rs77931234 — ACADM c.985A>G (p.Lys329Glu)

Pathogenic missense variant in ACADM reducing MCAD enzyme activity, predisposing to fatty acid oxidation failure and cardiac stress during fasting, illness, or exercise

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When Fat Can't Fuel the Heart — ACADM and MCAD Deficiency

The body runs on two primary fuels: glucose and fat. During fasting, prolonged exercise, or illness, glucose runs low and the heart, liver, and muscles switch to burning fatty acids. This switch depends on mitochondrial beta-oxidation11 mitochondrial beta-oxidation
A multi-step enzymatic cascade that strips two carbons at a time from fatty acid chains, generating acetyl-CoA and the electron carriers NADH and FADH2 that drive ATP production. Medium-chain acyl-CoA dehydrogenase (MCAD), encoded by ACADM, is the gatekeeper for fatty acids of 6–12 carbon chain length — the dominant fuel in fasting metabolism.

The c.985A>G variant (p.Lys329Glu) is the defining mutation of MCAD deficiency (MCADD)22 MCAD deficiency (MCADD)
The most common inborn error of fatty acid oxidation, with newborn screening incidence of ~1:10,000 in northern Europeans. It accounts for approximately 90% of all disease-causing ACADM alleles in people of European descent and reflects a single northwestern European founder event33 northwestern European founder event
Gregersen et al. 1993 documented 100% haplotype association of G985 across 17 families from Belgium, Denmark, England, Ireland, Italy, and the Netherlands. Because MCADD is autosomal recessive, one copy (carrier state) is generally well-tolerated, but two copies cause complete or near-complete loss of MCAD activity — leaving the individual unable to process medium-chain fatty acids during metabolic stress.

The Mechanism

At position 329 in the MCAD protein, a lysine residue (positively charged) is replaced by glutamate (negatively charged). This charge reversal destabilizes the MCAD enzyme tetramer and impairs binding of the FAD cofactor essential for the acyl-CoA dehydrogenation reaction44 acyl-CoA dehydrogenation reaction
The reaction that removes the first two hydrogens from a fatty acyl-CoA chain, initiating each cycle of beta-oxidation. The result is severe reduction in MCAD catalytic activity — and in homozygous individuals, virtual absence of the ability to oxidize C6–C12 fatty acids.

When MCAD is absent and the body is forced into fatty acid oxidation (fasting, fever, prolonged exercise), medium-chain acyl-CoA intermediates accumulate. These toxic intermediates interfere with the tricarboxylic acid cycle, disrupt gluconeogenesis (preventing the liver from generating glucose), and impair the urea cycle. The result is hypoglycemia, hyperammonemia, and energy failure — conditions that hit the heart hard. The myocardium is uniquely fatty-acid dependent, deriving 60–70% of its ATP from fat oxidation under normal conditions. When this pathway is blocked during demand, cardiac failure follows rapidly.

The Evidence

Cardiac involvement in MCADD is well-documented. Wiles et al. 201455 Wiles et al. 2014
First reported case of acquired prolonged QTc (517 ms) in MCADD — a neonate homozygous for c.985A>G whose ECG normalized within 41 days of metabolic stabilization established the arrhythmia connection. The QTc prolongation was attributed directly to the metabolic derangement — electrolyte imbalance and energy depletion in cardiac tissue — rather than a structural cardiac defect.

More dramatically, Morana et al. 202666 Morana et al. 2026
Novel tachycardiomyopathy presentation in a neonate homozygous for c.985A>C (p.Lys329Gln); complete recovery within 48 hours of IV glucose and carnitine — both p.Lys329 variants share the same functional consequence documented refractory supraventricular tachyarrhythmias, severe biventricular systolic dysfunction, and biventricular dilation in a neonate. Within 48 hours of disease-specific management (IV glucose, carnitine), cardiac function normalized completely — underscoring that these cardiac events are metabolic emergencies, not permanent structural disease.

Anderson et al. 202077 Anderson et al. 2020
Retrospective of 90 MCADD patients showing homozygous p.Lys329Glu carriers had C8-acylcarnitine of 23.4 ± 19.6 μmol/L; clinically diagnosed patients averaged 2.15 hypoglycemic events vs. 0.62 in screened cases quantified the biochemical severity: elevated C8-carnitine concentrations serve both as the diagnostic marker and the ongoing metabolic monitor. In a 66-patient Portuguese follow-up, Janeiro et al. 201988 Janeiro et al. 2019
Acute decompensations with cardiac failure and sudden cardiac death occurred even in newborn-screened patients, demonstrating that lifelong vigilance is required confirmed that newborn screening reduces but does not eliminate the risk of life-threatening events.

Everard et al. 202499 Everard et al. 2024
Belgian multi-center retrospective of 54 FAO disorder patients; MCADD was 75.9% of cases; acute crises produced cardiomegaly, arrhythmias, hepatomegaly, rhabdomyolysis provided the most recent multi-center confirmation of cardiac involvement, noting that triggers include prolonged fasting, intercurrent infections, and intense physical activity.

Population carrier rates reflect the northwestern European founder effect: approximately 1 in 68–101 individuals in the UK and Denmark, 1 in 84 in North Carolina Caucasians, and 1 in 333 in Italy Gregersen et al. 19931010 Gregersen et al. 1993.

Practical Actions

For carriers (AG genotype), the key concern is the residual risk during extreme metabolic stress and — critically — the risk to offspring if a partner also carries the variant. For homozygous individuals (GG genotype), avoidance of fasting is non-negotiable. The GeneReviews MCADD chapter1111 GeneReviews MCADD chapter
Management authored by Chang, Lam, and Vockley at University of Washington; comprehensively updated through 2024 specifies: dietary fat capped at 30% of total energy, avoidance of medium-chain triglyceride-containing formulas and products, and age-appropriate fasting limits (2–3 hour feeds in infancy, overnight cornstarch in older children and adults).

Acylcarnitine monitoring via dried blood spot or plasma C8-acylcarnitine allows clinicians to detect metabolic stress before symptoms appear. Emergency protocols center on rapid IV glucose to suppress fatty acid mobilization — the metabolic equivalent of removing the trigger.

Interactions

Variants in complementary fatty acid oxidation genes — including ACADVL (very long chain ACAD), ACADS (short chain ACAD), and HADHA (long chain 3-hydroxyacyl-CoA dehydrogenase) — affect adjacent steps in the same beta-oxidation cascade. Compound heterozygosity between ACADM variants (e.g., c.985A>G on one allele and a rarer frameshift or nonsense ACADM variant on the other) is the second most common genetic configuration in MCADD and typically produces a phenotype similar to homozygous c.985A>G. Carnitine transporter variants (SLC22A5) can reduce carnitine availability, compounding the metabolic stress when MCAD activity is already impaired.

Nutrient Interactions

carnitine increased_need
medium-chain triglycerides altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

AA Normal MCAD Activity Normal

Standard MCAD enzyme function; normal fatty acid oxidation

You carry two copies of the reference allele, indicating no pathogenic ACADM c.985A>G variant. Your MCAD enzyme is expected to function normally, processing medium-chain fatty acids efficiently during fasting, illness, or prolonged exercise. The vast majority of people — approximately 99% globally — share this genotype. Your fatty acid oxidation capacity from this pathway is unaffected.

AG MCAD Carrier Carrier

One copy of the MCAD-deficiency variant; generally healthy but important for family planning

Carriers of a single ACADM pathogenic variant rarely develop clinically significant MCAD deficiency because one functional gene copy provides enough enzyme activity for normal metabolism. That said, isolated case reports have noted that some carriers develop modest C8-acylcarnitine elevation during prolonged fasting or severe catabolic stress (major surgery, sepsis), though symptomatic crises in confirmed heterozygotes are extremely rare.

The primary relevance of carrier status is reproductive. MCADD follows strict autosomal recessive inheritance: both parents must contribute a non-functional ACADM allele for a child to be affected. Given the high carrier prevalence in northwestern European populations (up to 1%), carrier couples are not rare. Newborn screening programs now detect MCADD at birth through elevated C8-acylcarnitine on dried blood spot — enabling immediate dietary management before any crisis occurs. Pre-conception knowledge of carrier status allows couples to access genetic counseling and, where relevant, preimplantation genetic testing.

GG MCAD Deficiency Homozygous

Homozygous for the MCAD-deficiency variant; requires strict fasting avoidance and metabolic monitoring

Homozygous c.985A>G is the most common genotype producing full MCAD deficiency. The lysine-to-glutamate substitution at position 329 disrupts MCAD tetramer stability and FAD cofactor binding, reducing enzyme activity to near zero. This is a metabolically silent deficiency at rest — problems arise only when the body attempts to switch from glucose to fatty acid fuel during extended fasting, intercurrent illness (especially viral illness with reduced oral intake), or intense exercise beyond glycogen stores.

Cardiac manifestations are among the most dangerous: elevated C8-acylcarnitine and accumulating toxic medium-chain intermediates directly impair cardiac energy metabolism, producing QTc prolongation, supraventricular tachyarrhythmias, and dilated cardiomyopathy — all reversible with prompt IV glucose and metabolic correction. Sudden cardiac death is documented in undiagnosed and undertreated cases.

Management is highly effective when applied consistently. The primary strategy is to eliminate metabolic triggers: maintain regular carbohydrate intake to keep fatty acid mobilization suppressed. Dietary fat is capped at 30% of total energy, and medium-chain triglyceride products (MCT oil, some infant formulas, coconut oil) are specifically contraindicated. During illness, an emergency glucose protocol — oral glucose polymer or IV dextrose — should be initiated immediately. All acute presentations require emergency IV glucose at 10–12 mg/kg/minute.

Most adults with well-managed MCADD live normal, healthy lives. The key risk periods are infancy (before diagnosis in the absence of newborn screening), febrile illness, and intentional fasting (weight loss, religious fasting, extended sports events).