ALA Dehydratase Deficiency Porphyria 

Updated: Mar 25, 2021
Author: Smeeta Sinha, MD; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Porphyrias are diseases caused by enzymatic defects in the biosynthetic pathway of heme; sensorimotor neuropathy and cutaneous photosensitivity may manifest, depending on where in the pathway the insult occurs. Delta-aminolevulinic acid dehydratase (ALAD), also known as porphobilinogen synthase, catalyzes the second step of heme synthesis. Deficiency of this enzyme produces ALAD deficiency porphyria (ADP), an extremely rare cause of acute porphyria.

ADP is characterized by autosomal recessive inheritance and only neurovisceral manifestations.[1, 2, 3, 4]  In ADP the enzymatic activity is less than 3% of normal (asymptomatic carriers have 50% of normal enzyme activity).[5]

ADP was first described in 1979 and, to date, fewer than 10 cases have been identified and confirmed by gene mutation analysis.[6]

Pathophysiology

ALAD catalyzes the conversion of 2 molecules of delta-aminolevulinic acid (ALA) into the cyclic compound porphobilinogen (PBG). In ALAD deficiency porphyria (ADP), deficient ALAD activity leads to a build-up of upstream intermediates in the metabolic pathway.[4, 7] ALA accumulates in the body and is subsequently excreted in increased amounts in the urine.[1, 2, 3]

Decreased heme production de-represses ALA synthetase and further increases ALA levels. Urine coproporphyrin III and erythrocyte protoporphyrin IX levels are also elevated, although the pathogenesis of these findings is not understood.[8] Tissue accumulation of ALA, a neurotoxin, produces neurovisceral symptoms.

ALA synthetase activity is also closely associated with cytochrome P-450 activity. Induction of the P-450 system by exogenous agents causes ALA accumulation and predisposes patients to acute attacks of porphyria.

A review of the disease progression among the eight reported cases found an elevation in circulating levels of the rate-limiting hepatic enzyme 5-aminolevulinic acid synthase-1 (ALAS1) and response to treatment with hemin. The authors concluded that this finding suggests that the liver is an important source of excess ALA in ADP, although the marrow may also be a contributor.[9]

Lead poisoning may produce a clinical picture that mimics ADP. This condition is termed plumboporphyria, because the heavy metal is a potent inhibitor of ALAD.[1]

Etiology

ALAD deficiency porphyria (ADP) is an autosomal recessive porphyria that results from mutations in the ALAD gene on chromosome band 9q34. The heterogeneity of the mutations accounts for the varied phenotypes in the studied cases.[10] Erythrocyte ALAD activity is less than 3% of normal in homozygotes and 50% of normal in heterozygotes.[5]

Precipitants of the acute attack include the following[11] :

  • Decreased caloric intake

  • Dehydration

  • Alcohol

  • Drugs that induce the cytochrome P-450 system: Classically unsafe drugs include barbiturates (eg, phenobarbital), phenytoin, griseofulvin, sulfonamides, and valproic acid

  • Estrogen or progesterone use

  • Acute physical and psychologic stressors

  • Infection

Epidemiology

ADP is extremely rare. Only 8 confirmed cases of ALA dehydratase deficiency porphyria (ADP) have been reported worldwide, with only one of them in the United States.[11]

ADP occurs too rarely to determine the frequency in specific races. Of the 8 known cases, 6 were identified in Europe: 3 of the patients are of German lineage, 2 are Swedish, and 1 is Belgian. The seventh case was reported in the United States.[12]

No known reason for a sexual predilection exists for ADP. However, all 8 cases occurred in males.

The clinical onset of ADP typically occurs at birth or during childhood. However, late-onset disease has been recognized.

Prognosis

The 8 reported patients with ALAD deficiency porphyria (ADP) had markedly differing clinical courses. Patients with ADP have had highly variable presentations, ranging from failure to thrive in an infant to the development of a polyneuropathy in a 63-year-old man. Recurrent attacks of neurovisceral symptoms may be life threatening. 

Neurovisceral attacks can recur throughout adulthood in otherwise healthy individuals.

A Swedish boy who had experienced severe ALAD deficiency porphyria (ADP) attacks refractory to treatment since birth underwent liver transplantation at age 6. A modest improvement in symptoms was noted, but the child died from pneumonia at age 9.[13]

A patient who presented with late-onset porphyria died from a comorbid hematologic malignancy.

Patient Education

Patients with ALAD deficiency porphyria (ADP) should be informed about the triggers of acute ALAD deficiency porphyria (ADP), as well as safe medications (as discussed in Medication).

The American Porphyria Foundation Web site contains lists of safe and unsafe medications, along with other pertinent information for patients with porphyria diseases.

 

Presentation

History

ALAD deficiency porphyria (ADP) is an acute hepatic porphyria that produces only neurovisceral signs and symptoms. Heterozygotes are asymptomatic.

The clinical manifestations mimic those seen in acute intermittent porphyria, as follows:

  • Abdominal pain is frequently reported; it is colicky in nature and may mimic a surgical abdomen

  • Nausea, vomiting, constipation, diarrhea, and urinary retention are possible

  • Neuropathy may be motor or sensory in nature; common symptoms include upper- and lower-extremity weakness and tingling

  • Respiratory impairment is possible

  • Seizures are possible

  • Psychosis may occur in severe attacks

Exacerbation of symptoms occurs with stress, decreased calorie intake, and alcohol consumption. Note: This form of porphyria is not associated with cutaneous photosensitivity

The clinician should rule out the following:

  • Exposure to exogenous inhibitors of ALAD, including styrene, lead, trichloroethylene, and bromobenzene

  • Hereditary tyrosinemia, which leads to accumulation of succinylacetone, an ALAD inhibitor

Physical Examination

On physical examination, patients with ALAD deficiency porphyria (ADP) may show evidence of abdominal tenderness or neuropathy.[14]  Autonomic neuropathy, including tachycardia and systemic arterial hypertension, are common presenting signs during acute attacks. Bulbar and respiratory muscle paresis can occur. Muscle hypotonia of the arms and legs is noted in some patients.

 

DDx

 

Workup

Laboratory Studies

Findings on laboratory studies in patients with delta-aminolevulinic acid dehydratase (ALAD) deficiency porphyria (ADP) are as follows:

  • Urine ALA levels are increased and correlate with the clinical severity

  • Erythrocyte zinc protoporphyrin levels are markedly elevated

  • Urine coproporphyrin III and protoporphyrin IX levels are also elevated

  • Erythrocyte ALAD activity is typically decreased by greater than 80% of normal

  • Despite the fact that this is a disease of hemoglobin synthesis, the complete blood cell count (CBC) remains within the reference range

  • Urine porphobilinogen (PBG) levels are within the reference range; this distinguishes ALAD deficiency porphyria (ADP) from acute intermittent porphyria, which is characterized by increased urinary excretion of PBG

  • Fecal porphyrin levels are normal

  • Blood lead levels should be tested to rule out acquired ALAD deficiency

  • Hyponatremia may be noted during acute attacks of ALAD deficiency porphyria (ADP) and is attributed to infusion of hypotonic dextrose-containing fluids or to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

Hyponatremia and hypomagnesemia are both risk factors for development of seizures, which occur in 20-30% of acute attacks.[15]

Other Tests

DNA analysis to identify mutations in the ALAD gene is the most specific test for ALAD deficiency porphyria (ADP).

 

Treatment

Approach Considerations

Treatment of the acute attack of ALAD deficiency porphyria (ADP) should begin by removing the precipitating factors. This includes discontinuing drugs that induce the cytochrome P-450 system, promptly treating infections, and maintaining a high-carbohydrate intake.

Prompt treatment with intravenous hemin is needed to avoid the development of potentially irreversible neurologic sequelae.[5, 9] Hemin (Panhematin) is an orphan drug that has been approved by the US Food and Drug Administration (FDA) for heme therapy. If hemin cannot be obtained quickly enough, glucose (administered both orally and intravenously) may be used; it has an effect similar to that of hemin.[11]

Pain control can be safely achieved with parenteral morphine. Nausea, vomiting, and anxiety may be safely treated with phenothiazines. Acute attacks can cause respiratory muscle paralysis; airway protection should be frequently assessed and mechanical ventilation implemented, as needed.

Seizure control may be achieved with benzodiazepines; alternatively, gabapentin and vigabatrin are two antiepileptic medications safe for use in ADP. Correcting underlying hyponatremia is essential. Treat tachycardia and hypertension with beta-blockers.

Liver transplantation has not been shown to be useful in treating ADP.[16, 13]

Diet

Patients with ALAD deficiency porphyria (ADP) should maintain a diet high in carbohydrates, consuming at least 300 g of glucose daily. Glucose inhibits ALA synthetase, thus decreasing ALA levels.

Long-Term Monitoring

The mainstay of ALAD deficiency porphyria (ADP) outpatient therapy is to prevent future acute attacks. Patients should be counseled to avoid the following:

  • Exposure to inducing medications (ie, drugs that induce the cytochrome P-450 system, exogenous estrogen and progesteronal agents)
  • Exposure to other exogenous inducing substances, such as styrene, lead, trichloroethylene, and bromobenzene
  • Fasting 
  • Smoking, which is an inducer of the cytochrome P-450 system and may increase ADP attacks
 

Medication

Medication Summary

Specific treatments for acute attacks of ALAD deficiency porphyria (ADP) include heme replacement with intravenous hematin and carbohydrate loading with intravenous dextrose.[17, 18] Hematin, the ferric hydroxylated form of heme, should be administered within 24 hours for severe ADP attacks, or for mild symptoms that fail to improve after 24 hours.

Some common medications that are known to be safe for use in ALAD deficiency porphyria (ADP) include the following:

  • Aspirin
  • Acetaminophen
  • Ibuprofen
  • Benzodiazepines
  • Penicillin and its derivatives
  • Tetracyclines
  • Aminoglycosides
  • Insulin
  • Phenothiazines
  • Glucocorticoids
  • Atropine
  • Beta-blockers
  • Ranitidine
  • Thyroxine
  • Gabapentin
  • Vigabatrin

Metalloporphyrin Agents

Class Summary

Metalloporphyrin agents reduce morbidity and prevent complications: Attacks of porphyria may progress to irreversible neuronal damage. Hemin therapy is used to prevent an attack from causing neuronal degeneration; it is not effective in repairing neuronal damage.

Hemin (Panhematin)

Previously known as hematin (hematin is a term used to describe chemical reaction products of hemin and sodium carbonate solution). Enzyme inhibitor derived from processed RBCs and an iron-containing metalloporphyrin. Decreases production of ALA synthetase, thus decreasing ALA levels. DOC for acute attacks of ALAD deficiency porphyria (ADP).