HMBS – Acute Intermittent Porphyria

Acute intermittent porphyria (AIP) is an autosomal dominant neurovisceral disorder caused by partial deficiency of hydroxymethylbilane synthase (HMBS), the third enzyme in heme biosynthesis. Pathogenic HMBS variants impair conversion of porphobilinogen to hydroxymethylbilane, leading to accumulation of neurotoxic precursors and episodic attacks of abdominal pain, neuropathy, and neuropsychiatric features ([PMID:2246852]).

Clinical validity is definitive: AIP has been reported in over 160 unrelated families harboring HMBS variants with consistent segregation and concordant biochemical findings across diverse populations ([PMID:38148975]); enzyme assays and mutation screening demonstrate half-normal HMBS activity in symptomatic and asymptomatic carriers across generations ([PMID:10343207]).

Genetic evidence (Strong): More than 170 unique HMBS variants—including missense, nonsense, frameshift, splice-site, and indels—have been identified in over 500 probands worldwide, with segregation in family studies (17 affected relatives in one kindred) confirming pathogenicity ([PMID:30740734]; [PMID:10343207]). Variant spectrum spans recurrent founder alleles (e.g., c.517C>T) and population-specific mutations, supporting a broad allelic heterogeneity.

Functional studies (Strong): Expression of HMBS mutants in prokaryotic and mammalian systems shows residual enzyme activity ≤5% for most pathogenic alleles, with proteasomal degradation of unstable polypeptides and disrupted cofactor binding demonstrated in cellular models ([PMID:16935474]; [PMID:30085095]). Mechanistic investigations reveal haploinsufficiency and dominant-negative effects, with key residues (Arg26, Arg167) mediating substrate turnover and chain elongation ([PMID:29632172]).

No substantial conflicting evidence has emerged; pleiotropic presentations (e.g., pediatric onset, compound heterozygosity, mosaicism) further delineate the clinical spectrum without refuting the core association.

Integration: Genetic and biochemical assays, complemented by molecular diagnostics, enable definitive AIP diagnosis, carrier detection, and informed management. Treatment with carbohydrate loading, hemin infusion, or emerging gene therapies hinges on prompt recognition of HMBS variants.

Key Take-home: HMBS pathogenic variants cause autosomal dominant acute intermittent porphyria via haploinsufficiency; genetic diagnosis is essential for timely prophylaxis and targeted therapy.

References

• Journal of inherited metabolic disease • 1990 • Identification of the mutations in the parents of a patient with a putative compound heterozygosity for acute intermittent porphyria. PMID:2246852
• Frontiers in genetics • 2023 • Clinical feature and genetic analysis of HMBS gene in Chinese patients with acute intermittent porphyria: a systematic review. PMID:38148975
• Biochimica et biophysica acta • 2006 • Proteasomal degradation regulates expression of porphobilinogen deaminase (PBGD) mutants of acute intermittent porphyria. PMID:16935474
• Human molecular genetics • 2018 • Bioengineered PBGD variant improves the therapeutic index of gene therapy vectors for acute intermittent porphyria. PMID:30085095
• Journal of inherited metabolic disease • 2019 • Identification and characterization of 40 novel hydroxymethylbilane synthase mutations that cause acute intermittent porphyria. PMID:30740734
• Skin pharmacology and applied skin physiology • 1998 • Acute intermittent porphyria: mutation analysis and identification of gene carriers in a German kindred by PCR-DGGE analysis. PMID:10343207

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