eMedicine Specialties > Hematology > Heme Synthesis and Disorders

ALA Dehydratase Deficiency Porphyria

Author: Smeeta Sinha, MD, Staff Physician, Department of Dermatology, UMDNJ-New Jersey Medical School
Coauthor(s): Pere Gascon, MD, PhD, Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain; Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Mark J Shumate, MD, MPH, Assistant Professor, Department of Internal Medicine, Division of Hematology/Oncology, Emory University
Contributor Information and Disclosures

Updated: Nov 20, 2008

Introduction

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 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.

ALAD deficiency porphyria (ADP) is characterized by autosomal recessive inheritance and only neurologic manifestations.^1,2,3,4 It was first described in 1979 and, to date, only a few cases have been identified and confirmed by gene mutation analysis.⁵

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.^4,6 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. 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 ALAD deficiency porphyria (ADP), termed plumboporphyria, because the heavy metal is a potent inhibitor of ALAD.¹

Frequency

United States

Only 1 case of ALA dehydratase (ALAD) has been reported in the United States.⁷

International

ALAD deficiency porphyria (ADP) is extremely rare, with only 7 confirmed cases worldwide.

Mortality/Morbidity

All 7 known patients with ALAD deficiency porphyria (ADP) 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

ALAD deficiency porphyria (ADP) occurs too rarely to determine the 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 ALAD deficiency porphyria (ADP), but 6 of the 7 reported cases occurred in males.

Age

The onset of ALAD deficiency porphyria (ADP) typically occurs at birth or during childhood, although late-onset disease has been recognized.

Clinical

History

ALAD deficiency porphyria (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 ALAD, including styrene, lead, trichloroethylene, and bromobenzene.
• Rule out hereditary tyrosinemia, which leads to accumulation of succinylacetone, an ALAD inhibitor.

Physical

Physical examination in those affected by ALAD deficiency porphyria (ADP) 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

ALAD deficiency porphyria (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 ALAD 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 psychologic stressors

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