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

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.