AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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 (ALA) dehydratase catalyzes the second step of heme synthesis. Deficiency of this enzyme produces ALA dehydratase deficiency porphyria (ADP), an extremely rare cause of acute porphyria. ADP is characterized by autosomal recessive inheritance and only neurologic manifestations. It was first described in 1979 and, to date, only 7 cases have been identified and confirmed by gene mutation analysis.

Pathophysiology

ALA dehydratase (ALA-D) catalyzes the conversion of 2 molecules of ALA into the cyclic compound porphobilinogen (PBG). In ADP, deficient ALA-D activity leads to a build-up of upstream intermediates in the metabolic pathway. ALA accumulates in the body and subsequently is excreted in increased amounts in the urine. 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. 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.

Lead poisoning may produce a clinical picture that mimics ADP, termed plumboporphyria, since the heavy metal is a potent inhibitor of ALA-D.

Frequency

United States

Only 1 case of ADP has been reported in the United States.

International

ADP is extremely rare, with only 7 confirmed cases worldwide.

Mortality/Morbidity

All 7 known patients had highly variable symptomatology, 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.

Race

ADP occurs too rarely to determine frequency in specific races. Of the 7 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.

Sex

No known sexual predilection exists for ADP, but 6 of the 7 reported cases occurred in males.

Age

Onset of ADP typically occurs at birth or during childhood, although late-onset disease has been recognized.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

ADP is an acute hepatic porphyria that produces only neurologic symptoms. Heterozygotes are asymptomatic.

• The symptoms mimic those seen in acute intermittent porphyria.
• • 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.
• Rule out exposure to exogenous inhibitors of ALA dehydratase, including styrene, lead, trichloroethylene, and bromobenzene.
• Rule out hereditary tyrosinemia, which leads to accumulation of succinylacetone, an ALA dehydratase inhibitor.

Physical

Physical examination may show evidence of abdominal tenderness or neuropathy.

• 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.

Causes

ADP is an autosomal recessive porphyria due to mutations in the ALAD gene on chromosome band 9q34. The heterogeneity of the mutations accounts for the varied phenotypes in the 7 studied cases. Erythrocyte ALA dehydratase activity is 1% of normal in homozygotes and 50% of normal in heterozygotes.

• Precipitants of the acute attack include the following:
• • Decreased caloric intake
  • Drugs that induce the cytochrome P-450 system: Classically unsafe drugs include barbiturates (eg, phenobarbital), diphenylhydantoin, griseofulvin, phenytoin, sulfonamides, and valproic acid.
  • Estrogen or progesterone use
  • Acute physical and psychological stressors

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Hereditary tyrosinemia, type I
Acute intermittent porphyria (also causes an acute porphyria with only neurologic manifestations)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Urine ALA levels are increased and correlate with clinical severity.
• Erythrocyte zinc protoporphyrin levels are markedly elevated.
• Urine coproporphyrin III and protoporphyrin IX levels are also elevated.
• Erythrocyte ALA dehydratase 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 remains within the reference range.
• Urine PBG levels are within the reference range. This distinguishes 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 ALA dehydratase deficiency.
• Hyponatremia may be noted during acute attacks of ADP and is attributed to infusion of hypotonic dextrose-containing fluids or to the syndrome of inappropriate secretion of antidiuretic hormone.

Other Tests

• DNA analysis to identify mutations in the ALAD gene is the most specific test for ADP.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

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

• 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.
• Intravenous hematin should be administered during acute attacks of ADP.

Surgical Care

Liver transplant has not been shown to be useful in treating ADP.

Consultations

Hematologist

Diet

Maintain a diet high in carbohydrates, consuming at least 300 g of glucose daily. Glucose inhibits ALA synthetase thus decreasing ALA levels.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Specific treatments for acute attacks of ADP include heme replacement with intravenous hematin, and carbohydrate loading with intravenous dextrose. Hematin, the ferric hydroxylated form of heme, should be administered within 24 hours for severe attacks, or for mild symptoms, after 24 hours without improvement.

Drug Category: Metalloporphyrin agents

These 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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Some common medications that are known to be safe for use in ADP include the following: aspirin, acetaminophen, aminoglycosides, benzodiazepines, penicillin and its derivatives, ibuprofen, insulin, phenothiazines, glucocorticoids, atropine, beta-blockers, ranitidine, tetracyclines, thyroxine, gabapentin, and vigabatrin.
• Avoid drugs that induce the cytochrome P-450 system.
• Avoid exogenous estrogen and progesteronal agents.

Deterrence/Prevention

• The mainstay of outpatient therapy is to prevent future acute attacks of ADP.
• • The patient should be counseled to avoid exposure to inducing medications (unsafe medications discussed above) and other exogenous substances such as styrene, lead, trichloroethylene, and bromobenzene.
  • Fasting should be avoided.
  • Smoking, an inducer of the cytochrome P-450 system, may increase attacks and should also be avoided.

Prognosis

• The 7 reported patients with ADP had markedly differing clinical courses.
• Neurovisceral attacks can recur throughout adulthood in otherwise healthy individuals.
• A Swedish boy who had experienced severe 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.
• The patient who presented with late-onset porphyria died from a comorbid hematologic malignancy.

Patient Education

• Patients with ADP should be informed about triggers of acute ADP, as well as safe medications (as discussed in Further Inpatient Care).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize this rare disease entity

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Akagi R, Kato N, Inoue R, et al. delta-Aminolevulinate dehydratase (ALAD) porphyria: the first case in North America with two novel ALAD mutations. Mol Genet Metab. Apr 2006;87(4):329-36.
• Akagi R, Yasui Y, Harper P, Sassa S. A novel mutation of delta-aminolaevulinate dehydratase in a healthy child with 12% erythrocyte enzyme activity. Br J Haematol. Sep 1999;106(4):931-7.
• Bissell DM. Treatment of acute hepatic porphyria with hematin. J Hepatol. Feb 1988;6(1):1-7. [Medline].
• Bonkovsky HL. Neurovisceral porphyrias: what a hematologist needs to know. Hematology (Am Soc Hematol Educ Program). 2005;24-30.
• Doss MO, Stauch T, Gross U, et al. The third case of Doss porphyria (delta-amino-levulinic acid dehydratase deficiency) in Germany. J Inherit Metab Dis. 2004;27(4):529-36.
• Gorchein A. Drug treatment in acute porphyria. Br J Clin Pharmacol. Nov 1997;44(5):427-34. [Medline].
• Gross U, Sassa S, Jacob K, et al. 5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up. Clin Chem. Sep 1998;44(9):1892-6.
• Maruno M, Furuyama K, Akagi R, et al. Highly heterogeneous nature of delta-aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria. Blood. May 15 2001;97(10):2972-8.
• Mercelis R, Hassoun A, Verstraeten L, et al. Porphyric neuropathy and hereditary delta-aminolevulinic acid dehydratase deficiency in an adult. J Neurol Sci. Jan 1990;95(1):39-47. [Medline].
• Sassa S. ALAD porphyria. Semin Liver Dis. 1998;18(1):95-101. [Medline].
• de Verneuil H, Doss M, Brusco N, et al. Hereditary hepatic porphyria with delta aminolevulinate dehydrase deficiency: immunologic characterization of the non-catalytic enzyme. Hum Genet. 1985;69(2):174-7. [Medline].

Article Last Updated: Aug 3, 2006