Ala Dehydratase Deficiency Porphyria
Porphyria is derived from the Greek word "porphyra," which signifies the purple-red color of urine due to the accumulation of porphyrins. Delta-aminolevulinic acid (ALA) dehydratase deficiency porphyria (ADP) is a type of rare acute porphyria involving the ALA dehydratase enzyme, which is the second enzyme in the heme synthesis pathway after ALA synthase. Heme is a fundamental component of blood.
ADP is an autosomal recessive disorder and is the rarest of the inherited porphyrias. The disease was identified first by M.Doss in Germany, and the disease is, therefore, also known as Doss porphyria. It is also called plumboporphyria because clinical findings of ADP mimics lead poisoning in biochemical and clinical findings due to the ability of lead to inhibit the ALA dehydratase enzyme. ADP is one of the four acute hepatic porphyrias and is characterized by variable extrahepatic gastrointestinal, neurological-psychiatric, and cardiovascular manifestations. It can also have a significant erythropoietic component that may cause cutaneous symptoms in early childhood and complicated by cholestatic liver cirrhosis and progressive hepatic failure.
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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. ADP is highly heterogeneous at the molecular level, with 14 ALA dehydratase mutations observed in the eight patients with ADP.
ALA dehydratase porphyria is an extremely rare porphyria, and so far, only 8 cases have been diagnosed. Of these 8 cases, 2 of them were identified at birth, one of them at age 7, four patients were diagnosed at age 12-15, and one patient in Belgium was diagnosed at age 63 who had symptoms when he developed a myeloproliferative neoplasm (polycythemia vera). All the cases known so far are males.
ALA dehydratase enzymes catalyze the conversion of ALA into porphobilinogen (PBG) in the cytosol of cells in the liver and red blood cells and play a chief role in the biosynthetic pathway of heme. Due to defects in the enzyme, ALA accumulates within the red blood cells and hepatocytes. They can subsequently leak into the plasma and can cause toxicity to various tissues.
History and Physical
Attacks of all acute porphyrias are quite similar, but those of ADP and acute intermittent porphyria (AIP) are a bit more severe. ALA dehydratase porphyria presents with neurovisceral symptoms. Neurological symptoms are mainly of 2 types: neuropsychiatric symptoms and peripheral neuropathy.
Neuropsychiatric symptoms can include disorientation, agitation, anxiety, restlessness, hysteria, hallucinations, delirium, altered consciousness, apathy, depression, and phobias. Neuropathic symptoms can include sensory and motor neuropathy. Motor dysfunction and muscle weakness were seen in 6 out of the 8 patients. The most common visceral symptom is abdominal pain. Other symptoms include nausea, vomiting, constipation, bloating, and rarely diarrhea. Since the pain is neurological, abdominal tenderness/ rebound, leucocytosis, and fever are either minimal or absent. No cutaneous findings were noted.
An infant diagnosed in Sweden had severe symptoms that progressed to pain, polyneuropathy, hyponatremia, vomiting, and respiratory dysfunction. The male from Belgium developed symptoms of acute porphyria along with myeloproliferative disorder (polycythemia vera) at 63 years of age. His motor neuropathy gradually progressed to cause the loss of strength in both his arms. Many times, the symptoms are exacerbated by drugs, which can induce CYP enzymes. CYP enzymes lead to the induction of ALA synthase 1 (ALAS1) in the liver. Induction of ALAS1 causes exacerbation or precipitation of symptoms.
The classic triad of abdominal pain, peripheral neuropathy, and neuropsychiatric symptoms should always prompt consideration of all the acute porphyrias into the differential. Initial screening should include a spot urine sample, obtained preferably during an acute porphyria attack, to measure urinary porphobilinogen (PBG) and total porphyrins. The total urine porphyrin level will be elevated. Urinary porphobilinogen is not significantly increased in ALA dehydratase porphyria (ADP).
If these initials tests are normal in a patient with classic symptoms of ADP, then it is suggested to repeat the first-line tests rather than proceeding to second-line testing. Second-line testing in a patient is performed if it is found that total urine porphyrins are elevated without PBG elevation (findings suggestive of ADP), and clinical suspicion of acute porphyria is very high. Second-line testing includes urine ALA level, fractionation of porphyrins, and measurement of erythrocyte protoporphyrin. ALA and erythrocyte protoporphyrin is markedly elevated, and there is a predominance of coproporphyrin III noted. Diagnosis is confirmed by measuring ALA levels in erythrocytes and ALAD mutation analysis, which reveals heterozygous or homozygous ALAD mutations.
Treatment / Management
Acute attacks are managed by withdrawing the offending agents that can precipitate acute attacks and supportive care for nausea, vomiting, pain, seizures, and electrolyte imbalances. Offending agents can include alcohol, oral contraceptives, antibiotics (such as nitrofurantoin, rifampin, trimethoprim-sulfamethoxazole), anti-seizure medications (such as topiramate, phenytoin, phenobarbital, ethosuximide, valproic acid), and many more medications. A list of medications is available on the American Porphyria Foundation and the European Porphyria Network website. Once the diagnosis of an acute attack of porphyria has been established, hemin should be administered immediately. Physical, psychological, and emotional stress may also precipitate attacks and must be minimized.
Giving IV hemin causes negative feedback to heme synthesis by inhibiting the synthesis of the ALA synthase enzyme (rate-limiting step), which limits hepatic and marrow porphyrin synthesis. Suppression of ALA synthase leads to decreased accumulation of heme precursors and their byproducts and rapid and dramatic reductions in plasma and urinary PBG and ALA.
Indications for the use of hemin include attacks severe enough to require hospitalization, opioid analgesia, or other intravenous medication; or accompanied by nausea and vomiting, motor neuropathy, paresis, seizures, agitation, delirium, psychosis, ileus that prevents oral intake, or hyponatremia. Hemin should be administered at a dose of 3 to 4 mg/kg body weight intravenously as a single daily dose for four days (dosing more than once per day is not recommended as it is unlikely to improve efficacy). Hemin is mixed with 25 percent human albumin for infusion (it was previously mixed with sterile water but resulted in adverse reactions). Treatment duration can be extended beyond four days in patients with advanced motor neuropathy where resolution is not seen. Pregnancy is not a contraindication for hemin.
The use of hemin decreased hospital stay by 3 days and reduced opioid usage. All four adolescent cases with onset of symptoms at ages 12 to 15 years showed effective resolution of attacks with hemin, and in two of these cases, prophylactic hemin infusions prevented recurrent attacks. However, a Swedish child with early-onset ADP did not respond to hemin. Glucose loading may be tried for mild symptoms if hemin is not readily available, but there is not sufficient evidence to support this. Blood transfusions and hydroxyurea (hydroxycarbamide) to suppress erythropoiesis showed beneficial results in one case. This deserves further study. Givosiran, an RNA interference (RNAi) drug, may be effective in cases with an elevation in exosomal ALAS1 mRNA. It is unclear if a liver transplant may be of benefit in less severe refractory cases, but it failed to benefit a child with severe ADP.
Diseases with manifestations similar to the non-specific findings of ADP include other acute porphyrias that have neurovisceral manifestations. These include acute intermittent porphyria (AIP), variegate porphyria (VP), and hereditary coproporphyria (HCP). Each of them has a characteristic elevation of different urinary biomarkers.
Acute intermittent porphyria is characterized by elevated urinary PBG on an initial urine sample, unlike ADP. Variegate porphyria presents with neurovisceral symptoms and cutaneous manifestations such as blistering skin lesions. VP is characterized by elevated urinary PBG and elevated plasma and fecal porphyrins, unlike ADP. Hereditary coproporphyria presents with acute neurovisceral symptoms similar to ALAD but may also have blistering skin lesions. HCP is characterized by elevated urinary PBG and fecal porphyrins on the initial spot urine sample, unlike ADP. Other differentials include diseases where ALAD is inhibited.
Lead poisoning can also mimic ADP. Lead is a potent inhibitor of ALAD, and lead poisoning (plumbism) can produce the same symptoms and biochemical abnormalities as ADP, including increased urinary ALA and coproporphyrin III, and erythrocyte zinc protoporphyrin. However, lead levels are normal in ADP but elevated in lead poisoning. Succinylacetone is also a potent inhibitor of ALAD and is found in high quantities in the blood and urine of patients with hereditary tyrosinemia type 1 (HT1). Approximately 40% of children with HT1 develop signs and symptoms of ADP. Children with HT1 also have symptoms related to other metabolic effects, including progressive liver disease and renal tubular dysfunction. Those with HT1 have elevated urinary organic acids and FAH gene mutations.
Only two patients have had complete follow-up. One was a Swedish infant who eventually required liver transplantation but died 3 years after transplantation at 9 years. The other was a Belgian male diagnosed at 63 years old; he went on to develop a myeloproliferative disorder (polycythemia vera) and eventually succumbed to his hematological malignancy, not the porphyria.
Progressive disease and recurrent attacks lead to severe motor weakness involving all limbs, dysarthria and may even progress to severe respiratory insufficiency requiring mechanical ventilation. Early-onset ADP in the Swedish infant was complicated by mild intellectual disability, autism, impaired hearing, and walking difficulties due to bilateral ankle contractures. Myeloproliferative disorder (polycythemia vera) was noted in the Belgian male.
It is unlikely to be associated with ADP but could have contributed to disease severity since this myeloproliferative disorder is associated with increased production of hemoglobin and erythrocytes, thus unmasking his underlying pre-existing ADP. Complications related to hemin infusion include infusion site phlebitis and iron overload after multiple hemin transfusions (monitor serum ferritin).
Deterrence and Patient Education
ADP is an extremely rare autosomal recessive condition with a chronic course punctuated with acute attacks. Once diagnosed, patients must be counseled and educated on the presentation of an acute attack and must be instructed to visit the nearest emergency room in case of abdominal pain. Patients must be made aware that treatment is currently only for acute attacks and that the mainstay of management is to prevent attacks by avoiding triggers. To facilitate this, patients should be provided with a list of medications that are safe and unsafe. Patients must be counseled to avoid alcohol and tobacco smoking, as they can also induce attacks. Finally, they must be educated on the autosomal recessive pattern of inheritance and risk for future generations.
Enhancing Healthcare Team Outcomes
The clinical triad of abdominal pain, peripheral neuropathy, and neuropsychiatric manifestations must prompt suspicion of acute porphyrias. ADP is an extremely rare form of acute porphyria and requires a high index of suspicion for diagnosis. Patients commonly present with recurrent abdominal pain and may end up in a surgical service. Hence the surgical teams must be aware of this nonsurgical cause of recurrent abdominal pain with normal abdominal imaging studies and must look for neuropsychiatric signs and neuropathy when patients present with recurrent abdominal pain. The diagnostic algorithm for acute porphyrias must be followed to diagnose this extremely rare condition.
Interprofessional involvement of the primary care clinician, hematologist, nursing, surgeon, genetic/metabolic disease expert, biochemist, and pharmacist is necessary for early identification of this disease. A high index of suspicion can prevent multiple episodes and unnecessary diagnostic tests. Nursing must be educated on the administration of hemin and monitor for adverse reactions. Pharmacists have an important role in verifying drug interactions and making sure no drug that can trigger an episode is administered to a patient. Finally, patient counseling is very important as they must be aware of the importance of avoiding triggers that precipitate attacks. Open communication and collaboration between interprofessional members of the team are necessary to ensure early diagnosis, enhance outcomes, and prevent recurrent episodes. [Level 5]
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