ALAD porphyria is a very rare genetic metabolic disease characterized by an almost complete deficiency of the enzyme delta-aminolevulinic acid (ALA) dehydratase. The deficiency of this enzyme leads to the accumulation of the porphyrin precursor ALA, which can potentially result in a variety of symptoms. Symptoms vary from one person to another but usually come from the neurological and gastrointestinal systems. This disease is inherited as an autosomal recessive disorder. Porphyrins are precursors of heme, an essential component of hemoglobin. Each subunit of hemoglobin is a globular protein containing an embedded heme group that contains one iron atom, capable of binding one oxygen molecule. The heme synthesis pathway is a multi-step process that involves a specific enzyme at every step.
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. An ALAD porphyria is a hepatic form of porphyria.
Aminolevulinic acid dehydratase deficiency porphyria (also known as “Doss porphyria “plumboporphyria, or “ADP) is a 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). Lead poisoning can also disrupt ALAD and result in elevated ALA causing the same symptoms. Heme is a component of hemoglobin that carries oxygen in red blood cells.
Causes
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 is on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier of the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
The ALAD gene contains instructions for creating the enzyme aminolevulinate dehydratase (ALAD), 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 are necessary for the creation of heme.
Mutations of the ALAD gene result in deficient levels of porphobilinogen in the body, with an accumulation of ALA, which causes the symptoms associated with ALAD porphyria.
A variety of different triggers have been identified that can precipitate 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 suspected of triggering an acute attack.
ALA dehydratase porphyria (ADP) is caused by a severe deficiency in delta-aminolevulinic acid (ALA) dehydratase enzyme (ALAD), also called porphobilinogen synthase (PBGS). ALAD catalyzes two molecules of ALA to form one monopyrrole porphobilinogen (PBG). The ALAD gene is located on chromosome 9q34.[rx] ADP is highly heterogeneous at the molecular level, with 14 ALA dehydratase mutations observed in the eight patients with ADP.[rx][rx]
Diagnosis
A diagnosis of ALAD porphyria is made based upon the identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation and of specialized tests that can detect delta-aminolevulinic acid in the urine.
The diagnosis of acute intermittent porphyria results from finding elevated PBG in urine in a random sample kept protected from light. Diagnostic confirmation should include quantitative measurement of PBG, ALA, and total porphyrins from the same urine sample. Normal values are 0 to 4 mg/L, but values may reach as high as 25 to 100 mg of ALA and 50 to 200 mg of PBG during an acute attack of AIP.
A urinary PBG level of only 0 to 4 mg/L during acute symptoms almost rules out acute porphyria as the cause of neurovisceral symptoms.
Although urine collection for quantification of PBG and ALA is optimal during the peak of an attack of AIP, it may be collected within a few days to weeks after the acute episode also, owing to the persistent elevation of urinary ALA and PBG for many months to years after an attack.[rx] The only exception to this leniency is the timed collection of urine, which arises if the patient has received treatment with a 4- to 5-day course of intravenous heme.[rx]
Elevation of urine porphyrins, especially copro porphobilinogen (caused by spontaneous polymerization of porphobilinogen in the urine), is often observable. However, it merits noting that the nonspecific elevation of urine porphyrins, especially coproporphyrins (1 to 2 times the reference range), is common and not specific for porphyria. Stool porphyrins are typically within the reference range or just mildly elevated.
An increase in plasma porphyrin confirmed by increased fluorescence emission scan peak at 619 nm can present. Molecular and DNA testing of HMBS deficiency is unnecessary for the diagnosis but has utility for family screening.[rx][rx][rx]
Associated Laboratory Abnormalities (During An Acute Attack):
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Hyponatremia – most common
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Hypomagnesemia is also common
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Mild aminotransferase elevations
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Mild leucocytosis
Differentiating Between Acute Porphyrias
As mentioned below (vide infra), most acute porphyrias’ symptomatology shows significant overlap. Symptoms of AIP are often clinically indistinguishable from those of hereditary coproporphyria and variegate porphyria. Although the diagnostic approach to distinguish AIP from other acute porphyrias has little evidence backing at present, new evidence-based diagnostic strategies are under development for these conditions.
Plasma Fluorescence Staining
In contrast to AIP, HCP, and other porphyrias in which the sera of subjects with biochemically active disease have emission peaks at approximately 619 nm to 620 nm, the serum from patients with VP have a unique porphyrin-peptide in plasma that has its peak fluorescence at approximately 626 nm, following excitation by light of 410 nm (the Soret band). This reaction forms the basis of the utility of fluorescence of diluted sera at physiologic pH to differentiate VP from other acute as well as cutaneous porphyrias.[rx]
Emerging Role of Genetic Mutation Analysis in Diagnostic Confirmation
The specific type of acute porphyria is now discernable by genetic testing, which is available commercially at several labs. The approach involves sequencing of the four genes that are defective in the acute porphyrias:[rx]
Gene/Type of Acute Porphyria
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ALAD/ALAD-deficient porphyria (Doss porphyria)
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HMBS/AIP
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CPOX/HCP
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PPOX/VP
The evolution of next-generation sequencing (NGS) to porphyria diagnosis is ongoing, with investigators having recently designed a panel containing four genes – ALAS1, HMBS, CPOX, and PPOX for mutational analysis of AIP, HCP, and VP.[rx]
Molecular genetic testing can confirm a diagnosis of ALAD porphyria by identifying the characteristic genetic mutation that causes the disorder.
Treatment
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.
Initial And Symptom-Oriented Treatment
Owing to the simulation of symptoms of acute intermittent porphyria by several abdominal, metabolic, and neuropsychiatric conditions, establishing a confirmed diagnosis forms the core of the management of AIP.
Avoidance of precipitants, especially drugs, requires extreme emphasis, ingraining it in the patient and relatives’ psyche. (vide infra)
When a patient with confirmed AIP presents with an acute attack, the usual first approach is to load the patient with a high carbohydrate diet or intravenously administered dextrose to inhibit hepatic ALAS1 transcription. Administration of 10% dextrose in 0.45% saline should start immediately. If the patient does not present with weakness, vomiting, or hyponatremia, a trial of a high carbohydrate diet for 48 hours before starting specific treatment is the current recommendation.[20][13][11]
For pain, parenteral opiates are the best option (morphine, diamorphine, and fentanyl). Nausea and vomiting are controllable with prochlorperazine, promazine, and ondansetron. These symptoms usually start abating in 72 to 96 hours.[20] For tachycardia and hypertension, preferred medications are beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers (diltiazem). If the patient presents with seizures, they are controllable with diazepam, magnesium sulfate, or clonazepam.[11]
Specific Treatment
Intravenous administration of heme is the specific therapy. It replenishes the hepatocyte heme pool and down-regulates ALAS1, resulting in reduced production of porphyrin precursors and corresponding improvement in symptoms.[21] Heme not only controls hepatic ALAS1 by down-regulating ALAS1 transcription but also by inducing mRNA destabilization or by blocking the mitochondrial import of the mature enzyme.[3]
Owing to the delayed effect of heme therapy on reducing plasma ALA and PBG levels, intravenous heme therapy (IHT) should be administered without delay in severe acute attacks and maintained for four days (3 to 4 mg/kg of heme/day). A response usually appears on the third day with a decrease of urine and serum PBG. Panhematin administration should be through a large peripheral vein or central line due to the risk of phlebitis in small veins, a risk also reduced by preparing it with human albumin instead of water. Other complications are an increase in prothrombin time during the first 2 hours and increased iron production in the liver. Patient discharge can take place when parenteral opioids can stop, and they can tolerate oral drugs.[20]
Excepting occasional complaints of headache or pyrexia, IHT is well tolerated. However, there are inherent risks associated with recurrent treatments with IHT, of which every caregiver should be cognizant.
Risks Associated With Recurrent IHT
The following enumerates the significant issues associated with recurrent IHT – the need to replace the venous access to prevent thromboembolic disease, risk of liver fibrosis, hepatic iron overload, and development of therapeutic ‘tolerance’ to heme infusion. Research has shown that heme infusion can induce the expression of hepatic heme oxygenase 1 (HMOX1, EC 1.14.99.3, HGNC: 5013).[22][23][24] HMOX1 is the crucial enzyme of heme catabolism. Its induction by heme therapy results in the reduction of hepatocyte heme pool and consequently enhanced expression of ALAS1.[25] This heme-induced auto-catabolic effect generates the tolerance reported in some patients.
Currently, the only established cure for acute intermittent porphyria is orthotopic liver transplantation (OLT) with a reported survival rate of around 80%.[26][27] However, a high risk (40%) of hepatic artery thrombosis with OLT prompted the same authors to recommend reserving the procedure for patients with severe recurrent acute attacks and highly impaired quality of life (QoL).
Some studies are looking for other alternatives. These are in different phases of clinical trials, and this CME chapter at present, only seeks to inform the readers of these potential and futuristic therapies:
Potential/Experimental Therapies For AIP
Enzyme Replacement Therapy [ERT] – Based on the experience of administering doses of recombinant human HMBS/PBGD (rhPBGD) protein in a mouse model of AIP that reduced plasma PBG accumulation during an acute attack induced after phenobarbital challenge, in 2002 the European Medicines Agency (EMA) granted recombinant human HMBS/PBGD an orphan designation (EU/3/ 02/103). Researchers conducted clinical trials in healthy subjects, asymptomatic HMBS-deficient subjects with increased porphyrin precursor excretion, and AIP patients with repeated attacks.[28][29] Although the enzyme was able to detoxify PBG metabolites, the treatment approach limitations included its short half-life in circulation and the lack of liver targeting.
Liver Gene Therapy – Clinical trials using two strategies, HMBS-gene therapy and interference RNA for ALAS1 gene inhibition, are being conducted in patients with AIP. The two strategies include – the delivery of the HMBS gene to the hepatocytes using a viral vector. The other option is a small interfering RNA (siRNA) directed against aminolevulinic acid synthase, with the objective of reducing delta ALA production. Both of them are still in the trial phase and await approval, pending larger trials that would hopefully provide consistent efficacy and safety.[20][30]
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.
References
