rs74315294 — CPT2 p.Ser113Leu (S113L)

CPT2 S113L — When Your Cells Cannot Fuel Muscles With Fat

Your muscles have two main fuels: carbohydrates (glucose stored as glycogen) and fats (fatty acids stored in adipose tissue). During moderate or prolonged exercise — and especially during fasting — muscles shift toward fat as their primary energy source. To burn long-chain fatty acids (the dominant fat in your diet and your body), those fatty acid chains must first cross into the mitochondria, the cell's power plant. That transport step requires a molecular ferry called carnitine palmitoyltransferase 2 (CPT2)¹¹ carnitine palmitoyltransferase 2 (CPT2)
A 658-amino-acid enzyme embedded in the inner mitochondrial membrane that transfers long-chain acylcarnitines across the inner membrane into the mitochondrial matrix, where β-oxidation then dismantles them into acetyl-CoA for energy. Without CPT2, long-chain fatty acids pile up outside the mitochondria, and muscle cells are forced to rely almost entirely on glycogen — which runs out quickly during sustained activity.

The p.Ser113Leu variant (c.338C>T in the CPT2 coding sequence) is the single most common mutation causing myopathic CPT II deficiency. Two copies of this variant — one from each parent — produce an enzyme that unfolds under physiological stress, leaving muscles metabolically stranded during the activities that demand fat-burning the most.

The Mechanism

The serine-to-leucine substitution at amino acid position 113 lies in a conserved region of the mature CPT2 protein. Functional studies²² Functional studies
Motlagh et al. 2016, PMID 27123472 — recombinant S113L CPT2 shows markedly increased thermolability and reduced steady-state protein levels in both fibroblasts and transfected cells show that p.Ser113Leu does not abolish enzyme synthesis — the mutant protein is made at near-normal levels — but it is substantially less stable, degrading faster than wild-type CPT2 under conditions of metabolic stress. The result is a reduced steady-state amount of functional enzyme (roughly 25–40% of normal residual activity in some assays), particularly at elevated temperatures.

This thermolability explains a hallmark feature of myopathic CPT II deficiency: febrile illness is among the most potent triggers³³ febrile illness is among the most potent triggers
Body temperatures above 38–39°C further destabilize the already marginally stable S113L protein, acutely dropping residual enzyme activity below the threshold needed to sustain muscle energy metabolism. The three classic triggers — prolonged exercise, fever, and fasting — all share a common mechanism: they increase the muscle's demand for long-chain fat oxidation at precisely the moment the S113L enzyme is least able to deliver it.

The Evidence

The S113L mutation was first identified as the common CPT2 disease allele by Taroni et al. 1993⁴⁴ Taroni et al. 1993
Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients. Nature Genetics, 1993, who found it in 56% of mutant CPT2 alleles across 8 unrelated pedigrees with familial recurrent myoglobinuria. Subsequent population studies in European cohorts have consistently found the T allele accounting for 60–90% of CPT II deficiency alleles in Caucasians.

The overall population carrier frequency of the T allele is approximately 0.15% in gnomAD v2.1 (393/282,834 alleles globally), with a higher frequency of ~0.75% in the Ashkenazi Jewish subpopulation. Homozygotes (TT) are exceptionally rare in the population database, consistent with the clinical rarity of the condition (estimated at 1 in several hundred thousand live births for the symptomatic myopathic form).

A systematic review by Ivin et al. 2020⁵⁵ Ivin et al. 2020
Rhabdomyolysis caused by carnitine palmitoyltransferase 2 deficiency: A case report and systematic review. Journal of the Intensive Care Society, 2020 documents the cardinal clinical presentations: recurrent episodes of rhabdomyolysis (muscle fiber breakdown detectable as markedly elevated serum creatine kinase) and myoglobinuria (dark urine from released myoglobin), frequently resulting in acute kidney injury if fluid intake is insufficient during an episode. Symptoms typically begin in adolescence or early adulthood, often triggered by sustained exercise (particularly endurance activities), prolonged fasting, cold exposure, infection with fever, or combinations thereof.

For treatment, the fibrate drug bezafibrate — a PPAR-alpha/delta agonist — was shown by Bonnefont et al. 2010⁶⁶ Bonnefont et al. 2010
Long-term follow-up of bezafibrate treatment in patients with myopathic CPT2 deficiency. Clin Pharmacol Ther, 2010 to increase skeletal muscle palmitoyl-CoA oxidation rates by 39–206% in 6 patients with CPT2 deficiency (including S113L homozygotes), by upregulating residual CPT2 mRNA and enzyme expression through PPAR-mediated transcription. Patients reported increased physical activity and decreased muscular pain. Bezafibrate is not currently available in the United States (it is available in Europe and Canada) — fenofibrate is an alternative fibrate with a similar mechanism.

Practical Implications

For homozygous TT carriers, management centers on reducing dependence on long-chain fat oxidation during exercise and illness. Key strategies recommended in clinical guidelines and reviews include:

• Avoid prolonged fasting. Fasting forces muscles to rely on fatty acid oxidation. Eating regular meals with carbohydrate content is the single most effective daily precaution.
• Eat carbohydrates before sustained exercise. Pre-loading with slow-release carbohydrates (complex carbohydrates 1–2 hours before exercise) tops up muscle glycogen and delays the shift to fat oxidation during activity.
• Keep exercise sessions shorter and higher-intensity. Brief, high-intensity exercise (glycolytic by nature) is better tolerated than prolonged moderate-intensity endurance activity (which demands fat oxidation). Walking 20 minutes is less likely to trigger a crisis than jogging for 90 minutes.
• Aggressive fever management. Promptly treating febrile illness with antipyretics and ensuring adequate carbohydrate and fluid intake during infection substantially reduces crisis risk.
• Discuss fibrate therapy with your neurologist. Bezafibrate or fenofibrate may improve enzyme expression and exercise tolerance.

Heterozygous CT carriers typically have one functional CPT2 allele and maintain sufficient enzyme activity to avoid clinical disease. At least 21 heterozygous carriers have been documented with muscle CPT activity at 39–45% of normal — mildly reduced but usually asymptomatic at rest. A subset develop mild symptoms with very prolonged exertion or concurrent illness; most carriers are unaffected.

Interactions

CPT2 deficiency is a single-gene recessive disorder. Clinical severity is determined primarily by the number of T alleles and whether the second allele (in compound heterozygotes) is a null mutation or a milder missense. Compound heterozygosity for S113L (c.338C>T) plus a second rarer CPT2 mutation is the second most common genotype for adult myopathic CPT II deficiency after S113L/S113L homozygosity. The severity of compound heterozygous states depends on the residual activity of the second allele — null variants produce more severe phenotypes than missense variants.

The condition interacts with CPT1 variants (rs113994098 — CPT1B gene) at the physiological level: CPT1 and CPT2 together form the carnitine shuttle system. Variants reducing CPT1 activity from the outer mitochondrial membrane side compound with CPT2 dysfunction from the inner membrane side, though clinical interaction data for specific combined genotypes are limited.