Biochemical Diagnosis of an Hereditary Aminolaevulinate Dehydratase Deflciency in a 63-Year-Old Man

Hassoun, A.; Verstraeten, L.; Mercelis, R.; Martin, Joseph E.

doi:10.1515/cclm.1989.27.10.781

Cited by 19 publications

(31 citation statements)

References 22 publications

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“…AIP is a dominant porphyria due to half-normal levels of the third enzyme in the heme biosynthesis pathway. Furthermore, affected individuals with the recessive ALAD-deficient porphyria manifest chronic neurologic manifestations (20)(21)(22). Finally, asymptomatic heterozygotes for the latter porphyria develop acute lead poisoning when exposed to low levels of lead (23,24).…”

Section: Introductionmentioning

confidence: 99%

Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden.

Wetmur

1994

Environ Health Perspect

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&Aminolevulinate dehydratase (ALAD) is the second enzyme in the heme biosynthesis pathway. ALAD is a zinc metalloenzyme, and its inhibition by lead substitution for zinc is one of the most sensitive indicators of blood-lead accumulation, a measure of recent lead exposure. Stoichiometry calculations indicate that a significant portion of blood lead is stored in ALAD. Human ALAD exhibits a charge polymorphism, with about 20% of Caucasians expressing the rarer ALAD2 allele. Human ALAD1 and ALAD2 cDNAs and the 16-kb ALAD gene have been cloned and sequenced. A simple polymerase chain reaction test has been established and validated for determining ALAD genotypes. Two population studies have indicated that lead-exposed individuals with the ALAD allele have blood-lead levels about 10 pg/dl greater than similarly exposed individuals carrying only the ALAD1 allele. Ongoing work is directed toward determining the biochemistry underlying the allele-specific accumulation of blood lead, and toward determining the contribution of human ALAD genotype to lead accumulation in other tissues in transgenic mouse models and to final lead deposition in bone in both mouse and man. -Environ Health Perspect 102(Suppl 3): 215-219 (1994)

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Section: Introductionmentioning

confidence: 99%

Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden.

Wetmur

1994

Environ Health Perspect

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“…27 Belgian patient. 9 The patient was a 63-year-old man. At the age of 63, he developed a gradually worsening loss of strength in both arms.…”

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confidence: 99%

Highly heterogeneous nature of δ-aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria

Maruno

Furuyama

Akagi

et al. 2001

Blood

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The properties of 9 ␦-aminolevulinate dehydratase (ALAD) mutants from patients with ALAD porphyria (ADP) were examined by bacterial expression of their complementary DNAs and by enzymologic and immunologic assays. ALADs were expressed as glutathione-S-transferase (GST) fusion proteins in Escherichia coli and purified by glutathioneaffinity column chromatography. The GST-ALAD fusion proteins were recognized by anti-ALAD antibodies and were enzymatically active as ALAD. The enzymatic activities of 3 ALAD mutants, K59N, A274T, and V153M, were 69.9%, 19.3%, and 41.0% of that of the wild-type ALAD, respectively, whereas 6 mutants, G133R, K59N/G133R, F12L, R240W, V275M, and delTC, showed little activity (< 8%). These variations generally reflect the phenotype of ALAD in vivo in patients with ADP and indicate that GST-ALAD fusion protein is indeed useful for predicting of the phenotype of ALAD mutants. The location of F12L mutation in the enzyme's molecular structure indicates that its disturbance of the quaternary contact of the ALAD dimer appears to have a significant influence on the enzymatic activity. Mouse monoclonal antibodies to human ALAD were developed that specifically recognized a carboxy terminal portion of ALAD, or other regions in the enzyme. This study represents the first complete analysis of 9 mutants of ALAD identified in ADP and indicates the highly heterogeneous nature of mutations in this disorder. IntroductionDelta-aminolevulinate dehydratase (ALAD) deficiency porphyria (ADP) is an autosomal recessive disorder caused by a homozygous ALAD deficiency. Patients with this condition have clinical symptoms of acute hepatic porphyria such as abdominal pain, vomiting, pain in the arms and legs, and neuropathy. ALAD is the second enzyme in the heme biosynthetic pathway. It catalyzes the Knorr-type condensation of 2 molecules of aminolevulinate acid (ALA) to form a monopyrrole, porphobilinogen (PBG). 1 This enzyme activity is present in large excess compared to other enzymes in the heme biosynthetic pathway, and its partial deficiency does not usually result in any clinical consequences. Seven patients with ADP have been reported to date, 2-6 though only 4 of them have been confirmed by immunochemical or molecular analysis. [2][3][4] Of these 4 cases, the first 2 were German patients reported by Doss and coworkers, 7 the third was a Swedish baby boy studied by Thunell and colleagues, 8 and the fourth was an elderly Belgian man reported by Hassoun and associates. 9 Recently, an asymptomatic Swedish baby girl has been identified to have a markedly decreased ALAD activity. 10 Thus far, a total of 9 point mutations of the alad gene have been identified in these 5 subjects, which resulted in different amino acid changes. However, the enzymatic activity of ALAD expressed by mutant ALAD was investigated only for 4 mutants, A274T and R240W, in German patient B, 3 and V153M and delTC in German patient H 11 (singleletter amino acid codes). This previous study with German patient B demonstrated that ALAD activity co...

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“…Urinary 5-aminolaevulinic acid and porphobilinogen were determined spectrophotometrically after elution from ion-exchange resins (Bio-Rad, Germany), according to Mauzerall & Granick (9 Urinary and faecal porphyrins were determined by high performance liquid chromatography (HPLC) as previously described (9). Plasma porphyrins were determined by HPLC, using a method derived from that of Longas & Poh-Fiizpairick (10).…”

Section: Methodsmentioning

confidence: 99%

Biochemical Diagnosis of a Fatal Case of Günther’s Disease in a Newborn with Hydrops Foetalis

Verstraeten

Regemorter²,

Pardou³

et al. 1993

Clinical Chemistry and Laboratory Medicine

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Summary:The birth of a male baby was induced at 32 weeks. In utero, the child presented, inter alia, signs of hydrops, hepatosplenomegaly and anaemia. Two in utero transfusions for correction of the anaemia were performed at 28 and 29 weeks, respectively. The baby rapidly presented respiratory distress with mixed acidosis. Three hours after birth, pink urine was excreted. Signs of icterus necessitated phototherapy, after which photosensitivity occurred. Erythrocytes were fluorescent under long-wavelength UV light. The baby died 24 hours after birth, displaying severe acidosis, a diffuse haemorrhagic syndrome, and repeated bradycardia which did not respond to isoprenaline.The analysis of porphyrins in urine, blood and faeces of the baby gave the following results: 1) uroporphyrin (I and III isomeric series) was increased in urine and faeces, with traces in erythrocytes and plasma;2) heptacarboxyporphyrin I was found mainly in urine and much less in erythrocytes, plasma and faeces;3) coproporphyrin I was increased in urine, erythrocytes, plasma and faeces, and 4) 5-aminolaevulinic acid and porphobilinogen in urine and plasma were within the reference ranges.Determination of the enzymes of haem biosynthesis in erythrocytes and lymphocytes showed that both parents possessed only 50% of the normal activity of cosynthase.

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Biochemical Diagnosis of an Hereditary Aminolaevulinate Dehydratase Deflciency in a 63-Year-Old Man

Cited by 19 publications

References 22 publications

Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden.

Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden.

Highly heterogeneous nature of δ-aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria

Biochemical Diagnosis of a Fatal Case of Günther’s Disease in a Newborn with Hydrops Foetalis

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