CPT2 Genotype (Ser113Leu)

If you have ever ended a hard workout, a long fast, or a fever with severe muscle pain and dark, cola-colored urine, your DNA may carry the explanation. The Ser113Leu (S113L) change in the CPT2 gene is the single most common genetic cause of the muscle form of carnitine palmitoyltransferase II (CPT II) deficiency, an inherited problem with how your muscles burn fat for energy.

Knowing your status changes how you train, how you fast, what medications you tolerate, and how you should respond to a fever. It also helps you understand whether unexplained muscle damage in your past was a one-off or part of a lifelong pattern your body will keep producing under the right conditions.

What This Variant Actually Does

Your muscle, heart, liver, and kidneys all rely on a tiny shuttle inside their power plants (mitochondria) that pulls long-chain fats into the furnace to make energy. CPT II (carnitine palmitoyltransferase II) is the second half of that shuttle. The Ser113Leu variant is a one-letter change in the gene that builds CPT II. Cells still produce roughly normal amounts of the protein, but the protein itself is unstable, especially when your body warms up. At higher body temperatures it loses activity, which is why it is called thermolabile.

When you are calm and well-fed, sugar covers most of your energy needs and the weakened CPT II is enough. When you push past about 30 to 60 minutes of exercise, skip meals, run a fever, or get cold, your muscles switch over to fat for fuel. With Ser113Leu, that switch fails. Long-chain fats build up in muscle cells, energy production drops, and muscle fibers begin to break down.

How It Is Inherited

CPT II deficiency is what geneticists call autosomal recessive: you generally need two affected copies of the gene to have the full disease. Most people with the muscle form carry Ser113Leu on both copies (homozygous) or one copy of Ser113Leu and a different damaging change on the other copy (compound heterozygous). In one cohort of 22 people with CPT II deficiency, Ser113Leu accounted for 67.5% of the affected gene copies, and the variant has been described as the most frequent cause of CPT II deficiency in families with recurrent muscle breakdown.

People with only one copy (heterozygous carriers) usually have no symptoms or only mild ones, but case reports show that some heterozygous individuals can still have rhabdomyolysis episodes under enough metabolic stress. Even in close relatives who share the same genotype, the age of first attack and the severity of episodes vary widely, partly because of differences in residual enzyme activity and how each person handles physical and hormonal stress.

Recurrent Rhabdomyolysis and Muscle Pain

The hallmark feature is repeated episodes of muscle pain and rhabdomyolysis, where muscle fibers break down and dump their contents into the bloodstream. A protein called myoglobin floods into the urine and turns it dark, and creatine kinase (CK), an enzyme released from injured muscle, can spike to tens of thousands of units per liter. Episodes are typically set off by sustained exercise, fasting, infection, fever, or cold exposure.

Across case series and reviews, this pattern is described as the dominant clinical picture for Ser113Leu carriers: stress-triggered attacks of muscle pain and breakdown, with normal strength between episodes. In the largest series of muscle-form CPT II deficiency, 100 patients showed the same recurring pattern of rhabdomyolytic attacks and myoglobinuria, with some experiencing life-threatening episodes.

Acute Kidney Injury

When myoglobin pours into the bloodstream during a severe attack, it can clog the filtering tubes inside the kidneys and cause acute kidney injury. Multiple case reports of Ser113Leu carriers describe rhabdomyolysis severe enough to lead to acute renal failure, sometimes requiring intensive care and dialysis. A systematic review of CPT II deficiency notes that with prompt recognition and supportive care, kidney function usually recovers, and overall mortality from the muscle form is low.

Drug-Triggered Episodes

Certain medications can tip a Ser113Leu carrier into a full rhabdomyolysis attack. Valproic acid, an anti-seizure drug, has been reported to trigger acute rhabdomyolysis and renal failure in a person carrying Ser113Leu, and the authors of that case advise avoiding it in CPT II deficiency. The lesson is practical: knowing your CPT2 status before an unrelated illness leads to a new prescription can change what your physician prescribes.

Fever, Infection, and Encephalopathy

Because the Ser113Leu enzyme weakens further as body temperature rises, fevers are dangerous. Acute respiratory infection has been documented as the trigger that unmasked CPT II deficiency in a 3-year-old homozygous for Ser113Leu, and SARS-CoV-2 infection has been reported to set off rhabdomyolysis in a Ser113Leu carrier. In a study of 516 children, thermolabile CPT2 polymorphisms were identified as a genetic risk factor for acute encephalopathy during febrile illness, and a separate case-control study of 34 patients linked these unstable variants to influenza-associated encephalopathy in Japanese children.

What this means for you: if you carry Ser113Leu, treat any fever as an event that requires hydration, sugar-containing fluids, and a low threshold to call a clinician, rather than something to push through.

Heart and Multi-Organ Risk

CPT II is also expressed in heart, liver, and kidney tissue. Ser113Leu is mainly tied to the milder muscle form, not the lethal newborn form caused by other CPT2 variants, but case reports document arrhythmias and acute multi-organ failure in severe CPT II deficiency. A study of 28 adults with long-chain fatty-acid oxidation deficiency using cardiac MRI found subclinical heart abnormalities, suggesting the chronic energy shortfall can leave a faint imprint on the heart even in adults who feel well.

How the Test Reads Your DNA

This test looks at one specific spot in the CPT2 gene and reports your genotype at the Ser113Leu (c.338C>T) position. Because it is a fixed inherited change, the answer does not move over time. Your result will fall into one of three categories.

These genotype categories describe what was found at this single position. They do not rule out other CPT2 variants that this targeted test may not capture.

Why a Single Reading Is Enough, But Follow-Up Testing Is Not

Unlike cholesterol or blood sugar, your CPT2 genotype does not change. One accurate reading is your reading for life. What does need ongoing monitoring is the downstream biology this variant affects. If you carry one or two copies, your clinician may order baseline and periodic checks of creatine kinase (CK) to gauge background muscle damage and an acylcarnitine profile to look at how your body is handling long-chain fats. During or shortly after a suspected episode, an acylcarnitine profile can show elevated long-chain species (C16, C18, C18:1) and a high (C16+C18:1)/C2 ratio, while between attacks these values can be normal in the muscle form.

A reasonable cadence is a baseline CK and acylcarnitine profile at diagnosis, repeat testing during or right after any suspected attack, and at least annual checks thereafter. Episode tracking matters more than absolute numbers: a personal log of triggers, intensity, and recovery time gives you and your clinician far more signal than a single lab value.

When Results Can Be Misleading

• Targeted vs. comprehensive testing: this test reads only the Ser113Leu position. If you have classic muscle-form symptoms but a negative result, a broader CPT2 sequencing test is warranted, because other CPT2 variants can cause the same picture.
• Heterozygous results misread as protective: a single Ser113Leu copy is usually mild, but case reports show that compound heterozygous individuals (one Ser113Leu plus another CPT2 change not detected here) can have severe disease.
• Sample contamination or labeling errors: as with any DNA test, mix-ups happen. If the result conflicts with strong clinical evidence, repeat testing on a fresh sample is reasonable.
• Carrier status interpretation across populations: Ser113Leu is most common in European and Caucasian cohorts. In other ancestries, different CPT2 variants may dominate, so a negative Ser113Leu result is less informative for ruling out CPT II deficiency.

What To Do With An Abnormal Result

If you carry one or two copies of Ser113Leu, your next steps depend on whether you have had symptoms. For anyone with a positive result, the practical pathway is the same in spirit: get a baseline CK and acylcarnitine profile, ask a metabolic specialist or neurologist familiar with fatty-acid oxidation disorders to interpret the picture, and discuss whether full CPT2 sequencing is needed to characterize both gene copies.

Two people who should also know: your primary care clinician (so future prescriptions account for your status, particularly avoiding valproic acid) and any first-degree relatives, because CPT2 variants run in families and a sibling or child may carry the same change.

If you have a homozygous or compound heterozygous result and a history of unexplained muscle pain or dark urine, the workup typically extends to muscle CK trends, acylcarnitine testing during a stable period and during any suspected episode, and a written action plan for fever, fasting, and prolonged exertion.