What is Ala Dehydratase Deficiency Porphyria?
Porphyria is a medical term rooted in the Greek word “porphyra”, which refers to the purple-red color of urine caused by an accumulation of certain chemicals called porphyrins. There are different types of porphyria, one of which is Delta-aminolevulinic acid (ALA) dehydratase deficiency porphyria (ADP). This particular type involves an enzyme known as ALA dehydratase, which plays a crucial role in the creation of a key component of blood called heme.
ADP is a rare disorder inherited from both parents, making it the most uncommon of all the inherited types of porphyria. The disease was first discovered in Germany by a scientist named M. Doss, and thus it’s also known as Doss porphyria. There’s another name as well – plumboporphyria. That’s because the symptoms encountered in ADP are very similar to those observed in lead poisoning. This is due to lead’s ability to inhibit the proper functioning of the ALA dehydratase enzyme.
ADP is part of a group of porphyrias that specifically affect the liver and can cause various digestive, nerve and mental, and heart-related conditions. Additionally, it can also impact the process of creating red blood cells, leading to skin symptoms in early childhood. The condition can even cause liver diseases that lead to a gradual failure of the liver’s functions.
What Causes Ala Dehydratase Deficiency Porphyria?
ALA dehydratase porphyria (ADP) is a condition that happens when there’s a serious lack of a certain enzyme called delta-aminolevulinic acid (ALA) dehydratase, also known as porphobilinogen synthase (PBGS). This enzyme’s job is to combine two ALA molecules to create a single molecule called monopyrrole porphobilinogen (PBG).
The gene related to this enzyme is found on chromosome 9q34. ADP varies a lot at the molecular level, with 14 different mutations of the ALA dehydratase enzyme having been found in the eight known patients with ADP.
Risk Factors and Frequency for Ala Dehydratase Deficiency Porphyria
ALA dehydratase porphyria is a very rare type of porphyria with only 8 known cases to date. The ages at which these cases were diagnosed vary greatly, with some being identified at birth while others only being recognized later in life. For example, two cases were diagnosed at birth, another one at age 7, four further cases were identified between the ages of 12 and 15, and one person was diagnosed at the age of 63 following the development of a type of blood disorder called a myeloproliferative neoplasm (specifically, polycythemia vera). Interestingly, all documented cases thus far have been in males.
Signs and Symptoms of Ala Dehydratase Deficiency Porphyria
Acute porphyrias, including ADP and acute intermittent porphyria (AIP), cause episodes or ‘attacks’ with similar symptoms. These symptoms can be thought of in two categories: Neuropsychiatric symptoms and peripheral neuropathy. Neurological issues associated with ALA dehydratase porphyria, a type of acute porphyria, are particularly severe.
- Neuropsychiatric symptoms may include confusion, nervousness, anxiety, restlessness, extreme emotion, hallucinations, delirium, changes in conscious state, indifference, depression and phobias.
- Peripheral neuropathy symptoms usually involve sensory and motor issues. For instance, motor dysfunction and muscle weakness were observed in 6 out of 8 patients.
The most common physical symptom among these conditions is abdominal pain, but patients may also experience nausea, vomiting, constipation, bloating, and rarely, diarrhea. Because these symptoms are caused by nerve abnormalities, there might be minimal or no abdominal sensitivity or fever, and a lack of increase in white blood cells. There are no skin changes that occur with these conditions.
Specific cases of acute porphyrias have shown that severe symptoms can develop. For example, an infant in Sweden had symptoms that got more intense, including pain, neuropathy, low sodium levels, vomiting and problems with breathing. Another patient, a man from Belgium, developed symptoms of acute porphyria and an illness in which the body makes too many red blood cells (polycythemia vera) when he was 63 years old. His motor nerve condition got worse over time, leading to weakness in both his arms. It’s worth noting that certain medications can also make the symptoms worse. These drugs trigger enzymes in the liver which can greatly increase symptoms.
Testing for Ala Dehydratase Deficiency Porphyria
If someone is experiencing a combination of stomach pain, nerve damage, and mental health symptoms, doctors must consider the possibility of acute porphyrias. This is a group of rare genetic disorders that affect the nervous system and skin. To check for these conditions, doctors can perform a quick screening test using a urine sample. This test measures different substances linked to these disorders, such as porphobilinogen (PBG) and total porphyrins. During an acute porphyria attack, the level of total urine porphyrins will be high.
However, for a particular type of porphyria, called ALA dehydratase porphyria (ADP), the PBG level in urine won’t be much higher than normal. So, if someone is showing classic symptoms of ADP but the initial tests are normal, the doctor may recommend repeating the first-line tests instead of moving to more extensive testing.
Second-line tests come into picture if the total urine porphyrins are elevated without any noted increase in PBG. This scenario hints towards ADP, especially when the suspicion of acute porphyria is high. These more extensive tests measure different substances in the urine and red blood cells, like ALA and protoporphyrin. In ADP, ALA and protoporphyrin will be unusually high, and a particular type of porphyrin, coproporphyrin III, will be prevalent. To confirm the diagnosis, doctors will measure ALA levels in red blood cells and check for ALAD mutations, which are common in people with ADP.
Treatment Options for Ala Dehydratase Deficiency Porphyria
Acute porphyria attacks are typically addressed by removing any triggers that could worsen the attack and by managing the symptoms such as nausea, vomiting, seizures, and imbalances in the body’s electrolyte levels. The triggers could include alcohol, certain birth control pills, multiple types of antibiotics and anti-seizure medications, amongst others. Websites like the American Porphyria Foundation and the European Porphyria Network provide a comprehensive list of these medications.
Once a diagnosis of an acute porphyria attack is confirmed, a medicine known as hemin should be immediately given to the patient. Stress, whether physical, mental, or emotional, could also lead to attacks and should be avoided as much as possible.
Administering hemin through an IV provides a negative feedback loop to the process of creating heme in our bodies by limiting the production of an enzyme pivotal in this process. This, in turn, leads to a decrease in the harmful byproducts that cause symptoms of porphyria.
Hemin is generally used in cases where the attack of porphyria is severe enough that it requires hospitalization, opioid pain medications, or other strong IV drugs. It’s also used when the patient has symptoms like severe nausea and vomiting, muscle weakness, seizures, mental confusion, delusions, severe abdominal pain that prevents oral food and drink intake, or low sodium levels in the blood. Hemin is typically administered as a single daily IV dose for four days, the amount based on the patient’s body weight. In some cases, the treatment duration can be extended beyond four days.
Usage of hemin can cut down hospital stay by up to 3 days and can also decrease the need for opioid pain medications. While hemin has proven effective in resolving attacks in numerous adolescent patients, there have been instances where it did not have the desired effect. Other approaches like glucose loading, blood transfusions, or hydroxyurea may be tried, but more study is needed. Givosiran, an RNA interference drug, shows potential, and it may help in cases with an increase in exosomal ALAS1 mRNA. Liver transplants may also be considered, although the benefits are not clear and failed to help in a specific severe case.
What else can Ala Dehydratase Deficiency Porphyria be?
There are a number of conditions that might be mistaken for ADP (acute delta-aminolevulinic acid dehydratase porphyria) since they can often present with similar symptoms. These could be other forms of porphyrias that have both neurological and visceral symptoms. Some of these conditions include:
- Acute intermittent porphyria (AIP)
- Variegate porphyria (VP)
- Hereditary coproporphyria (HCP)
These conditions can be differentiated based on specific biomarkers found in urine. For example, AIP exhibits elevated levels of urinary PBG, which isn’t usually a characteristic of ADP. On the other hand, individuals suffering from VP also show skin blistering alongside nerve and organ symptoms, while presenting higher numbers of urinary PBG and plasma and fecal porphyrins compared to those with ADP. Similarly, HCP may lead to skin blistering and shows heightened levels of urinary PBG and fecal porphyrins.
Interestingly, lead poisoning can also resemble the symptoms of ADP. This is because lead suppresses ALAD, an enzyme key in hemoglobin synthesis. It’s worth noting though, that unlike in ADP, lead levels are higher in cases of lead poisoning.
Lastly, an inherited condition known as hereditary tyrosinemia type 1 (HT1) could also be a potential differential diagnosis. This is due to the fact that succinylacetone – a substance found in high quantities in the blood and urine of HT1 patients – is also a suppressant of the ALAD enzyme. Around 40% of children with HT1 could show signs mimicking ADP alongside other symptoms relating to metabolic effects, such as progressive liver disease and renal tubular dysfunction. In the case of HT1, however, one might detect elevated levels of urinary organic acids and FAH gene mutations.
What to expect with Ala Dehydratase Deficiency Porphyria
Only two patients have fully completed their treatment programs. The first patient was a Swedish baby who ultimately needed a liver transplant. Unfortunately, the child passed away three years after the transplant, at the age of nine. The other patient was a 63-year-old man from Belgium. He was later diagnosed with a blood disorder called polycythemia vera. Unfortunately, he eventually passed away from this blood cancer, not from the porphyria condition.
Possible Complications When Diagnosed with Ala Dehydratase Deficiency Porphyria
With progressive and reoccurring attacks, the disease can lead to severe weakness in all limbs, problems with speaking and could progress to serious breathing issues that require the assistance of a ventilator. One specific situation with early-onset ADP in a Swedish infant involved complications such as mild intellectual disability, autism, hearing problems, and issues with walking because of stiff ankles. Interestingly, a Belgian male with ADP was also diagnosed with a blood disorder called polycythemia vera.
However, it’s important to note that this blood disorder may not directly relate to ADP. Yet, it could make the ADP symptoms worse as this disorder leads to the overproduction of hemoglobin and red blood cells, highlighting any underlying ADP. There can also be complications from treating ADP with hemin infusions. These complications may include inflammation at the infusion site and an overload of iron in the blood after several hemin transfusions, so it’s crucial to keep an eye on the patient’s ferritin levels.
Common Complications:
- Severe weakness in all limbs
- Problems with speech
- Serious breathing issues
- Mild intellectual disability
- Autism
- Hearing problems
- Difficulties in walking due to stiff ankles
- Inflammation at the infusion site after hemin treatment
- Overload of iron in the blood after several hemin transfusions
Preventing Ala Dehydratase Deficiency Porphyria
ADP is a very rare condition that is passed down through families and features a long-term pattern that can be disrupted by sudden severe attacks. After being diagnosed, it’s crucial for patients to understand how severe attacks present themselves and to immediately go to the emergency room if they experience abdominal pain. It’s important for patients to know that there is currently only treatment for severe attacks, and that the best approach is to prevent these attacks by avoiding specific triggers. To help with this, doctors should provide a list of safe and unsafe medications.
Patients should also be advised to stay away from alcohol and tobacco, as these can trigger attacks. Finally, it’s part of the vital education that patients must know about the way this condition is inherited, and how it might affect future generations.
