Prior to symptom onset, SB had a history of celiac disease, exercise-induced asthma, and ADHD, which were well-controlled with a strict gluten-free diet, extended-release Adderall 20 mg daily (discontinued upon beginning selegiline/rasagiline), and an albuterol inhaler as needed. SB never used use tobacco and ceased moderate alcohol intake after the onset of post-ethanol symptoms and tyramine sensitivity (symptoms 10 and 12, Table 1). His family history included type I diabetes, hypermobile Ehler’s-Danlos syndrome, heart disease, and skin cancer. SB had no criminal history and no history of childhood abuse or significant violent trauma.

SB presented with a constellation of progressive symptoms which accelerated over the course of the illness, characterized by worsening of extant symptoms and emergence of new symptoms (Table 1). Progression accelerated during periods of inadequate sleep and when symptoms were inadequately controlled. When pharmacological control was achieved, progression slowed dramatically. SB reported perceptible short-term reductions in symptom severity following intense cardiovascular exercise, during severe sleep deficits, and when exposed to bright sunlight or a seasonal affective disorder sun lamp. SB’s symptoms were more severe at night, with a circadian cycle of modulation. While many of these symptoms are, on their own, nonspecific, the authors have been unable to identify any extant disorder documented as having presented with this aggregate set of symptoms, particularly the noradrenergic specificity of sympathetic symptoms combined with the distinctive tyramine-induced ‘cheese response’, producing a rise in blood pressure from 116/77 to 149/97 within 30 min of the consumption of aged cheddar cheese (measured in 2020). The tyramine-induced cheese response is specific to inhibited MAO-A activity, and is associated with no other genetic or metabolic disorders (Cassis et al., 1986). Beyond the avoidance of tyramine alleviating the cheese response, dietary changes (including elimination diets, and a steep reduction in foods known to inhibit MAO-A as a consequence of the low-tyramine diet) did not impact the severity of any of the other symptoms listed in Table 1.

Given the severe impact of these symptoms on SB’s quality of life, a broad work up was pursued. Baseline laboratory studies were within normal limits, including complete blood count, comprehensive metabolic panel, lipid profile, serum aldosterone, renin, cortisol, prolactin, thyroid-stimulating hormone (TSH), free T4, and paraneoplastic antibody panel. Serum adrenaline and taurine were normal, excluding these pathways from the differential.

Pheochromocytoma was excluded via normal fractionated free plasma metanephrine and normetanephrine and abdominal computed tomography (CT) scan. Further imaging studies, including magnetic resonance imaging (MRI) of the brain, cervical, and thoracic spine, were normal. A sleep study could not be completed due to insomnia. Autonomic testing, including heart rate response to deep breathing, blood pressure and heart rate response to Valsalva, sudomotor responses, and tilt table testing, was normal. Whole exome sequencing (WES) was performed in SB and both parents (CentoXome® Trio, CentoMito® Genome Cambridge, USA). No known pathological mutations were identified. This ruled out Fatal Familial Insomnia as well. The sporadic version was ruled out due to persistent lack of patient fatality. An intronic MAOA variant of unknown significance (VUS) was identified (NM_000240.4:c.956134_956133insAACAT; NG_008957.2:g.81405_81406insAACAT) but is unlikely to have direct coding consequence (NP_000231.1:p.?). The same WES ruled out Fatal Familial Insomnia as well. The sporadic version was ruled out due to persistent lack of patient fatality. Psychiatric disorders were excluded after repeated psychiatric evaluations, and symptoms did not improve with reduced life stressors, as with the completion of SB’s graduate studies in 2017, or with trials of standard therapies for anxiety and depression.

Fractionated urine catecholamines showed no elevation in adrenaline, NA, or dopamine (DA) on two separate tests. 24-h urine catecholamines showed normal adrenaline, NA, DA, and vanillylmandelic acid (VMA). NA metabolites (serum normetanephrine, fractionated free metanephrine, and free serum mass) were normal.

Pharmacologically, the following medications were trialed between 2010 and 2018 without significant relief: bupropion, ziprazidone, escitalopram, citalopram, paroxetine, clonazepam, prednisone, fexofenadine, venlafaxine, trazodone, rozerem, tizanidine, and ivermectin.

Clonidine and aripirazole both provided partial relief of several symptoms; however, they were discontinued due to unsustainable side effects. Propranalol and gabapentin provided limited relief and were discontinued when effective management was initiated.

While initial exclusionary bloodwork showed no elevated NE, EPI or DA plasma catecholamines, this absence was potentially explained by COMT activity, which effects an alternative pathway for noradrenaline breakdown (Eisenhofer et al., 2001). To reduce the confounding impact of COMT, the patient was prescribed entacapone 200 mg, a reversible COMT antagonist (Figure 1). A single dose of entacapone 200 mg inhibits COMT enzymatic activity by 65%, reaching maximum effect within 30 min of oral administration (Inaba-Hasegawa et al., 2013; Jian et al., 2021; Keränen et al., 1993). However, healthy human subjects do not display a change in plasma NE even when very high doses of entacapone are administered due to compensatory MAO-A activity. (Koulu et al., 1989). After a tapered cessation of rasagiline and administration of entacapone, a baseline blood sample was acquired and then 200 mg of entacapone was orally administered. SB then remained seated and refrained from significant mental or physical activity for the next 2 hours, whereupon a second blood sample was taken. The blood samples were tested for plasma NE levels as well as free normetanephrines (NMN). This procedure was then repeated six times following resumption of rasagiline.

The most direct test performed was measurement of deaminated catechols (catecholamine metabolites) performed non-experimentally at a CLIA certified laboratory at the National Institutes of Health. After tapering off all prior medications until symptoms re-emerged and stabilized, controlling blood pressure with amlodipine, a resting antecubital blood sample was obtained and plasma was separated by centrifuge at 4 °C, 4000 rpm for 15 min (Lachoi Centrifuge). Samples were stored at −80 °C using a portable freezer (Stirling Model Ult25NEU Portable freezer) and then packed in dry ice and shipped immediately to the laboratory. There, the samples were thawed and underwent alumina extraction of catechols (Lenders et al., 1996a) and were processed using a pump and refrigerated autosampler connected to a reversed-phase liquid chromatography column, kept at constant temperature using a column jacket. The column effluent was then passed through an electrochemical detection system, and measurements of dihydroxyphenylglycol (DHPG), NE, dihydroxyphenylalanine (DOPA), epinephrine (EPI), DA, and dihydroxyphenalyacetic acid (DOPAC) were obtained.

To contextualize SB’s biochemical abnormalities, we compared his quantitative blood test values with previously published studies of patients with X-linked MAO-A microdeletion (Männistö et al., 2024). Comparisons were made with two Brunner syndrome patients and with a population of healthy control subjects, examining values for dihydroxyphenylglycol (DHPG), noradrenaline (NA), dihydroxyphenylalanine (DOPA), adrenaline (ADR), dopamine (DA), and dihydroxyphenlyacetic acid (DOPAC), free or non-sulfate conjugated normetanephrine (NMN) and the calculated ratio of NMN: DHPG.

Carvedilol is a nonselective alpha1- and beta-adrenergic blocker, which prevents binding of NA to its receptor. Following clonidine discontinuation, the patient was prescribed 6.25 mg carvedilol twice per day in 2018. This was converted to 20 mg extended release in the same year and has since been adjusted as needed to control symptoms.

Rasagiline and selegiline are selective MAO-B inhibitors which have been shown to upregulate MAO-A expression in human subjects via Sp1/KLE11 signaling [reviewed in (Eisenhofer et al., 2004)]. In 2020, dextroamphetamine prescribed for the patient’s attention deficit disorder was discontinued and rasagiline (MAO-B inhibitor/MAO-A up-regulator) was prescribed and transitioned to selegiline in 2024 at the request of insurance.

To rule out habituation as an explanation for required dosage increases, in 2020—prior to the initiation of rasagiline—SB executed a month-long taper and cessation of treatment with carvedilol. Blood pressure was controlled using amlodipine (5 mg/day), a calcium channel blocking anti-hypertensive, after SB reached stage II hypertension. Once the taper was complete, he underwent formal autonomic reflex testing at Brigham & Women’s Hospital in Boston, USA and subsequently titrated back to a dose of carvedilol sufficient to achieve symptom control.

After a tapered cessation of rasagiline and administration of entacapone, SB’s plasma NA increased by 89%. When repeated on concomitant rasagiline, NA increased by a mean of 19.7% (standard deviation 37.50%). Notably, the percentage change under entacapone is reduced when the dose of rasagiline is increased (see Table 2).

DHPG and DOPAC, catecholamine by-products of MAO-A metabolism, were found to be significantly reduced (286 pg./mL (normal value 500–1,400 pg./mL) and 957 pg./mL, (normal value 1,000–3,000 pg./mL) respectively (Table 3). This confirmed an abnormally low level of MAO-A activity. (Mejia et al., 2001)

In comparison with published data from X-linked MAO-A microdeletion (Männistö et al., 2024), we found similar biochemical abnormalities in our patient (Table 3). Both our patient and the X-linked MAO-A group had reduced plasma DPHG and DOPAC. While our patient’s NMN was not measured at the same time as the DHPG measurement, the baseline plasma value measured during entacapone challenge #7 (performed 6 months prior) was used to estimate the ratio of free NMN to DHPG. This estimated free NMN to DHPG ratio in our patient was 0.78 while the two MAO-A X-linked patients also had similar ratios of 2.33 and 5.9 (patient 3 and 4) respectively. In contrast, the free NMN: DHPG ratio in the control group was 0.045 and even when maximum ranges were used the maximum ratio was 0.17. Generally, SB displays the same deviations from controls as Brunner syndrome patients, but at lower amplitudes.

Carvedilol provided significant relief of a subset of symptoms (Table 1) - and the patient reported no side effects. Relief was of short duration on the immediate release version, with symptoms returning 3 hours after administration. Extended-release doses twice per day were able to provide continuous relief. After 6 months the controlled symptoms began to re-emerge, and dosage was titrated until control of the re-emerging symptoms was achieved. This pattern has repeated in a stepwise fashion, with symptom severity progressing rapidly when uncontrolled, and quite slowly once a therapeutic dosing is achieved. Despite the maximum dosing recommendations of carvedilol, the patient consistently responded to supramaximal dosages without any known side-effects, including orthostatic intolerance, bradycardia, fatigue, or syncope. The amount of carvedilol needed to manage symptoms has consistently maintained the patient’s blood pressure in mid-to-upper normal ranges.

Rasagiline (and later selegiline) was found to be effective at supramaximum dosing with further additional control of symptoms (Table 1) and without adverse side effects. Interestingly, despite ADHD symptom severity increasing during the cessation of dextroamphetamine, the patient noted significant relief from ADHD symptoms and reported symptoms returning coincident with the requirement for increased dosing of rasagiline.

Required carvedilol dosing was reduced by 40% from 200 mg daily to 120 mg daily, suggesting that upregulation of MAO-A reduced the need for adrenergic blockade. Additionally, the plateau period of the stepwise symptom progression noted above was significantly extended by joint administration of carvedilol and rasagiline/selegiline.

As of writing, SB is on carvedilol ER 160 mg twice per day (320 mg/day), and selegiline HCL 15 mg twice daily (30 mg/day), having been transitioned to an equivalent dose from rasagiline at the request of insurance. Blood pressure and heart rate remain normal, with no indications of hypotension, and the patient reports no side effects. SB’s symptoms are well controlled.

Symptoms returned during the taper and cessation. Autonomic testing was normal. However, upon titration back onto carvedilol the dosing requirement was higher than previously needed to control the symptoms, suggesting that the patient had not habituated to this medication.

Further investigation is warranted on several fronts. The prevalence of this disorder is unknown but given the difficult path to confirmation and successful treatment experienced by SB, we caution against any assumption that a lack of previous reporting indicates rarity. A population suffering from this disorder could plausibly make up a sizeable percentage of autonomic patients who suffer sympathetically mediated symptoms but do not meet the diagnostic criteria for PTSD, generalized anxiety disorder (GAD), or postural orthostatic tachycardia syndrome (POTS). With confirmation available via blood tests (see below), other patients displaying a similar pattern of symptoms could be tested, and an estimate of the affected population size might be obtained.

Measurements of plasma catechol’s in a CLIA-certified laboratory played a critical role in diagnosing MAO-A (and potentially MAO-B or MAO-AB) dysfunction without requiring SB’s enrollment in an experimental protocol. Such measurements, being available in only a small number of labs, are not widely commercially accessible to patients. We demonstrate the feasibility of outpatient sample collection, but without widespread commercial availability the identification of additional patients is likely to rely on enrollment of prospective patients in experimental protocols. In addition to DHPG measurement, several complementary experimental methodologies exist which and could facilitate diagnosis and potentially offer further understanding of the underlying mechanism. MAO assays using Fibroblast cultures were used in the initial discovery of Brunner Syndrome (Brunner et al., 1993), and have been applied more recently in the functional confirmation of MAO-A variants (Oliver et al., 2022). Positron Emission Tomography with [11C]-Harmine (a competitive and reversible inhibitor of MAO-A) allows for in-vivo measurements of MAO-A activity in the human brain (TMA et al., 2021). Fluorescence PCR (Simonsen et al., 2002) has shown efficacy in genotyping alleles of interest. Westernblot techniques (Thor, 2003) can measure expression in tissue samples, or potentially even macrophages, and finally small molecule fluorescent probes (Jian et al., 2021) can allow measurement of monoamine oxidase-A and monoamine oxidase-B expression in vivo.

While the underlying mechanism has been confirmed as MAO-A hypofunction, it remains unknown whether the hypofunction arises from a low-functioning variant in the MAO-A enzyme or from under expression of the MAO-A gene. Either one could account for the results, and further investigation via laboratory testing could clarify the situation considerably or even suggest more effective methods of treatment. While current tests have not offered the ability to differentiate the two possible cases, tests such as those in (Oliver et al., 2022) allow more direct measurement of enzymatic kinetic parameters.

Although SB has a documented VUS in the MAOA coding region, it is possible that his symptoms are not due to a genetic mutation. Epigenetic changes such as DNA methylation, histone modification, and chromatin remodeling are heritable chemical changes that alter gene expression without changing the underlying genetic sequence. Epigenetic changes could potentially account for low-functioning of a normal MAOA gene, or even a progressively increasing sensitivity to environmental inhibitors of MAO-A. Alternatively, under expression could be assessed by measuring messenger ribonucleic acid (mRNA) levels in peripheral neurons.