Aminolevulinic acid dehydratase deficiency porphyria | |
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Other names | Porphyria due to ALA dehydratase deficiency |
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ALA dehydratase deficiency has an autosomal recessive pattern of inheritance. | |
Specialty | Gastroenterology, dermatology, medical genetics, endocrinology ![]() |
Differential diagnosis | Lead poisoning, Tyrosinemia type I |
Aminolevulinic acid dehydratase deficiency porphyria (also known as Doss porphyria, [1] plumboporphyria, [1] or ADP [2] ) is an extremely rare autosomal recessive metabolic disorder that results from inappropriately low levels of the enzyme delta-aminolevulinic acid dehydratase (ALAD), which is required for normal heme synthesis. This deficiency results in the accumulation of a toxic metabolic precursor in the heme synthesis pathway called aminolevulinic acid (ALA). [2] Lead poisoning can also disrupt ALAD and result in elevated ALA causing the same symptoms. [3] [4] [5] [6] [7] Heme is a component of hemoglobin which carries oxygen in red blood cells.
ALA dehydratase deficiency is a rare cause of hepatic porphyria, meaning that excess porphyrins originate from the liver rather than the bone marrow as in erythropoietic porphyrias. [8] [9]
The clinical presentation of ADP includes a wide range of neurologic and gastrointestinal symptoms. [2] The disease can present during early childhood (as well as in adulthood) with acute neurologic symptoms that resemble those encountered in acute intermittent porphyria. [1] Patients can also have gastrointestinal symptoms during acute attacks, including abdominal cramping, vomiting, and constipation. [2] Gastrointestinal symptoms can result in failure to thrive and poor weight gain in children. Other symptoms that can occur during an acute attack include a rapid heart beat, high blood pressure, and respiratory difficulties. [2]
Acute attacks can last for weeks and are also called "neurovisceral" attacks due to the neurological complications associated. Patients have reported numbness and tingling in the extremities, seizures, burning pain, poor coordination, inability to move muscles voluntarily, and psychological disturbances. [2] Psychosis, though rare, has occurred in severe instances.
Many triggers have been identified for acute ADP attacks including fasting, a low carb diet, dehydration, alcohol intake, the use of estrogen or progesterone, certain drugs, and other mental and physical stressors. [2]
ALA dehydratase deficiency is inherited in an autosomal recessive manner. [8]
In conditions where both parents are carriers:
To make a diagnosis, the relevant presenting symptoms and a detailed patient history must be considered in addition to obtaining biomarkers in the urine or blood. These biomarkers include urine porphobilinogen (PBG), aminolevulinic acid (ALA), and porphyrins found in blood and urine. [2] PBG levels fluctuate and are best measured during the onset of acute symptoms. [2] ALA levels are increased in ADP and correlate with the severity of the disease. [11]
If levels of porphyrins are significantly elevated, DNA testing can be performed to determine the specific mutations in the ALAD gene. [2] [11] DNA analysis is the most specific test for making a diagnosis of ADP. [11]
Both lead poisoning and succinylacetone, whose levels are increased in tyrosinemia type I, [12] inhibit ALAD. Therefore, these conditions should also be considered when elevated levels of porphyrins are found.
Supportive care and treatment of symptoms are the typical management options for ADP. During acute attacks, patients are often hospitalized and given medications for nausea/vomiting, rapid heartbeat, and hypertension while their fluid and electrolyte levels are monitored. [2] Glucose supplementation and intravenous hematin are the mainstay of treatment for acute attacks. [2] Avoiding physical and psychological stressors has been shown to limit the reoccurrence of attacks. [2] [10]
The condition is extremely rare, with fewer than 10 cases ever reported. [13] All reported cases have been seen in males. [2] A feature of ADP that separates it from other porphyrias is that it is more prevalent in males than in females. [2] However, it theoretically affects males and females at the same rate. Most cases have been identified in Europe but it can occur in any population. [10]
Porphyria is a group of disorders in which substances called porphyrins build up in the body, adversely affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are rapid in onset and short in duration. Symptoms of an attack include abdominal pain, chest pain, vomiting, confusion, constipation, fever, high blood pressure, and high heart rate. The attacks usually last for days to weeks. Complications may include paralysis, low blood sodium levels, and seizures. Attacks may be triggered by alcohol, smoking, hormonal changes, fasting, stress, or certain medications. If the skin is affected, blisters or itching may occur with sunlight exposure.
Heme, or haem, is a ring-shaped iron-containing molecular component of hemoglobin, which is necessary to bind oxygen in the bloodstream. It is composed of four pyrrole rings with 2 vinyl and 2 propionic acid side chains. Heme is biosynthesized in both the bone marrow and the liver.
Porphyrins are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). In vertebrates, an essential member of the porphyrin group is heme, which is a component of hemoproteins, whose functions include carrying oxygen in the bloodstream. In plants, an essential porphyrin derivative is chlorophyll, which is involved in light harvesting and electron transfer in photosynthesis.
Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down rapidly, often due to high intensity exercise over a short period of time. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of the muscle breakdown products, such as the protein myoglobin, are harmful to the kidneys and can cause acute kidney injury.
Hereditary coproporphyria (HCP) is a disorder of heme biosynthesis, classified as an acute hepatic porphyria. HCP is caused by a deficiency of the enzyme coproporphyrinogen oxidase, coded for by the CPOX gene, and is inherited in an autosomal dominant fashion, although homozygous individuals have been identified. Unlike acute intermittent porphyria, individuals with HCP can present with cutaneous findings similar to those found in porphyria cutanea tarda in addition to the acute attacks of abdominal pain, vomiting and neurological dysfunction characteristic of acute porphyrias. Like other porphyrias, attacks of HCP can be induced by certain drugs, environmental stressors or diet changes. Biochemical and molecular testing can be used to narrow down the diagnosis of a porphyria and identify the specific genetic defect. Overall, porphyrias are rare diseases. The combined incidence for all forms of the disease has been estimated at 1:20,000. The exact incidence of HCP is difficult to determine, due to its reduced penetrance.
Variegate porphyria, also known by several other names, is an autosomal dominant porphyria that can have acute symptoms along with symptoms that affect the skin. The disorder results from low levels of the enzyme responsible for the seventh step in heme production. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.
Porphyria cutanea tarda is the most common subtype of porphyria. The disease is named because it is a porphyria that often presents with skin manifestations later in life. The disorder results from low levels of the enzyme responsible for the fifth step in heme production. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.
Erythropoietic protoporphyria is a form of porphyria, which varies in severity and can be very painful. It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the red blood cells (erythrocytes), plasma, skin, and liver. The severity varies significantly from individual to individual.
Aminolevulinic acid synthase (ALA synthase, ALAS, or delta-aminolevulinic acid synthase) is an enzyme (EC 2.3.1.37) that catalyzes the synthesis of δ-aminolevulinic acid (ALA) the first common precursor in the biosynthesis of all tetrapyrroles such as hemes, cobalamins and chlorophylls. The reaction is as follows:
Dehydratases are a group of lyase enzymes that form double and triple bonds in a substrate through the removal of water. They can be found in many places including the mitochondria, peroxisome and cytosol. There are more than 150 different dehydratase enzymes that are classified into four groups. Dehydratases can act on hydroxyacyl-CoA with or without cofactors, and some have a metal and non-metal cluster act as their active site.
Gunther disease is a congenital form of erythropoietic porphyria. The word porphyria originated from the Greek word porphura. Porphura actually means "purple pigment", which, in suggestion, the color that the body fluid changes when a person has Gunther's disease. It is a rare, autosomal recessive metabolic disorder affecting heme, caused by deficiency of the enzyme uroporphyrinogen cosynthetase. It is extremely rare, with a prevalence estimated at 1 in 1,000,000 or less. There have been times that prior to birth of a fetus, Gunther's disease has been shown to lead to anemia. In milder cases patients have not presented any symptoms until they have reached adulthood. In Gunther's disease, porphyrins are accumulated in the teeth and bones and an increased amount are seen in the plasma, bone marrow, feces, red blood cells, and urine.
Acute intermittent porphyria (AIP) is a rare metabolic disorder affecting the production of heme resulting from a deficiency of the enzyme porphobilinogen deaminase. It is the most common of the acute porphyrias.
Porphobilinogen deaminase (hydroxymethylbilane synthase, or uroporphyrinogen I synthase) is an enzyme (EC 2.5.1.61) that in humans is encoded by the HMBS gene. Porphobilinogen deaminase is involved in the third step of the heme biosynthetic pathway. It catalyzes the head to tail condensation of four porphobilinogen molecules into the linear hydroxymethylbilane while releasing four ammonia molecules:
Porphobilinogen (PBG) is an organic compound that occurs in living organisms as an intermediate in the biosynthesis of porphyrins, which include critical substances like hemoglobin and chlorophyll.
Erythropoietic porphyria is a type of porphyria associated with erythropoietic cells. In erythropoietic porphyrias, the enzyme deficiency occurs in the red blood cells.
Heme arginate is a compound of heme and arginine used in the treatment of acute porphyrias. This heme product is only available outside the United States and is equivalent to hematin.
Aminolevulinic acid dehydratase (porphobilinogen synthase, or ALA dehydratase, or aminolevulinate dehydratase) is an enzyme (EC 4.2.1.24) that in humans is encoded by the ALAD gene. Porphobilinogen synthase (or ALA dehydratase, or aminolevulinate dehydratase) synthesizes porphobilinogen through the asymmetric condensation of two molecules of aminolevulinic acid. All natural tetrapyrroles, including hemes, chlorophylls and vitamin B12, share porphobilinogen as a common precursor. Porphobilinogen synthase is the prototype morpheein.
Harderoporphyria is a rare disorder of heme biosynthesis, inherited in an autosomal recessive manner caused by specific mutations in the CPOX gene. Mutations in CPOX usually cause hereditary coproporphyria, an acute hepatic porphyria, however the K404E mutation in a homozygous or compound heterozygous state with a null allele cause the more severe harderoporphyria. Harderoporphyria is the first known metabolic disorder where the disease phenotype depended on the type and location of the mutations in a gene associated with multiple disorders.
Succinylacetone is a chemical compound that is formed by the oxidation of glycine and is a precursor of methylglyoxal. It is a pathognomonic compound found in the urine of patients with tyrosinemia type 1, which is due to congenital deficiency of an enzyme, fumarylacetoacetate hydrolase. This enzyme is involved in the catabolism of tyrosine, and if deficient, leads to accumulation of fumarylacetoacetate which is subsequently converted to succinylacetone which can be detected in the urine by GCMS. Succinylacetone also inhibits ALA dehydratase which increases ALA and precipitates acute neuropathic symptoms, similar to porphyria.
Tyrosinemia type I is a genetic disorder that disrupts the metabolism of the amino acid tyrosine, resulting in damage primarily to the liver along with the kidneys and peripheral nerves. The inability of cells to process tyrosine can lead to chronic liver damage ending in liver failure, as well as renal disease and rickets. Symptoms such as poor growth and enlarged liver are associated with the clinical presentation of the disease. If not detected via newborn screening and management not begun before symptoms appear, clinical manifestation of disease occurs typically within the first two years of life. The severity of the disease is correlated with the timing of onset of symptoms, earlier being more severe. If diagnosed through newborn screening prior to clinical manifestation, and well managed with diet and medication, normal growth and development is possible.
Indeed, lead poisoning, like all porphyrin diseases, is accompanied by obstinate constipation, nervous lesions, hyperpigmentation and abdominal attacks.
The metabolic abnormalities in lead poisoning are very similar with the ALADP (Doss porphyria)
the symptoms in lead poisoning closely mimic those of acute porphyria