Overview
HMBS (formerly known as Porphobilinogen Deaminase, PBGD) encodes an enzyme that plays a central role in heme biosynthesis. Heme is an essential component of hemoglobin and many other proteins. Mutations in HMBS lead to Acute Intermittent Porphyria (AIP), a rare metabolic disease characterized by episodic, potentially life-threatening crises.
11q23.3 (Chromosome 11)
Hereditary Diseases / Metabolism
Autosomal dominant (with variable penetrance)
~1:10,000 to 1:20,000 (genetic), clinically manifest cases are rarer
Function & Significance
HMBS catalyzes the third step of heme biosynthesis: the conversion of four molecules of porphobilinogen (PBG) into hydroxymethylbilane. This process occurs in all body cells but is particularly important in the liver and bone marrow, where large amounts of heme are required.
In mutations in HMBS, enzyme activity is reduced to approximately 50%. Under normal circumstances this is sufficient, but with certain triggers (medications, hormones, fasting, stress), an overproduction of the precursors PBG and δ-aminolevulinic acid (ALA) can occur, which are neurotoxic and trigger acute attacks.
🔬 Heme Biosynthesis
Heme biosynthesis is a complex, eight-step process. Disruptions at different steps lead to different forms of porphyria. AIP is the most common acute hepatic porphyria and can be life-threatening if untreated.
Associated Diseases
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⚡ Acute Intermittent Porphyria (AIP)
Episodic abdominal pain, neurological symptoms, psychiatric manifestations
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🧠 Neurological Crises
Peripheral neuropathy, paralysis, seizures, confusion
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💊 Drug-induced Attacks
Many medications can trigger attacks (e.g., barbiturates, sulfonamides)
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🩸 Hyponatremia
Low sodium levels during acute attacks
🧬 Relevant SNPs
11:119082566
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Significance: Arg173Trp (R173W) – Common pathogenic variant that significantly reduces enzyme activity. Heterozygous carriers have an increased risk of acute porphyria attacks.
11:119082623
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Significance: Arg167Gln (R167Q) – Another pathogenic variant with reduced enzyme activity. Clinical penetrance is variable.
⚕️ Clinical Significance
Diagnosis of AIP is made by measuring PBG and ALA in the urine during an acute attack. Genetic tests confirm the diagnosis and enable family screening. Important: Many gene carriers remain asymptomatic throughout their lives.
Emergency Treatment: Acute attacks require immediate treatment with heme arginate (Normosang®) or Givosiran (Givlaari®), a new RNA interference therapeutic. Trigger avoidance is essential (consult drug safety lists!).
Avoid Triggers: Fasting, alcohol, certain medications, hormonal fluctuations, infections, stress.
📚 Data Sources
The information on this page is based on the following scientific sources:
- OMIM: #176000 (Porphyria, Acute Intermittent)
- dbSNP: rs121908008, rs121912613
- ClinVar: Pathogenic HMBS variants
- PubMed: Literature on acute intermittent porphyria
- Orphanet: ORPHA79276 (Acute intermittent porphyria)
- Porphyria Drug Database: porphyriafoundation.org
Last update: February 2026
Biological Function
Associated Conditions
Analyzed Markers
Trp198Stop - Leads to truncated, inactive enzyme.
Arg173Trp - Common mutation in AIP.