ArticleHuman mutation2016
Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease.
Article in Human mutation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
93 citing papers in PubMed, 2 syntheses or guidelines pooled it, 163 citations in OpenAlex.
- AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review.Gastroenterology · 2023Guideline
- Clinical feature and genetic analysis ofFrontiers in genetics · 2023Pooled it
- Understanding the Clinical Spectrum of the Cutaneous and Acute Hepatic Porphyrias.American journal of clinical dermatology · 2026Review
- Severe peripheral neuropathy secondary to acute intermittent porphyria caused by a rare HMBS gene mutation: a case report.BMC neurology · 2026Article
- Biochemically Evolving Acute Hepatic Porphyria With Postpartum Progression to Severe Recurrent Neurovisceral Disease.Cureus · 2026Article
- Biallelic pathogenic hydroxymethylbilane synthase gene variants of a neurodegenerative disorder with progressive cystic leukoencephalopathy: a case report.Journal of medical case reports · 2026Article
- Liver Transplantation and Other Hepatically Directed Therapies Do Not Change the Biochemical Phenotype nor Halt Progression of Leukodystrophy due to BiallelicJIMD reports · 2026Article
- Understanding Coproporphyrins and Their Disposition: Coproporphyrinuria is Common, of Diverse Cause, and Rarely Indicates Porphyria.The American journal of medicine · 2025Review
- A Prospective, Blinded Study of Symptom Prevalence and Specificity of Porphyrin Precursors in Carriers of Acute Hepatic Porphyria.Liver international : official journal of the International Association for the Study of the Liver · 2025Article
- Clinical Features and Outcomes of Acute Intermittent Porphyria Presenting With Acute Quadriparesis: A Case Series and Follow-Up Study.European journal of neurology · 2025Article
- Variant effect predictor correlation with functional assays is reflective of clinical classification performance.Genome biology · 2025Article
- Unmasked acute intermittent porphyria in a patient with COVID-19-associated posterior reversible encephalopathy syndrome.BMC neurology · 2025Article
- Practical recommendations for biochemical and genetic diagnosis of the porphyrias.Liver international : official journal of the International Association for the Study of the Liver · 2025Review
- An easily overlooked disease in the early stages: acute intermittent porphyria.BMC neurology · 2025Article
- Estimating carrier rates and prevalence of porphyria-associated gene variants in the Chinese population based on genetic databases.Orphanet journal of rare diseases · 2024Article
- Drug-associated porphyria: a pharmacovigilance study.Orphanet journal of rare diseases · 2024Article
- Unraveling Complexity: Acute Intermittent Porphyria Complicated by Rhabdomyolysis and Acute Pancreatitis.Cureus · 2024Article
- Understanding Hepatic Porphyrias: Symptoms, Treatments, and Unmet Needs.Seminars in liver disease · 2024Review
- Obstacles to Early Diagnosis of Acute Hepatic Porphyria: Current Perspectives on Improving Early Diagnosis and Clinical Management.Clinical and experimental gastroenterology · 2024Review
- The Alpha-Lipoic Acid Improves Glucose Metabolism and Hyperinsulinemia in Acute Intermittent Porphyria: A Nutritional Concept for the Management of Rare Disorders.Cellular and molecular gastroenterology and hepatology · 2024Article
33 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Acute intermittent porphyria results from hydroxymethylbilane synthase (HMBS) mutations that markedly decrease HMBS enzymatic activity. This dominant disease is diagnosed when heterozygotes have life-threatening acute attacks, while most heterozygotes remain asymptomatic and undiagnosed. Although >400 HMBS mutations have been reported, the prevalence of pathogenic HMBS mutations in genomic/exomic databases, and the actual disease penetrance are unknown. Thus, we interrogated genomic/exomic databases, identified non-synonymous variants (NSVs) and consensus splice-site variants (CSSVs) in various demographic/racial groups, and determined the NSV's pathogenicity by prediction algorithms and in vitro expression assays. Caucasians had the most: 58 NSVs and two CSSVs among ∼92,000 alleles, a 0.00575 combined allele frequency. In silico algorithms predicted 14 out of 58 NSVs as "likely-pathogenic." In vitro expression identified 10 out of 58 NSVs as likely-pathogenic (seven predicted in silico), which together with two CSSVs had a combined allele frequency of 0.00056. Notably, six presumably pathogenic mutations/NSVs in the Human Gene Mutation Database were benign. Compared with the recent prevalence estimate of symptomatic European heterozygotes (∼0.000005), the prevalence of likely-pathogenic HMBS mutations among Caucasians was >100 times more frequent. Thus, the estimated penetrance of acute attacks was ∼1% of heterozygotes with likely-pathogenic mutations, highlighting the importance of predisposing/protective genes and environmental modifiers that precipitate/prevent the attacks.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.