Question

Explain why a partial defect in PBG deaminase (converts PBG into hydroxymethylbilane) would or would not result in symptoms of photosensitivity.

Answer 1

The porphyrias are a group of congenital errors of metabolism caused by enzymatic defects in the heme biosynthetic pathway. The formation of heme is a multistep process that involves a specific enzyme at every step. Porphyrias are distinct clinical conditions that results from deficiet of particular enzyme for a specific step in heme synthesis resulting in accumulation of intermediate metabolites causing characteristic clinical manifestations including neurological, psychological symptoms and cutaneous photosensitivity.

The porphyrias can be classified as acute ans nonacute and may be either erythropoietic or hepatic depending on the site of accumulation. Among these, the acute intermittent porphyria (AIP) ranks the most common and severe form of acute porphyria. It is associated with mutations in HMBS gene resulting in deficiency of enzyme hydroxymetylbilane synthase or Porphobilinogen deaminase (PBGD) which converts Porphobilinogen (PBG) to hydroxymethylbilane. Majority of people affected with AIP remain asymptomatic most of the time while 10-20% of people show symptoms of it. In most of the asymptomatic individuals PBGD levels remain more or less constant, so a partial defect in PBGD activity will not display any symptoms of AIP. So the level of PBGD enzyme activity is evaluated in conjugation with urine analysis as certain intermediate accumulation level is raised in AIP affected asymptomatic individuals. The urinary aminolevulinic acid (ALA), Porphobilinogen (PBG) level increased in asymptomatic individuals along with other intermediates like uroporphyrin, coproporphyrin (sometimes). These intermediates level may also sometimes raised in feces and plasma. The PBGD level normally fluctuates considerably in the body, so its partial defect is not the ultimate tool to diagnose an affected asymptomatic carrier, as cases of misdiagnosis can lead to life threatening situation. So for the people to get symptomatic the partial defect of PBGD is not alone sufficient, but other factors like certain steroid hormones, drugs, dietary changes are inevitable.