Porphyrias, mutations

Acute intermittent porphyria Mutation analysis has been shown to be 5-15% more reliable than enzymatic and biochemical screening [4]. The mostly private (family specific) mutation of the PBG-deaminase gene should be identified firstly in the index patient and then the relatives are to be tested for the presence or absence of this mutation [7]. 

Porphyria cutanea tarda (very often associated with HFE mutations)... 

Floderus, Y., Shoolingin-Jordan, R M. and Harper, P. Acute intermittent porphyria in Sweden. Molecular, functional and clinical consequences of some new mutations found in the porphobilinogen deaminase gene. Clin. Genet. 62 288-297, 2002. 

E1MBS activity is lowered in AIP. In the case of a newly diagnosed acute porphyria, determination of HMBS activity enables the diagnosis of AIP. We further use it in AIP family screening combined with mutation analysis. 

Grandchamp B, Picat C, Mignotte V, Wilson JH, Velde K, Sandkuyl L, Romeo PH, Goos-sens M, Nordmann Y (1989) Tissue-specific splicing mutation in acute intermittent porphyria. Proc Natl Acad Sci USA 86 661-664... 

Porphyrias are caused by inherited (or occasionally acquired) defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors (see Summary Figure 21.7). With the exception of congenital erythropoietic porphyria, which is a genetically recessive disease, all porphyrias are inherited as autosomal dominant disorders. The mutations that cause the porphyrias are heterogenous (not all are at the same DNA locus), and nearly every affected family has its own mutation. Each porphyria results in the accumulation of a unique pattern of intermediates caused by the deficiency of an enzyme in the heme synthetic pathway. 

Protoporphyrinogen oxidase converts protoporphyrinogen IX to the fully desaturated porphyrin in a reaction that uses O2 as the terminal electron acceptor (Fig. 3). The crystal structure of the homodimeric enzyme shows it has one FAD per monomer, which presumably mediates the porphyrin oxidation reaction (19). Like the decarboxylation mediated by coproporphyrinogen oxidase, this reaction also occurs in the mitochondrion. Mutations in the protoporphyrinogen oxidase gene are responsible for variegate porphyria (21). Acute attacks of this disease can be effectively treated by intravenous administration of hematin. 

Whatley SD, Puy H, Morgan RR, Robreau AM, Roberts AG, Nordmann Y, Elder GH, Deybach JC. Variegate porphyria in 41. Western Europe identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation. Am. J. Hum. Genet. 42. 1999 65 984-994. 

The gene mutation inhibits hydrolytic cleavage of fumarylacetoacetate into fumarate and acetoacetate. Consequently, the toxic precursors maleylacetoacetate and fumarylacetoacetate accumulate in the liver and kidneys. They possess a reactive double bond and can therefore react with macromolecules to assume the properties of alkylating substances. In addition, intracellular glutathione deficiency develops due to the stable complex formation with glutathione, favouring lipid peroxidations. Enhanced formation of 5-aminolaevulinic acid can also be observed during occasional attacks of acute intermittent porphyria (G. Mitchel et al., 1990). 

Andersson, C., Thunell, S., Floderus, Y., Forsell, C., Lundin, G., Anvret, M., Lannfelt, L., Wetterberg, L., Lithner, F. Diagnosis of acute intermittent porphyria in northern Sweden an evaluation of mutation analysis and biochemical methods. J. Intern. Med. 1995 237 301 -308... 

Bjersing, L., Andersson, C., Lithner, F. Hepatocellular carcinoma in patients from northern Sweden with acute intermittent porphyria morphology and mutations. Cane. Epidem. Biomark. Prev. 1996 5 393-397... 

Egger, N.G., Goeger, D.E., Payne, D.A., Miskovsky, E.P., Weinman, S.A., Anderson, K.E. Porphyria cutanea tarda. Multiplicity of risk factors including HFE mutations, hepatitis C, and inherited uroporphyrinogen decarboxylase deficiency. Dig. Dis. Sci. 2002 47 419-426... 

This patient had previously had episodes of small blisters that spontaneously resolved, and hereditary porphyria cutanea tarda was demonstrated by chromatographic and mutation analysis. 

Effective ns chloroquinc has been, it is a piKir example of. selective toxicity. Adverse reactions include retinopathy, hemolysis in patients with gluco.sc-6-phosphalc dehydrogenase deficiency (same mutation lhal confers resistance ugaiiisl malaria), muscular weakness, exacerbation of psoriasis and porphyria, and impaired liver function. Further examples of poor selective toxicity include off-label indications such as rheumatoid arthritis, systemic and discoid lupus crylhcmulo-sus (possibly as an immunosupprc.ssanl). and a variety of dermatological conditions. 

About 25% of patients with overt acute porphyria have no family history of the disease. Such sporadic presentation is a reflection of the high prevalence of mutations in the population acute porphyria caused by de novo mutation is uncommon. 

TABLE 32-7 Presymptomatic Diagnosis of Autosomal Dominant Acute Porphyrias Metabolite Measurements in Asymptomatic individuals With Porphyria P roven by Mutational Analysis... 

Assay of the individual enzymes of the heme biosynthetic pathway is rarely required for the investigation of patients with symptoms of porphyria. However, measurement of enzyme activities is useful for family studies when the individual mutation cannot be identified or when DNA analysis is not available, and for the identification of subtypes such... 

Once the mutation that causes porphyria in a family has been identified, relatives are then screened for its presence either by using one of the screening methods listed above, by... 

Ged C, Morea-Gady I, Taire L et al. Prenatal diagnosis in congenital erythropoietic porphyria by metabolic measurement and DNA mutation analysis. Prenatal Diagnosis 1996 16 83-6. 

Ged C, Ozalla D, Herrero C, Lecha M, Mendez M, de Verneuil H, et al. Description of a new mutation in hepatoerythropoietic porphyria and prenatal exclusion of a homozygous fetus. Arch Dermatol 2002 138 957-60. 

Hilt RJ, Davidson BP, van der Hooft C, Meissner DM, Meissner PN. Plasma fluorescence scanning and fecal porphyrin analysis for the diagnosis of variegate porphyria precise determination of sensitivity and specificity with detection of protoporphyrinogen oxidase mutations as a reference standard. Clin Chem 2004 50 915-23. 

Mendez M, Sorkin L, Rossetti MV, Astrin KH, del C Batlle AM, Parera VE, et al. Familial porphyria cutanea tarda characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis aUeles. Am J Hum Genet 1998 63 1363-75. 

Nissen H, Petersen NE, Mustajoki S, Hansen TS, Mustajoki P, Kauppinen R, et al. Diagnostic strategy, genetic diagnosis and identification of a new mutation in acute intermittent porphyria by denaturing gradient gel electrophoresis. Hum Mutat 1997 9 122-30. 

Nordmann Y, Puy H, Da Sfiva V, Simonin S, Robreau AM, Bonaiti C, et al. Acute intermittent porphyria prevalence of mutations in the porphobilinogen deaminase gene in blood donors in France. J Intern Med 1997 242 213-7. 

Tchernitchko D, Lamoril J, Puy H, Robreau AM, Bogard C, Rosipal R, et al. Evaluation of mutation screening by heteroduplex analysis in acute intermittent porphyria. Clin Chim Acta 1999 279 133-43. 

The major types of porphyria are each caused by mutations in one of the genes required for heme production. 

---