Abstract
<title>Abstract</title> <p>Background. Alpha-gal syndrome (AGS) shows marked heterogeneity in symptom breadth, autonomic features, and recovery kinetics. IgE titer often correlates poorly with clinical severity. Host factors that may modify the expression of an already-established sensitization remain largely unexamined. Case. A man of Northwest European ancestry was clinically diagnosed with AGS (positive diagnostic serology; epinephrine prescribed) after delayed reactions to mammalian products. Multi-specialty evaluation before and after diagnosis did not yield a single unifying structural explanation. GeneSight pharmacogenetic testing (May 2025) listed COMT; broader array genotyping (February 2026) identified COMT rs4680 AA (Met/Met), HNMT rs11558538 CT (Thr105Ile), and PEMT rs7946 TT. Major AOC1/DAO risk alleles and classic MTHFR risk alleles were wild-type. After targeted one-carbon and related support under supervision, homocysteine fell from 20.87 to 6.62 µmol/L; related metabolic markers improved; long-term beta-blockade was discontinued (June 2026) with stable BP/HR; alpha-gal and meat-specific IgE were <0.10 kUA/L on serial testing (October 2025, March 2026); mammalian foods were reintroduced without recurrent allergic reactions. A residual lower-intensity stress-triggered phenotype persists. Guanfacine ER 2 mg daily was started July 2026 for a separate ADHD-spectrum indication. Hypothesis. Tick exposure initiates sensitization. COMT and HNMT are SAM-dependent; high methyl demand or limited one-carbon input can lower the SAM:SAH ratio and further impair clearance. Reduced histaminergic and catecholaminergic regulatory capacity may modify expression and recovery of established AGS — broader symptoms, stronger autonomic features, slower return to baseline, poorer IgE–severity correlation. Intermittent AGS mediator load can push a constrained system into a high-gain state; that state can make subsequent loads land harder. Supporting one-carbon status and reducing histamine effector tone is hypothesized only to lower total load, not to eliminate IgE. Open questions. Five population- and phenotype-level questions are stated. None is answered by n-of-1 data. The genotype combination is expected in ~4–6% of ancestry-matched populations; its presence in one person is unsurprising and carries no evidential weight alone.</p>