Detection of a high mutation frequency in exon 12 of the porphobilinogen deaminase gene in patients with acute intermittent porphyria

ABSTRACT This paper describes a mutator system in the nematode Caenorhabditis elegans var. Bergerac for the gene unc-22. Of nine C. elegans and two C. briggsae strains tested only the Bergerac BO strain yielded mutant animals at a high frequency and the unc-22 IV gene is a preferred mutational target. The forward spontaneous mutation frequency at the unc-22 locus in Bergerac BO is about 1 × 10-4, and most of these spontaneous unc-22 mutations revert at frequencies between 2 × 10-3 and 2 × 10-4. Both the forward mutation frequency and the reversion frequency are sensitive to genetic background. Spontaneous unc-22 mutations derived in a Bergerac background and placed in a primarily Bristol background revert at frequencies of <10-6. When reintroduced into a Bergerac/Bristol hybrid background the mutations once again become unstable. The mutator activity could not be localized to a discrete site in the Bergerac genome. Nor did mutator activity require the Bergerac unc-22 gene as a target since the Bristol unc-22 homolog placed in a Bergerac background also showed high mutation frequency. Intragenic mapping of two spontaneous unc-22 alleles, st136 and st137, place both mutations in the central region of the known unc-22 map. However, these mutations probably recombine with one another, suggesting that the unstable mutations can occur in more than one site in unc-22. Examination of the phenotypic effect of these mutations on muscle structure indicates that they are less severe in their effect than a known amber allele. We suggest that this mutator system is polygenic and dispersed over the nematode genome and could represent activity of the transposable element Tc1.

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Recurrence risk estimation of acute intermittent porphyria based on analysis of porphobilinogen deaminase activity: A Bayesian approach

American Journal of Medical Genetics ◽

10.1002/ajmg.1320190415 ◽

1984 ◽

Vol 19 (4) ◽

pp. 755-762 ◽

Cited By ~ 17

Author(s):

C. Bonaïti-Pellié ◽

L. Phung ◽

Y. Nordmann

Keyword(s):

Bayesian Approach ◽

Risk Estimation ◽

Acute Intermittent Porphyria ◽

Recurrence Risk ◽

Porphobilinogen Deaminase

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Prophylactic Heme Arginate Infusion for Acute Intermittent Porphyria

Frontiers in Pharmacology ◽

10.3389/fphar.2021.712305 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hung-Chou Kuo ◽

Chia-Ni Lin ◽

Yi-Fen Tang

Keyword(s):

Renal Function ◽

Body Weight ◽

Acute Intermittent Porphyria ◽

Porphobilinogen Deaminase ◽

Attack Frequency ◽

Weekly Administration ◽

Clinical Counseling ◽

Heme Arginate ◽

Before And After

Objectives: This study aimed to evaluate the efficacy of long-term weekly prophylactic heme arginate (HA) infusions in reducing attack frequency and severity in female AIP patients.Methods: We report the results of five female AIP patients with frequent recurrent attacks (>9/year) before and after institution of weekly prophylaxis with heme arginate (3 mg/kg body weight). All five cases had confirmed disease-associated mutations in the porphobilinogen deaminase gene, and all had received genetic and clinical counseling about AIP.Results: In the five included patients, average annual attack rate (AAR) in the year prior to HA prophylaxis was 11.82 (range 9.03–17.06), and average total HA usage was 32.60 doses (range: 13.71–53.13). After 2.58–14.64 years of HA prophylaxis, average AAR was reduced to 2.23 (range 0.00–5.58), and attack severity (i.e., doses required per attack) was reduced from 2.81 to 1.39 doses/attack. Liver and renal function remained stable during weekly administration of HA prophylaxis. The most common complications were port-A catheter-related events. No other complications or safety concerns occurred with long-term use of HA prophylaxis.Conclusion: Our study demonstrated women with AIP receiving weekly prophylactic HA infusions resulted in fewer episodes that required acute HA treatment while maintaining stable renal and liver function. Weekly prophylactic HA infusions effectively prevent frequent porphyric attacks and reduce attack severity.

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Reversible splenial lesion syndrome (RESLES) due to acute intermittent porphyria with a novel mutation in the hydroxymethylbilane synthase gene

10.21203/rs.2.19929/v2 ◽

2020 ◽

Author(s):

xiaoqing li ◽

fei han ◽

qianlong chen ◽

tienan zhu ◽

yongqiang zhao ◽

...

Keyword(s):

Biosynthetic Pathway ◽

Autosomal Dominant ◽

Stop Codon ◽

Novel Mutation ◽

Acute Intermittent Porphyria ◽

Porphobilinogen Deaminase ◽

Autosomal Dominant Disorder ◽

Splenial Lesion ◽

Partial Deficiency ◽

Reversible Splenial Lesion Syndrome

Abstract Background: Reversible splenial lesion syndrome (RESLES) is a clinico-radiological syndrome characterized by the presence of reversible lesions specifically involving the splenium of the corpus callosum (SCC). The cause of RESLES is unknown. However, infectious-related mild encephalitis/encephalopathy (MERS) with a reversible splenial lesion remains the most common cause of reversible splenial lesions. Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a partial deficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthetic pathway. It can affect the autonomic, peripheral, and central nervous system. Result: In this study, we report a 20-year-old woman with AIP who presented with MRI manifestations suggestive of RESLES, she had a novel HMBS nonsense mutation, a G to A mutation in base 594, which changed tryptophan to a stop codon (W198*). Conclusion: To the best of our knowledge, this is only one published case of RELES associated with AIP.

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Allele Frequency of the C.5G>A Mutation in the PRCD Gene Responsible for Progressive Retinal Atrophy in English Cocker Spaniel Dogs

Animals ◽

10.3390/ani9100844 ◽

2019 ◽

Vol 9 (10) ◽

pp. 844 ◽

Cited By ~ 1

Author(s):

Larissa R. Andrade ◽

Amanda M. Caceres ◽

Anelize S. Trecenti ◽

Claudia Valeria S. Brandão ◽

Micaella G. Gandolfi ◽

...

Keyword(s):

Allele Frequency ◽

Genetic Disease ◽

Mutation Frequency ◽

Progressive Retinal Atrophy ◽

Cocker Spaniel ◽

High Mutation Frequency ◽

Retinal Atrophy ◽

History Of ◽

Eye Examination ◽

Mutation Region

Progressive retinal atrophy (PRA) due to the c.5G>A mutation in the progressive rod–cone degeneration (PRCD) gene is an important genetic disease in English cocker spaniel (ECS) dogs. Because the prevalence of this disease has not been verified in Brazil, this study aimed to evaluate the allele frequency of the c.5G>A mutation in the PRCD gene. Purified DNA from 220 ECS dogs was used for genotyping, of which 131 were registered from 18 different kennels and 89 were unregistered. A clinical eye examination was performed in 28 of the genotyped animals; 10 were homozygous mutants. DNA fragments containing the mutation region were amplified by PCR and subjected to direct genomic sequencing. The prcd-PRA allele frequency was 25.5%. Among the registered dogs, the allele frequency was 14.9%; among the dogs with no history of registration, the allele frequency was 41%. Visual impairment was observed in 80% (8/10) of the homozygous mutant animals that underwent clinical eye examination. The high mutation frequency found in this study emphasizes the importance of genotyping ECSs as an early diagnostic test, especially as part of an informed breeding program, to avoid clinical cases of PRA.

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Influence of Age and Gender on the Clinical Expression of Acute Intermittent Porphyria Based on Molecular Study of Porphobilinogen Deaminase Gene Among Swiss Patients

Molecular Medicine ◽

10.1007/bf03401859 ◽

2001 ◽

Vol 7 (8) ◽

pp. 535-542 ◽

Cited By ~ 21

Author(s):

Macé M. Schuurmans ◽

Xiaoye Schneider-Yin ◽

Urszula B. Rüfenacht ◽

Cécile Schnyder ◽

Christoph E. Minder ◽

...

Keyword(s):

Acute Intermittent Porphyria ◽

Molecular Study ◽

Porphobilinogen Deaminase ◽

Clinical Expression ◽

Age And Gender ◽

And Gender

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Safety, Pharmacokinetics and Pharmocodynamics of Recombinant Human Porphobilinogen Deaminase in Healthy Subjects and Asymptomatic Carriers of the Acute Intermittent Porphyria Gene Who Have Increased Porphyrin Precursor Excretion

Clinical Pharmacokinetics ◽

10.2165/00003088-200746040-00006 ◽

2007 ◽

Vol 46 (4) ◽

pp. 335-349 ◽

Cited By ~ 23

Author(s):

Eliane Sardh ◽

Lillan Rejkj??r ◽

Dan E H Andersson ◽

Pauline Harper

Keyword(s):

Healthy Subjects ◽

Acute Intermittent Porphyria ◽

Porphobilinogen Deaminase ◽

Asymptomatic Carriers

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Variant acute intermittent porphyria in a child

Clinical Chemistry ◽

10.1093/clinchem/36.5.812 ◽

1990 ◽

Vol 36 (5) ◽

pp. 812-814 ◽

Cited By ~ 2

Author(s):

N R Badcock ◽

G D Zoanetti ◽

D A O'Reilly ◽

E F Robertson

Keyword(s):

Family History ◽

Parenteral Nutrition ◽

Enzyme Activities ◽

Clinical Symptoms ◽

Acute Intermittent Porphyria ◽

Normal Activity ◽

Porphobilinogen Deaminase ◽

Acute Porphyria ◽

Protoporphyrinogen Oxidase ◽

History Of

Abstract A child who was grossly malnourished and who showed increased excretion of porphyrin and porphyrin precursor had normal activity of erythrocyte porphobilinogen deaminase (EC 4.3.1.8) and leukocyte protoporphyrinogen oxidase (EC 1.3.3.4). Clinical symptoms, coincident with the excretion of rose-colored urine, were consistent with the diagnosis of an acute porphyria. The disease resolved spontaneously after the withdrawal of carbamazepine and sodium valproate and the commencement of parenteral nutrition with subsequent carbohydrate loading. In addition to normal concentrations of enzyme activities, the patient is unusual in presenting before puberty and in having no family history of porphyria.

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