Carnitine is a naturally occurring compound derived from the amino acids lysine and methionine. It plays a central role in cellular energy production by transporting long-chain fatty acids from the cell’s cytoplasm into the mitochondria, where they are converted into adenosine triphosphate (ATP), the body’s main energy currency.
Highly concentrated in tissues like skeletal muscles and the heart, carnitine also aids in removing waste products from cells, preventing the buildup of harmful fatty acyl intermediates. This ensures cells, especially those with high energy demands, efficiently convert fat into usable energy.
Causes of Carnitine Deficiency
Low carnitine levels stem from two origins: primary or secondary carnitine deficiency. Primary carnitine deficiency is a rare genetic disorder, inherited in an autosomal recessive pattern, meaning an individual must receive an abnormal gene copy from both parents. It arises from mutations in the SLC22A5 gene, which provides instructions for producing the OCTN2 protein.
The OCTN2 protein is responsible for transporting carnitine into cells, particularly in the kidneys and muscles. When this transporter is absent or dysfunctional, carnitine cannot be properly absorbed into cells and is excessively lost through urine, leading to systemic carnitine depletion. This genetic defect impairs the body’s ability to utilize fatty acids for energy, especially during periods without food.
Secondary carnitine deficiency is more commonly encountered and results from various underlying health conditions or medical treatments. Chronic kidney disease, especially in patients undergoing hemodialysis, is a frequent cause, as it can lead to reduced carnitine synthesis and increased loss during dialysis. Certain metabolic disorders, such as fatty acid oxidation disorders or organic acidemias, also contribute by causing an accumulation of acylcarnitines, which can inhibit carnitine transport or promote its excretion.
Liver disease can impair the body’s natural production of carnitine, as the liver is one of the organs responsible for its synthesis. Malnutrition or conditions that cause poor nutrient absorption, like severe malabsorptive states, can also lead to inadequate carnitine intake. Additionally, some medications, notably valproic acid, can interfere with the renal reabsorption of carnitine, thereby lowering its levels in the body.
Premature infants are also susceptible to secondary carnitine deficiency because their immature renal function and limited capacity for carnitine biosynthesis make them more dependent on external sources. While the body can synthesize enough carnitine, individuals following strict vegetarian or vegan diets might have lower intake, as carnitine is most abundant in animal products like red meat and dairy.
Symptoms and Health Implications of Low Carnitine
When carnitine levels are insufficient, the body struggles to convert fats into energy. This leads to symptoms from impaired energy metabolism and fatty acid buildup. Common initial signs include:
Severe fatigue
Generalized muscle weakness and decreased muscle tone (hypotonia)
Poor feeding
Irritability, especially in infants
The muscular system is significantly affected, as muscles rely heavily on fatty acids for fuel. Individuals may experience:
Weakness in the hips, shoulders, upper arms, legs, neck, and jaw muscles
Muscle pain
Reduced tolerance for exercise
Episodes of rhabdomyolysis (breakdown of muscle tissue)
The heart, a continuously working muscle with high energy demands, is particularly vulnerable to carnitine deficiency. Impaired fatty acid metabolism can lead to:
Cardiomyopathy (weakened and enlarged heart muscle)
Arrhythmias
Heart failure
Sudden cardiac death due to accumulating acylcarnitines
Liver function can also be compromised, leading to an enlarged liver (hepatomegaly). The liver’s inability to properly process fats can result in recurrent episodes of low blood sugar, especially during periods of fasting or illness. Elevated ammonia levels (hyperammonemia) can also develop due to disruptions in metabolic pathways within the liver.
The brain is also susceptible to the effects of low carnitine. This can manifest as:
Encephalopathy (impaired brain function causing confusion, memory loss, and other neurological symptoms)
Developmental delays
Seizures
A severe presentation resembling Reye syndrome, particularly when triggered by viral infections
Diagnosis and Treatment Approaches
Diagnosing low carnitine begins with blood tests measuring free and total carnitine levels in plasma. A low level of free carnitine, along with an altered ratio of acylcarnitine to free carnitine, can indicate a deficiency. Newborn screening programs in many regions now include testing for carnitine deficiency using tandem mass spectrometry, which allows for early detection and intervention.
Genetic testing is often employed to confirm a diagnosis of primary carnitine deficiency, specifically looking for mutations in the SLC22A5 gene. Additional diagnostic tools may include urine tests for ketones or organic acids. A muscle biopsy might be performed to assess muscle carnitine concentrations or identify underlying metabolic issues causing secondary deficiency. Heart tests, such as echocardiography, can evaluate the extent of cardiac involvement.
The primary treatment for carnitine deficiency is L-carnitine supplementation (levocarnitine), the form the body can utilize. This supplement is available in both oral and intravenous forms, with oral administration being common. Dosages are determined by a healthcare professional based on the individual’s age, the severity of the deficiency, and its underlying cause, often ranging from 50 to 400 mg/kg per day, divided into multiple doses.
For individuals with primary carnitine deficiency, lifelong supplementation is necessary to manage the condition and prevent serious complications. While increasing dietary intake of carnitine-rich foods like red meat and dairy can be supportive, supplementation is required to achieve clinically significant levels. Additionally, dietary adjustments, such as a high-carbohydrate, low-fat diet, may be recommended, particularly for those with associated fatty acid oxidation disorders.