Porphobilinogen deaminase (PBGD) is an enzyme, a type of protein that speeds up chemical reactions in the body. It plays a role in a series of steps that produce a compound called heme. Heme is a molecule that is fundamental for many processes within the body, including oxygen transport.
Role in Heme Production
Heme is a complex molecule that contains an iron atom at its center, which is responsible for its ability to bind oxygen. This molecule is a component of hemoglobin, the protein in red blood cells that transports oxygen from the lungs to tissues throughout the body. Heme is also present in myoglobin, which stores and releases oxygen in muscle cells, and in cytochromes, which are involved in energy production within cells.
The production of heme occurs through a multi-step pathway involving several enzymes. PBGD is the third enzyme in this pathway. Its specific function is to convert four molecules of porphobilinogen (PBG) into a linear molecule called hydroxymethylbilane.
This conversion is a condensation reaction where four ammonia molecules are released. Hydroxymethylbilane then undergoes further transformations catalyzed by other enzymes to eventually form heme. Inadequate PBGD activity disrupts this step in heme synthesis, which can lead to health problems.
Conditions Linked to PBGD Dysfunction
When porphobilinogen deaminase does not function correctly, it can lead to a group of metabolic disorders known as porphyrias. These conditions arise from disruptions in the heme synthesis pathway, causing an accumulation of porphyrin precursors, the substances that are normally converted into heme.
Acute Intermittent Porphyria (AIP) is the most common condition associated with PBGD deficiency. It is an inherited disorder, passed down in an autosomal dominant pattern, meaning a person needs only one copy of the altered gene to have the condition. The deficiency in PBGD activity, often around 50% of normal, leads to a buildup of porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) in the liver.
These accumulated precursors are thought to be responsible for the symptoms of AIP, which often manifest as acute attacks. Attacks can be triggered by various factors, including certain medications, alcohol consumption, infections, fasting, and hormonal changes, such as those related to the menstrual cycle. The most common symptom during an attack is severe abdominal pain, which can be accompanied by nausea, vomiting, and severe constipation.
Beyond abdominal issues, AIP can affect the nervous system, leading to a range of symptoms. These may include muscle weakness, sometimes progressing to paralysis, headaches, and even seizures. Psychiatric symptoms are also common, such as irritability, restlessness, insomnia, anxiety, depression, and, in some cases, confusion, delirium, or hallucinations.
Identifying PBGD-Related Conditions
Diagnosing conditions linked to PBGD dysfunction, such as Acute Intermittent Porphyria, involves specific laboratory tests. Initial screening for an acute porphyria attack focuses on measuring levels of porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) in urine. During an acute attack of AIP, these levels are significantly elevated, often more than 10 times the upper limit of normal.
A quantitative urine test for PBG is used to avoid delays in diagnosis. While an increase in total urine porphyrins might be observed, it is less specific than elevated PBG and ALA, as mild increases in porphyrins can occur in other medical conditions.
Once an acute porphyria is suspected based on elevated PBG and ALA, further testing helps confirm the specific type. Measurement of PBGD enzyme activity in red blood cells may be performed. Genetic testing, which involves analyzing the HMBS gene, confirms the diagnosis and identifies specific mutations responsible for the enzyme deficiency.
Managing PBGD-Related Conditions
Managing conditions arising from PBGD dysfunction, particularly Acute Intermittent Porphyria, involves strategies for both acute attacks and long-term prevention. For mild acute attacks, intravenous glucose infusions can be administered, as high doses of glucose can help inhibit heme synthesis.
For more severe attacks, especially those with significant neurological symptoms, intravenous hemin is the standard treatment. Hemin is a human blood derivative that helps to repress the overproduction of toxic porphyrin precursors by inhibiting the first enzyme in the heme synthesis pathway. Hemin is given for at least four days.
Beyond specific treatments for the underlying metabolic issue, supportive care is provided during an attack. This includes aggressive pain management and addressing symptoms like nausea, vomiting, or high blood pressure. Avoiding triggers such as certain medications, alcohol, and fasting is part of long-term management.
For patients experiencing frequent recurrent attacks, newer therapies like givosiran, an RNA interference medication, are available. Givosiran works by reducing the production of the enzyme that initiates the heme synthesis pathway, thereby decreasing the accumulation of toxic precursors. Liver transplantation is a last-resort option for individuals with severe, life-threatening, and intractable recurrent attacks.