted heme synthesis. This causes accumulation of porphyrins, resulting in visible discoloration of teeth and urine along with characteristic bone fluorescence. The disease is biochemically distinct from other feline porphyrias and lacks acute neurological signs typical of human AIP. Genetic testing supports diagnosis and breeding management, as there is no cure and care is supportive.
