Porphyric neuropathy and hereditary δ-aminolevulinic acid dehydratase deficiency in an adult

Mercelis, R.; Hassoun, A.; Verstraeten, L.; Bock, R. De; Martin, Jean‐Jacques

doi:10.1016/0022-510x(90)90115-4

Cited by 28 publications

(10 citation statements)

References 14 publications

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“…9 Both oral glucose and intravenous infusion of glucose were effective in ameliorating biochemical and clinical abnormalities related to porphyria. Family studies showed that, except for a brother who had normal levels of enzyme activity, a sister, a daughter, and a granddaughter of the patient had about 50% ALAD activity compared with normal controls, 28 indicating that these subjects are heterozygous carriers of ALAD deficiency. Molecular analysis revealed that the patient was heterozygous for G133R and K59N mutations in one ALAD allele.…”

Section: Case Reportsmentioning

confidence: 99%

“…At the age of 63, he developed a gradually worsening loss of strength in both arms. 28 The patient showed markedly elevated plasma ALA concentration (110 g/dL; normal Ͻ 10); plasma PBG was undetectable. Urinary ALA excretion (85 mg/dL; normal Ͻ 5) was also abnormally elevated, without an increase in PBG concentration.…”

Section: Case Reportsmentioning

confidence: 99%

“…[7][8][9] This patient also developed ADP in conjunction with polycythemia. 28 Polycythemia is a clonal disorder and progeny of a single cell can gain ascendancy in the bone marrow, which presumably carried the mutant alad allele, resulting in clinical ADP in the patient. 29 The study using antihuman ALAD mouse MAb in immunoblot analysis of ALAD deficiency in ADP has proven extremely useful in characterizing distinct immunologic epitopes of mutant ALAD identified in patients.…”

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confidence: 99%

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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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Section: Case Reportsmentioning

confidence: 99%

Section: Case Reportsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Maruno

Furuyama

Akagi

et al. 2001

Blood

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“…11 The level of ALA in our patient immediately after administration of ALA was probably very high too, but unfortunately was not determined.…”

Section: Discussionmentioning

confidence: 88%

Acute neuropathy mimicking porphyria induced by aminolevulinic acid during photodynamic therapy

et al. 2004

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An 82-year-old man developed severe, acute, predominantly motor polyneuropathy, signs of autonomic involvement, and skin changes following aminolevulinic acid (ALA) administration. The compound was used as a prodrug for photodynamic therapy of Barrett's esophagitis. Changes were observed in various parameters of the heme pathway. The case reported represents a rare response to ALA treatment, resembling an acute attack of hepatic porphyria with neurological features.

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“…137 The physiological consequences of ALA accumulation in the mitochondria due to defects in export may be extrapolated from patients who suffer ALAD deficiency-these patients suffer from porphyric neuropathy. 138 It is possible that patients who suffer from similar porphyrias that do not harbor mutations in hemesynthesis enzymes may carry loss of function mutations in ALA transporters, and that ALA transporters may be genetic modifiers for porphyrias. Exogenous ALA can also be imported into cells in a pH dependent manner via the cell-surface multipeptide transporters peptide transporter-1 (PEPT1) and PEPT2, which also increase ALA uptake in Xenopus oocytes.…”

Section: Trafficking Of Heme Synthesis Intermediatesmentioning

confidence: 99%

Iron and Heme Transport and Trafficking

Yien

Paw

2004

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Genetic defects in iron acquisition and export, and heme metabolism can result in pathologies including congenital anemia or porphyria. While the enzymes that govern heme synthesis have been elucidated and characterized, the proteins and genes that govern the transport of iron, heme, and heme intermediates are poorly studied. Knowledge of these transport mechanisms will shed light on important regulatory steps that govern heme and iron metabolism. This article focuses on summarizing current studies on heme, heme intermediates and iron transport, and attempts to identify gaps in our knowledge of these transport pathways. Additionally, we will highlight the contribution of model organisms to the understanding of heme/iron metabolism.

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Porphyric neuropathy and hereditary δ-aminolevulinic acid dehydratase deficiency in an adult

Cited by 28 publications

References 14 publications

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

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

Acute neuropathy mimicking porphyria induced by aminolevulinic acid during photodynamic therapy

Iron and Heme Transport and Trafficking

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