Porphobilinogen-synthase (?-aminolevulinic acid dehydratase) deficiency in bone marrow cells of two patients with porphobilinogen-synthase defect acute porphyria

Abstract

Two male patients aged 23 and 25 years with intermittent acute, frequently repeated porphyria syndromes presented an almost total deficiency of porphobilinogen-synthase [(PBG-S); synonym: delta-aminolevulinic acid dehydratase] in peripheral erythrocytes. PBG-S was investigated in bone marrow cells obtained by sternal puncture. A minimal enzyme activity of less than 3% of controls was established. Specific activity and protoporphyrin concentration decreased considerably during the course of erythropoiesis. Both patients are homozygous gene carriers; their parents (father and mother) as well as most of their brothers and sisters are heterozygotes with a PBG-S deficiency of approximately 50% of controls. All people with PBG-S deficiency are especially endangered by alcohol intake and lead exposure, because alcohol and lead toxically inhibit PBG-S.

Novel molecular defects of the δ-aminolevulinate dehydratase gene in a patient with inherited acute hepatic porphyria

“…Our findings in this study defined 2 novel mutations of the ALAD gene in the second German patient, with ADP, ''H,'' who was 1 of the 2 German patients originally described by Doss et al 5 Namely, the H1 defect was an G-to-A nucleotide transition at 457, resulting in a Val-to-Met substitution at amino acid residue 153, while H2 defect encoded 2 base deletions at 818 and 819, resulting in a frame shift with a premature stop codon at amino acid residue 294 (Fig. 1).…”

“…Clinical and biochemical features of this proband ''H'' and his family member were described previously. 5 The proband developed signs and symptoms of ADP at the age of 15, 5 and is still alive and well, nearly 30 years after the first acute attack of ADP. 10 Cell Cultures and Northern Blot Analysis of ALAD mRNA.…”

“…2,3 However, a markedly decreased enzyme activity caused by certain chemicals, e.g., lead, succinylacetone, or by an inherited enzyme deficiency may result in a clinical condition resembling those of severe acute hepatic porphyria. 4 Four unrelated cases of inherited ALAD deficiency porphyria (ADP) have been reported to date, i.e., 2 German male patients who developed the disease at adolescence, 5 1 Swedish boy who suffered from severe ADP from his birth, 6 and 1 Belgian male patient who developed the disease at the age of 63. 7 Molecular analysis of the gene defects have been reported for 2 of the 4 patients, i.e., a German patient B 8 and a Swedish boy, 9 while others have yet to be defined.…”

The cutaneous porphyrias: a review of diagnosis and management

“…A clinically based classification dividing porphyrias into acute and not-acute (Table 1), with and without skin manifestations, is more useful. Acute intermittent porphyria (AIP) and aminolaevulinic acid dehydratase (ALA-D) deficient porphyria [1] do not have skin manifestations. Other cutaneous porphyrias classified as acute (Table 1) include variegate porphyria (VP) and hereditary coproporphyria (HC).…”

Co-synthesis of Human δ-Aminolevulinate Dehydratase (ALAD) Mutants with the Wild-type Enzyme in Cell-free System—Critical Importance of Conformation on Enzyme Activity—

“…ALAD (PBG synthase; E.C.4.2.1.24) porphyria (ADP) is an autosomal recessive disorder caused by a homozygous ALAD deficiency. Six unrelated cases of ADP have been reported to date [ 2 – 7 ]. The molecular defects of the first three patients were due to six different mutations (R240W and A274T in German B, G133R and V275M in Swedish boy, and V153M and L273R in German H) which were inherited in a compound heterozygous manner, indicating a highly heterogeneous nature of this disease [ 4 , 8 , 9 ].…”