Molecular characterisation of acute intermittent porphyria in a cohort of South African patients and kinetic analysis of two expressed mutants

Fortgens, Philip H.; Pienaar, Elaine; Corrigall, Anne V.; Sonderup, Mark; Spearman, Wendy; Meissner, Peter N.

doi:10.1136/jclinpath-2016-203907

Cited by 5 publications

(4 citation statements)

References 38 publications

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“…Currently, some mutations have been tested for enzyme activity analysis in vitro, The enzyme activity of homozygotes of most mutations in vitro expressed <5%, which is consistent with the decrease of half the residual enzyme activity of heterozygotes in vivo. [9,10,20,21,23,24,32–38] However, some of the homozygotes in vitro expressed the enzyme activity close to normal, ex. c.532 G>A and c.176 C>T, the residual enzyme activity of the homozygote reached 81% in vitro, while the heterozygote residual enzyme activity was 40% in vivo, [10,34] the reasons for this phenomenon need to be further explored.…”

Section: Discussionmentioning

confidence: 99%

HMBS gene mutations and hydroxymethylbilane synthase activity in acute intermittent porphyria: A systematic review

Li,

Lei,

Dong

et al. 2023

Medicine

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Background: Acute intermittent porphyria (AIP) is caused by a partial deficiency of hydroxymethylbilane synthase and affects heme biosynthesis. Mutations in the HMBS gene result in HMBS deficiency. AIP is a rare disease, and there been insufficient studies on it. This report describes the molecular epidemiology of HMBS gene defects and hydroxymethylbilane synthase activity levels in classical AIP. Methods: Databases of PubMed, CNKI, and Wang Fang Database were searched for eligible studies to investigate HMBS gene mutations in peripheral blood samples and HMBS activity in erythrocytes of patients with classical AIP. Relevant studies published up to July 15, 2023, from several databases were independently searched and selected by 2 reviewers. Accuracy data and relevant information were extracted from each eligible study by 2 independent researchers and analyzed using statistical software. Results: After pooling the accuracy data from 232 patients of the 15 eligible studies, 90.5% (210/232) of AIP patients had decreased erythrocyte hydroxymethylbilane synthase activity (<70%), and 96 different mutations were identified in 232 patients, including 33 missense (34.4%), 27 splice (28.1%), 19 deletion (19.8%), 8 nonsense (8.3%), 9 insertion (9.4%) mutations. Residual enzyme activities (%) for different groups of type were expressed using mean and 95% confidence interval (95% CI): missense (51.2, 48.5–53.9), splice (57.5, 52.0–59.1), deletion (54.9, 50.7–59.1), nonsense (52.2, 44.4–60.0), insertion (53.2, 47.4–59.0), group analysis P = .17. Subgroups of missense mutations, domain 1 (50.2, 46.0–54.4), domain 2 (52.8, 49.1–56.4), and domain 3 (49.2, 38.3–60.0), Subgroup analysis, P = .62. Conclusion: Different mutation types and mutation positions are not associated with the level of hydroxymethylbilane synthase activity. Erythrocyte hydroxymethylbilane synthase activity is often reduced to half of normal in patients with AIP, and the enzyme activity assay has a high diagnostic value in AIP. AIP is highly molecularly heterogeneous, with missense mutations being the most common, followed by splice mutations. R173W and G111R are high-frequency mutations and have been found in multiple families from different countries.

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Section: Discussionmentioning

confidence: 99%

HMBS gene mutations and hydroxymethylbilane synthase activity in acute intermittent porphyria: A systematic review

Li,

Lei,

Dong

et al. 2023

Medicine

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“…(8) Although only few genetic studies in patients with VP or AIP have been performed in South Africa, these have identified novel mutations amongst black individuals and provide evidence for heterogeneity of molecular abnormalities in different populations. (7,26) Robreau-Fraolini et al (2000) performed the first porphobilinogen deaminase gene study within a black population, demonstrating that the spectrum of mutations differ compared to those found in white counterparts. (27) They identified four novel mutations and further discovered that certain single nucleotide polymorphisms existed only in black individuals and not in whites.…”

Section: Discussionmentioning

confidence: 99%

“…The true prevalence thereof is difficult to quantify as the clinical penetrance is low. (1,6,7) AIP is the most identified porphyria worldwide. (1,3,8,9) In South Africa, VP is the most common porphyria due to the founder R59W mutation introduced by a Dutch settler in 1688.…”

Section: Introductionmentioning

confidence: 99%

Porphyric neuropathy in black South Africans: a case series

Koufos¹,

Modi²

2023

Wits Journal of Clinical Medicine

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Porphyria is a rare disorder that results from mutations in the genes important in haem biosynthesis. Several types are described. Acute attacks lead to central, autonomic and peripheral nervous system manifestations. These acute attacks typically occur in acute intermittent porphyria, and less so in variegate porphyria. The neuropathy in this condition can mimic Guillain-Barré syndrome (GBS), and is often misdiagnosed and incorrectly treated. It is rare in general, but considered to be extremely uncommon in the black African population. We describe five black South African patients, three of whom were diagnosed with variegate porphyria, with the presenting manifestation of a severe neuropathy. The neuropathy was atypical in nature and variable in presentation and highlight the importance of considering porphyria in such patients.

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“…At present, there is a lack of epidemiological data on AIP worldwide, but Europe performed large scale prospective study to investigate the incidence of porphyrias ( Elder et al, 2013 ). And multiple countries such as South Africa ( Fortgens et al, 2017 ), the United States ( Bonkovsky et al, 2014 ), Argentina ( Cerbino et al, 2015 ), Colombia ( Jaramillo-Calle and Aguirre Acevedo, 2019 ), and Russia ( Goncharova et al, 2019 ) have reported cohort studies on AIP. And with the development of sequencing technology, more and more AIP patients have been reported in China.…”

Section: Introductionmentioning

confidence: 99%

Clinical feature and genetic analysis of HMBS gene in Chinese patients with acute intermittent porphyria: a systematic review

Ren,

Li,

Lei

et al. 2023

Front. Genet.

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Background: Early detection and diagnosis are important crucial to prevent life-threatening acute attacks in patients with acute intermittent porphyria (AIP). We aim to provide comprehensive data on the clinical and hydroxymethylbilane synthase (HMBS) gene variant characteristics and genotype-phenotype association of Chinese patients with AIP in order to improve clinicians’ knowledge of AIP and reduce misdiagnosis and mistaken treatment.Methods: We searched the literature on Chinese patients with AIP in PubMed, Web of Science, Wiley Online Library, ScienceDirect and Chinese literature databases up to August 2023 in our analysis to explore the clinical and HMBS gene variant characteristics of Chinese patients with AIP.Results: A total of 41 original articles associated with Chinese AIP patients were included for analysis: 97 variants were detected in 160 unrelated families, including 35 missense, 29 frameshift, 24 splicing and 9 nonsense variants, with c.517C>T being the most common variant. Clinical data were reported in 77 of 160 patients: Most of them were female (67/77) and the age was 28.8 ± 9.9 years. The most common symptom was abdominal pain (73/77, 94.8%), followed by central nervous system symptoms (45/77, 58.4%). 13.0% (10/77) of patients experienced psychiatric symptoms. Hyponatremia was the most common electrolyte abnormality (42/77). 31 patients received carbohydrate loading therapy, and 30 of them were improved. 6 patients were treated with carbohydrate loading combined with hemin therapy and 5 eventually improved. All variants causing premature stop codons, frameshifts or enzyme activity center may experience more severe clinical phenotypes such as seizures, respiratory paralysis, intracranial hemorrhage disorder or respiratory failure.Conclusion: The most common presenting symptom in Chinese AIP patients was abdominal pain, followed by central nervous system symptoms. The HMBS gene analysis in Chinese AIP patients revealed that the heterogeneity is strong and the most common variant was missense mutation, with c.517C>T being the most common variant. The genotype-phenotype association helps guide clinical diagnosis and treatment. However, the treatment for AIP in China is limited and monolithic, and more attention needs to be paid to the treatment.

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Molecular characterisation of acute intermittent porphyria in a cohort of South African patients and kinetic analysis of two expressed mutants

Cited by 5 publications

References 38 publications

HMBS gene mutations and hydroxymethylbilane synthase activity in acute intermittent porphyria: A systematic review

HMBS gene mutations and hydroxymethylbilane synthase activity in acute intermittent porphyria: A systematic review

Porphyric neuropathy in black South Africans: a case series

Clinical feature and genetic analysis of HMBS gene in Chinese patients with acute intermittent porphyria: a systematic review

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