ALAD porphyria is a very rare genetic metabolic disease characterized by almost complete deficiency of the enzyme delta-aminolevulinic acid (ALA) dehydratase. Deficiency of this enzyme leads to the accumulation of the porphyrin precursor ALA, which can potentially result in a variety of symptoms. Symptoms can vary from one person to another, but usually affect the neurological and gastrointestinal systems. This disease is inherited as an autosomal recessive disorder.
ALAD porphyria is in the group of disorders known as the porphyrias. The porphyrias are characterized by abnormally high levels of porphyrins and porphyrin precursors in the body due to deficiencies of enzymes essential to the creation (synthesis) of heme, a part of hemoglobin. There are at least seven types of porphyria. The symptoms associated with the various types of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the "hepatic" and "erythropoietic" types. Porphyrins and related substances originate in excess amounts from the liver in the hepatic types, and mostly from the bone marrow in the erythropoietic types. ALAD porphyria is a hepatic form of porphyria.
The onset, severity and type of symptoms can vary greatly in individuals with a specific type of porphyria. This variation may depend on, in part, the amount of residual enzyme activity in each individual. Individuals with more significant enzyme deficiency may have more severe symptoms and earlier onset. Individuals with partial deficiency will have milder symptoms, and some individuals will not develop any symptoms (asymptomatic). It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their medical team about their specific case, associated symptoms and overall prognosis.
Individuals with ALAD porphyria may have bouts or “attacks” when symptoms are intense, which are referred to as neurovisceral or acute attacks. An attack may last for several weeks. During an attack, affected individuals may experience severe abdominal cramping or pain accompanied by vomiting and constipation. During infancy, gastrointestinal abnormalities may cause an affected child to fail to grow and gain weight as expected.
Several other neurological symptoms can occur during an acute attack due to problems with the nerves outside the central nervous system (peripheral neuropathy), resulting in numbness or tingling in the hands and feet, burning pain, sensitivity to touch, and a lack of coordination. In severe cases, the motor nerves are involved, resulting in loss or partial impairment of the ability to use voluntary muscles. ALAD porphyria can also be associated with psychological changes during an acute attack. In severe cases, loss of contact from reality (psychosis) has been reported.
Additional symptoms that occur during acute attacks include a rapid heartbeat (tachycardia), high blood pressure (hypertension), seizures, and breathing (respiratory) impairment.
ALAD porphyria is caused by mutations in the ALAD gene, and the disease is inherited as an autosomal recessive disorder. This means that both copies of the ALAD gene have a mutation. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits an abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, and usually will not show symptoms. The risk for two carrier parents to have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
Investigators have determined that the ALAD gene is located on the long arm (q) of chromosome 9 (9q34). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 9q34″ refers to band 34 on the long arm of chromosome 9. The numbered bands specify the location of the genes that are present on each chromosome.
The ALAD gene contains instructions for creating the enzyme ALA which is necessary for the production of heme. Heme is part of hemoglobin, which is the oxygen-carrying component of red blood cells. Heme is mainly produced in the bone marrow and the liver. Eight different enzymes, including ALA are necessary for the creation of heme.
Mutations of the ALAD gene result in deficient levels of ALA in the body, which, in turn, disrupts the biochemical process to create heme. This disruption causes ALA to accumulate, which causes the symptoms associated with ALAD porphyria.
A variety of different triggers have been identified that can set off an acute attack in individuals with ALAD porphyria. These triggers include alcohol, certain drugs, physical and psychological stress, infection, fasting (reduced caloric intake) and dehydration. The use of estrogen or progesterone is also suspect of triggering an acute attack.
ALAD porphyria is an extremely rare disorder with few cases reported in the medical literature. Most cases have occurred in Europe. However, the disorder can potentially occur in any population. More males have been identified with ALAD porphyria than females in the medical literature, yet, most likely, the disorder affects males and females in equal numbers. Researchers suspect that some cases of ALAD porphyria go undiagnosed or misdiagnosed making if difficult to estimate the true frequency of this disorder in the general population. The onset of ALAD porphyria is usually during infancy or childhood, but late-onset of the disorder (well into adult life) has also been reported.
A diagnosis of ALAD porphyria is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests that can detect delta-aminolevulinic acid in the urine.
Molecular genetic testing can confirm a diagnosis of ALAD porphyria by identifying the characteristic genetic mutation that causes the disorder.
The treatment of ALAD porphyria is directed toward the specific symptoms that are present in each individual. Because there have been so few cases of ALAD porphyria, there is only limited information on treatment for the disorder.
Avoidance of triggering factors such as alcohol, certain drugs, fasting, and low carbohydrate diets is recommended for affected individuals. The specific drugs that may need to be avoided in one person can differ from the drugs that need to be avoided in another. More information on these preventive measures and a list of drugs that may potentially need to be avoided are available from the American Porphyria Foundation (see Resources section of this report).
Two standard treatments for acute porphyrias in general are intravenous infusions of hemin and supplementation with glucose. However, these therapies have not been universally effective in treating individuals with ALAD porphyria.
Hemin is an orphan drug that has been approved by the Food and Drug Administration (FDA) for the treatment of acute porphyria. The drug known as Panhematin® (hemin for injection) is usually given to treat an acute attack. The drug is manufactured by:
Recordati Rare Diseases, Inc.
100 Corporate Drive
Lebanon, NJ 08833
I. hemin cannot be obtained quickly enough, glucose administration both orally and intravenously (which has similar effect to hemin) may be used to treat individuals with ALAD porphyria.
Additional drugs may be used to treat affected individuals during an acute attack including pain medications such as opiates, beta-adrenergic blocking agents such as propranolol to treat a rapid heartbeat, sedatives to calm nerves, drugs that reduce nausea and vomiting (anti-emetics) and anti-seizure medications (anti-convulsants). In addition, intravenous fluid replacement may be necessary during an acute attack to ensure that proper fluid and electrolyte levels are maintained.
Individuals with ALAD porphyria should carry Medic Alert bracelets or wallet cards. Genetic counseling may be of benefit for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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