Winter 2007 PES Bulletin

HMBS gene involved in AIP

The HMBS gene produces an enzyme called hydroxymethylbilane synthase.
Hydroxymethylbilane synthase enzyme is responsible for the third step in heme production.
Heme is the portion of hemoglobin carries oxygen in the blood from the lungs to the rest of the body. Each of the steps in heme production is controlled by a separate gene and each separate gene is responsible for each different main type of porphyria.
Hydroxymethylbilane synthase assembles four molecules of porphobilinogen.
Five more enzymes eventually transform this product into heme.
Mutations of the HMBS gene can cause Acute Intermittent Porphyria.
More than 197 mutations that can cause this type of porphyria have been identified in the HMBS gene.
These mutations cause a switch in amino acids (the building blocks of proteins) in the enzyme made by HMBS. As a result, the activity of the enzyme is reduced, allowing byproducts of heme production to build up in the body. This buildup, in combination with nongenetic factors (such as certain drugs, alcohol, smoking, and dieting), causes the symptoms seen in acute intermittent porphyria.
Identification in the human genome has placed the location of HMBS at chromosome 11 q 23.3.

Randall Karsnick PhD
Genetics

Fatigue a Signal for Need to Rest

When you ask a porphyic patient to describe fatigue it is often very hard to describe.
Not only is fatigue hard to describe but it is also even harder to measure.
Many symptoms of porphyria can cause a feeling of weariness. Such fatigue can make finishing an activity very difficult.
Fatigue can include slow physical movement, muscle stiffness, depression. In addiiton such fatigue can include changes in being able to move or sleep.
At other times fatigue is experienced only when medications are wearing off.
Peripheral neuropathy due to porphyria is also to blame for much fatigue experienced by porphyria patients.
PN symptoms such as muscle stiffness, cramping, tremors or seizure activity, and even the difficulty initiating a movement tend to put stress on a person's muscles.
Many porphyria patients when not adequately diagnosed with peripheral neuropathy due to porphyria, often consult rheumatologists thinking that their condition may be the beginning of arthritis or fibromyalgia or fibromyositis.
It is muscle fatigue.
Porphyria patients who experience seizures will find that constant shaking can quickly fatigue the muscles.
Most anti-seizure medications are unsafe for porphyria patients. However luckily Neurontin also know as Gabapentin works fairly well for controlling seizures and also many patients report that the drug also reduces pain.
Neurontin can be used to treat the symptoms experienced by a porphyric patient, but also needs to be carefully monitored.
Atrophy is another thing that must be evaluated.
Muscles that do not move enough become deconditioned and reduced in size. This is known as atrophy.
The loss of muscle strength decreases stamina and endurance. Many porphyria patients describe this as fatigue as well.
This is why some exercise needs to be a routine part of the daily life habits of a porphyria patient.
It is well know that people who have exercise as a part of their daily routine experience less fatigue.
In visiting with many different porphyria patients one can find that there is a considerably large fluctuation in mobility.
Most find that they experience fluctuations in their mobility throughout any given day. Many describe this functuation as a "waxing and waning" effect.
For those with certain drugs, these periods of fluctuation follow the dosing cycle, such as in neurontin.
The porphyric will experience an increase in symptons at the end of a dose.
Some porphyria patients state that they have their best relief from symptoms in the morning after being full rested from a long night's sleep.
Such porphyics often try to get everything done in the morning when they feel well or at least better.
They also know that they need to prioritze their day, because most porphyria patients have learned that with overactivity, they will fallto fatigue.

Dr. Kenneth Carlson
Neuropsychiatric

Types of Porphyria Pain & Treatment

Porphyric pain may be acute or chronic.
Acute pain is a one-dimensional pain. This means that it is a symptom of an underlying pathology.
The primary goal of pain management therapy would be the treatment of the underlying disease which reduces or eliminates the pain. [We hope!!!]
Analgesics are used as adjunctive medications to provide short term comfort and prevent behabviors that interfere with the recovery process from an acute attack of porphyria.
On the other-hand chronic pain is a multi-dimensional type of pain. It is very complex. Because of the complexity the interplay between between the psychological, physical and social factors can actually worsen the symptoms.
There are three types of chronic pain. The first is pain resulting from a chronic condition. The second type of pain is from an acute injury that usually lasts longer than expected, and the third type of pain is a pain for which there is no discernible cause. Sound familiar? So it is with most porphyria pain.
Chronic pain in and by itself may be considered a disease. In this case reducing or eliminating the pain without increasing the risks is the primary desired result of treatment therapy.
In a 1998 study it was estimated that more than 75 million people in the United States alone have some kind of persistent recurrent pain. Among these are those who suffer lower back pain and chronic tension headaches.
Chronic pain as most porphyrics so well know, affects all aspects of their lives. Pain is described as being "an unpleasant sensory and emotional experience arising from actual or potential tissue damage .
The dual physical and emotional aspectsof the definition are important to remember because they are so very conencted.
The physiological and physical effects of pain include increased pulse, blood pressure, and respiration. It also means decreased activity and mobility. {Don't we all know!!!]
In addition chronic pain also causes fatugue, sleep disruption or restlessness, anxiety, agitation, anger, and all too often, depressiobn. Some aspects become too prevalent in a porphyric's life that they literally become unable to function.
The social consequences of pain include disruption of family life and also decreased productivity.

Beverly Thompson MNS
Pharmacology Department

Pain Medication in Porphyria

Pain medications vary in types and functions.
Analgesics are known as pain medications.
Pain medications vary considerably, they are not all the same.
Each pain medication has its advantages and risks.
Specific types of pain may respond better to one kind of medication than to another kind.
Each individual porphyria patient may have a slightly different response to a specific pain medication.
Over-the-counter medications are good for many types of pain.
Acetaminophen which is better known as Tylenol has been found to be beneficial for relieving pain and fever. Tylenol is less irritating to the stomach than other OTC medications.
Tylenol however, can be toxic to the liver if the recommended dose is exceeded. Many physicians do not recommend the use of Tylenol in hepatic porphyria patients because of possible further liver damage.
NSAIDs are another classification of pain medications
NSAIDs is the short term for non-steroidal anti-inflammatory drugs.
Aspirin, Alleve, Naproxen, Advil, Motrin, and ibuprofen are examples of non-steroidal anti-inflammatory drugs (NSAIDs).
NSAIDs reduce inflammation thus relieving pain.
Prescription medications may be needed for other types of pain.
Non-narcotic and narcotic pain medications have their specific uses and risks.
Besides pain medications pain can often be relieved through the use of TENS units, massage, biofeedback, relaxation techniques, ice or heat packs.
Some porphyria patients have found that a consultation with a pain clinic or other specialist may be helpful for control of long-term pain.

Dallas Engstrom PA
Pain Management Center

Porphyrins, Heme and Porphyrias

What are porphyrins and what function do porphyrins have?
The most important function of porphyrins is as components of heme.
From the time that a porphyria patients has heard of porphyria they too have heard of heme.
In simple chemistry is it known that Heme is made from iron + protoporphyrin.
Hemoglobin is made up of four globin proteins + 4 heme groups. Oxygen binds to the iron in the heme molecules.
Various kinds of porphyrins exist with the same basic structure, but with slightly different chemical appearance.
The major biochemical pathway (heme synthesis) includes conversions from porphyrins to delta-ALA, then to PBG, then uroporphyrin, then coproporphyrin, then protoporphyrin, and finally into the end product -- heme.
the delta-ALA and PBG are well known terms to porphyria patients because these two elements are repeatedly tested in urine, fecal and blood collections in obtaining a diagnosis of porphyria.
Each step of the heme biochemical pathway requires the presence of a specific enzyme.
If any of the enzymes are deficient (because of a genetic disease or inhibition by a toxic substance), these intermediates build up, and a type of porphyria results.

Jeff Watkins PhD
Biochemistry