Porphyria, Acute Hepatic

A number sign (#) is used with this entry because Doss hepatic porphyria is caused by mutation in the gene encoding delta-aminolevulinate dehydratase (ALAD, PBGS; 125270).

Description

ALAD porphyria is a rare autosomal recessive disorder that has been reported and confirmed by genetic analysis in only 5 patients (Jaffe and Stith, 2007).

Clinical Features

Bird et al. (1979) identified ALAD deficiency fortuitously during accumulation of control data on red cell uroporphyrinogen synthase I (HMBS; 609806). The screening assay measured conversion of ALA to porphyrin and thus included both ALAD and HMBS; specific testing in the individual with a defect revealed deficiency of ALAD. The individual was an 18-year-old healthy college student with 22% of mean ALAD control values. Subsequent examination of family members showed that many had values ranging from 22 to 41%. Deficiency was traced through 3 generations, and by implication through a fourth, with 1 instance of male-to-male transmission, consistent with autosomal dominant inheritance. There were no clinical manifestations; however, Bird et al. (1979) noted that ALAD activity is significantly inhibited by lead (Haeger-Aronsen et al., 1971), and speculated that persons with low ALAD activity may be especially sensitive to environmental lead exposure.

Doss et al. (1979) described 2 young boys with acute hepatic porphyria. There was an excessive urinary excretion of delta-aminolevulinic acid and porphyrins, and the activity of red cell ALAD was less than 1% of normal values. The parents and a number of other unaffected relatives exhibited an enzyme activity of about 50% of normal. Thus, the clinical disorder in these particular patients was consistent with autosomal recessive inheritance. Further studies in 1 of the patients reported by Doss et al. (1979) suggested a structural mutation in the PBGS gene (Brandt and Doss, 1981). Doss et al. (1983) presented further evidence that the boys were homozygous for the enzyme deficiency, with less that 3% of control enzyme activity in bone marrow cells, and that all parents and 'most of their brothers and sisters,' all asymptomatic, were heterozygous carriers, with enzyme level about 50% of normal. They pointed out that persons with PBGS deficiency are endangered by alcohol ingestion or lead exposure because both agents inhibit PBGS. In the 2 males apparently homozygous for ALAD deficiency (Doss et al., 1979), de Verneuil et al. (1985) demonstrated ALAD cross-reactive material, further suggesting a mutation in this gene. Doss et al. (2004) reported that the patients reported by Doss et al. (1979) were alive and well at ages 45 and 47 years, respectively.

Thunell et al. (1987) reported ALAD-deficient porphyria in a 3-year-old boy. He presented in the neonatal period and infancy with recurrent attacks of pain, vomiting, hyponatremia, and symptoms of polyneuropathy that compromised motor functions, including respiration. He excreted large amounts of 5-aminolevulinic acid and coproporphyrin and minor amounts of porphobilinogen in the urine. Diagnosis was established by the finding of erythrocyte ALAD activity at less than 5% in the patient and between 26 and 51% of normal in both parents, the grandfathers, and a sib. Thunell et al. (1992) noted that the patient with severe infantile onset of porphyria (Thunell et al., 1987) underwent liver transplantation at age 7 years in the hopes that a new liver would reduce the metabolic disturbance and thus avert the porphyric symptoms. After transplant, the patient was able to withstand several porphyrinogenic challenges without increasing the excretion of porphyrin. However, he continued to have episodes of neurologic and respiratory crises. Doss et al. (2004) reported that the patient reported by Thunell et al. (1987, 1992) died at age 9 years.

Sassa et al. (1991) studied 2 patients with homozygous ALAD deficiency: 1 had teenage onset of acute hepatic porphyria (Doss et al., 1979); the second was a patient with late onset of the disease, a man who was 63 years old at the time of diagnosis (Hassoun et al., 1989). Enzyme activity was markedly decreased in lymphocytes from both patients and moderately decreased in heterozygous members of the families. Immunochemical quantitation of red cell ALAD suggested the presence of cross-reactive material in the patient with late onset.

Doss et al. (2004) reported a 17-year-old German boy who had colicky abdominal pain and severe polyneuropathy for 2 years. Urinary ALAD was increased 32-fold, and coproporphyrin 76-fold compared to normal ranges. ALAD activity in erythrocytes was decreased to 10% of normal in the patient and about 50% in both parents. The patient was successfully treated with heme arginate infusion. The clinical condition improved, and urinary excretion of ALA and coproporphyrin fell to levels of approximately 50% compared to pretreatment levels during acute relapses. The heme therapy was continued once weekly for 1 year. At the end of 1 year, urinary ALA and porphyrin levels were significantly lowered, and the proband was almost free of clinical symptoms.

Susceptibility to Lead Poisoning

Doss and Muller (1982) reported the case of a 48-year-old man who was likely vulnerable to acute lead intoxication because of heterozygous PBGS deficiency. He developed an acute abdominal syndrome, anemia, and a grave toxic disorder of porphyrin metabolism, which was diagnosed as acute lead intoxication. Although the hematologic findings and porphyrins in the blood, as well as porphyrin precursors and porphyrin excretion in the urine, returned to normal within 5 months after exacerbation of the acute symptoms, PBGS activity was about 50% of normal controls 6 years later.

Doss et al. (1984) reported a 30-year-old painter with an acute abdominal-neurologic syndrome and anemia due to lead poisoning, despite only moderate levels of blood lead. During the illness, red cell ALAD levels were reduced to 8% of controls. Four years later the level remained diminished at 30% of controls, and the mother was found also to have ALAD levels in the heterozygous range.

Dyer et al. (1993) reported a lead worker who developed bilateral wrist drop characteristic of lead neuropathy but whose screening tests for blood and urine levels had been within the accepted safety limit during employment. Further investigation showed, however, that he had lead-associated porphyria (plumboporphyria) due to heterozygous ALAD deficiency which had been symptom-free until he was exposed to lead.

Clinical Management

Goetsch and Bissell (1986) found that the instability of hematin solutions was responsible for the failure of therapeutic benefit of this agent in patients with ALAD deficiency. In addition, the decayed material had anticoagulant effects, thus explaining one of the complications of hematin therapy.

Doss et al. (2004) reported successful treatment of ALAD porphyria with heme arginate infusion.

Molecular Genetics

In a Swedish boy with severe infantile onset of acute hepatic porphyria, Plewinska et al. (1991) identified compound heterozygosity for 2 mutations in the ALAD gene (125270.0001 and 125270.0002). ALAD activity in erythrocytes were less than 5% of control values.

In a patient with hepatic porphyria previously reported by Doss et al. (1979) and Sassa et al. (1991), Ishida et al. (1992) identified compound heterozygosity for 2 mutations in the ALAD gene (125270.0004 and 125240.0005).

In a 17-year-old German patient with hepatic porphyria, Doss et al. (2004) identified compound heterozygosity for 2 mutations in the ALAD gene (125270.0007 and 125270.0008).

Pathogenesis

Jaffe and Stith (2007) noted that the human PBGS enzyme exists as an equilibrium of functionally distinct quaternary structure assemblies, known as 'morpheeins,' in which one functional homo-oligomer can dissociate, change conformation, and reassociate into a different oligomer. In the case of human PBGS, the 2 assemblies are a high-activity octamer and a low-activity hexamer. Jaffe and Stith (2007) quantified the morpheein forms of human PBGS for the common and porphyria-associated variants. Heterologous expression in E. coli, followed by separation of the octameric and hexameric assemblies on an ion-exchange column, showed that the percentages of hexamers for F12L (125270.0006) (100%), R240W (125270.0004) (80%), G133R (125270.0001) (48%), A274T (125270.0005) (14%), and 2 other variants were appreciably larger than for the wildtype proteins K59 and N59 (see 125270.0003) (0% and 3%, respectively). All 8 porphyria-associated variants showed an increased propensity to form the hexamer, according to a kinetic analysis. Thus, all porphyria-associated human PBGS variants shift the morpheein equilibrium for PBGS toward the less active hexamer. Jaffe and Stith (2007) proposed that the disequilibrium of morpheein assemblies broadens the definition of conformational diseases beyond the prion disorders and that ALAD porphyria is the first example of a morpheein-based conformational disease.