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

Abstract Acute intermittent porphyria is an autosomal dominant disorder defined by a partial deficiency of porphobilinogen deaminase (EC 4.3.1.8). Clinical manifestations of the disease are characterized by acute attacks of neurological dysfunction often linked to environmental factors. Early diagnosis of gene carriers is important in the prevention of attacks and is usually achieved by determining the porphobilinogen deaminase activity in erythrocytes. However, in a subtype of acute intermittent porphyria, the enzymatic defect is restricted to nonerythropoietic cells. Different mutations have already been described that account for this phenotype in two unrelated families. We previously detected asymptomatic carriers by using mutation-specific probes after in vitro amplification of the target DNA sequence. In this study, we investigated the DNA of eight unrelated subjects with the same subtype of acute intermittent porphyria by using the polymerase chain reaction, with subsequent analysis of the amplified products by denaturing gradient gel electrophoresis. Five of these patients shared the same single-base change. This technique was quite simple and efficient for detecting asymptomatic carriers. Importantly, it is potentially useful for studying families with the same phenotypic subtype of the disease and possibly different mutations in the same DNA region.

Download Full-text

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

Download Full-text

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.

Download Full-text

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.

Download Full-text

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

Download Full-text

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.

Download Full-text