HMBS – Porphyria

Hydroxymethylbilane synthase (HMBS; HGNC:4982) encodes porphobilinogen deaminase, the third enzyme in the heme biosynthetic pathway. Heterozygous loss-of-function variants in HMBS cause acute intermittent porphyria (AIP), the most common acute hepatic porphyria subtype, characterized by neurovisceral attacks and biochemical accumulation of porphobilinogen and δ-aminolevulinic acid ([PMID:12699245]).

AIP is inherited in an autosomal dominant fashion with low penetrance. Segregation analysis in family studies has identified clinically affected relatives carrying HMBS pathogenic alleles; for example, the IVS2-2A>G variant segregated in a mother–daughter pair ([PMID:26228342]).

Multiple case reports describe probands presenting with acute porphyric attacks, hyponatremia, seizures, and abdominal pain in association with heterozygous HMBS variants. In an 18-year-old female, the missense variant c.583C>T (p.Arg195Cys) was confirmed by genetic testing after delayed diagnosis and successful hemin infusion ([PMID:35419127]).

Large cohort studies reinforce the allelic heterogeneity of HMBS in porphyria. In Italy, molecular characterization in 66 probands uncovered 22 distinct HMBS mutations, with 55 asymptomatic carriers among 115 relatives ([PMID:12699245]). Similarly, Swiss registry data covering 217 porphyria patients from 170 families identified founder and private HMBS alleles, facilitating presymptomatic diagnosis and management ([PMID:19350426]).

Functional assessment of HMBS variants in heterologous systems and animal models demonstrates a haploinsufficiency mechanism. In vitro expression and enzyme assays of missense and splice-site mutations show residual activity <5%, confirmed by CRIM status and structural studies of active-site dynamics ([PMID:7962538], [PMID:19207107]). A homozygous mouse knock-in model of the p.Arg167Gln mutation exhibits neurobehavioral deficits and mitochondrial dysfunction, mirroring human AIP pathology ([PMID:32197664]).

Collectively, over 170 pathogenic HMBS variants have been reported in hundreds of unrelated patients over three decades, with consistent segregation, biochemical, and functional concordance. Genetic testing for HMBS mutations provides a definitive diagnosis, informs prognostic counseling, and enables preventive management of porphyria triggers.

Key Take-home: HMBS genetic testing is clinically actionable for confirming acute porphyria diagnoses and guiding preventive strategies in at-risk relatives.

References

• Cellular and molecular biology • 2002 • Molecular characterization of porphyrias in Italy: a diagnostic flow-chart. PMID:12699245
• Swiss medical weekly • 2009 • Porphyria in Switzerland, 15 years experience. PMID:19350426
• The Neurohospitalist • 2022 • Clinical Challenges of Acute Porphyria in the Young Adult. PMID:35419127
• Human mutation • 1994 • Acute intermittent porphyria: identification and expression of exonic mutations in the hydroxymethylbilane synthase gene. PMID:7962538
• The Biochemical journal • 2009 • Structure of human porphobilinogen deaminase at 2.8 A: the molecular basis of acute intermittent porphyria. PMID:19207107
• Acta neuropathologica communications • 2020 • Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria. PMID:32197664

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