Introduction
The essential water-soluble chemical known as carnitine (beta-hydroxy-gamma-trimethylammonium butyrate) is produced from amino acids. Nearly three-fourths of the total body storage of carnitine in non-vegetarians come from dietary intake, which also serves as the main source of the substance. Red meat, poultry, and dairy products are the principal sources of carnitine in the human diet. Dietary carnitine ranges in bioavailability from 54 percent to 87 percent. The liver and kidneys may synthesize the remaining one-fourth of the body's carnitine pool endogenously from lysine and methionine. Compared to non-vegetarians, vegetarians have a relatively lower plasma carnitine level. The majority of carnitine (greater than 90 percent) is synthesized endogenously in severe vegetarians.
Carnitine deficiency is defined by low quantities of amino acids in the body. It is possible for carnitine insufficiency to be primary (caused by a problem with carnitine transport) or secondary to other diseases. Primary carnitine deficiency is an autosomal recessive genetic condition. Multiple factors, including a reduction in carnitine intake or, more frequently, a rise in renal excretion of acylcarnitine, could lead to a secondary carnitine deficit. The physiology of carnitine is important for lipid metabolism and intermediate metabolic pathways. Carnitine assists in moving long-chain fatty acids from the cytoplasm to the mitochondrial matrix for later breakdown for beta-oxidation through the carnitine cycle.
What Causes Carnitine Deficiency?
A hereditary condition known as primary carnitine deficiency caused by a carnitine transport defect affects the OCTN2 (organic carnitine transporter new type 2) carnitine-transporter system, which is represented by the SLC22A5 gene. Due to insufficient active carnitine transport across the plasma membrane, carnitine transport defects result in a considerable loss of carnitine and a reduction in intracellular carnitine accumulation.
Reduced intracellular carnitine, decreased plasma carnitine levels, and increased urine loss are the hallmarks of primary carnitine deficiency. OCTN2, which is mostly expressed in the skeletal and cardiac muscles, as well as the kidneys, transports carnitine intracellularly. Reduced intracellular updating of carnitine is the result of decreased OCTN2 on the plasma membrane. Due to decreased carnitine reabsorption in the kidneys, patients with primary carnitine deficiency may lose up to 95 percent of the filtered carnitine in the urine. Parents who are heterozygous carriers and have a kid with primary carnitine deficiency may excrete twice as much urine as usual. Additionally, primary carnitine deficiency has low plasma levels of acyl-carnitine esters.
What Are the Signs and Symptoms of Carnitine Deficiency?
Primary carnitine insufficiency is characterized by -
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Severe brain dysfunction (encephalopathy).
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Enlarged heart (cardiomyopathy).
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Disorientation.
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Vomiting.
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Muscle weakness.
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Low blood sugar throughout infancy or early childhood (hypoglycemia).
Some primary carnitine deficiency sufferers are asymptomatic, meaning they do not exhibit any symptoms or indicators of the illness. All sufferers of this condition run the risk of
sudden death, heart failure, liver issues, and coma. Periods of fasting or ailments like viral infections might lead to issues with primary carnitine insufficiency.
This condition is commonly confused with Reye syndrome, a serious illness that can appear to be improving in children who have viral infections like the flu or chicken pox. Aspirin use during these viral infections is linked to the majority of Reye syndrome cases.
What Is the Pathophysiology Behind Carnitine Deficiency?
1. Fatty acids are the principal source of energy when fasting under normal physiological circumstances.
2. The liver, heart, and skeletal muscles use the process of beta-oxidation to convert fatty acids into energy.
3. Only the mitochondrial matrix undergoes beta-oxidation of long-chain fatty acids.
4. Long-chain fatty acids cannot pass through the mitochondrial membrane; hence the carnitine shuttle is necessary.
5. Long-chain fatty acids must first be converted to long-chain fatty acyl-coenzyme A in the cytoplasm in order to be transported across the mitochondrial membrane (long-chain fatty acids-coenzyme A).
6. Long-chain fatty acyl-coenzyme A synthetase is the enzyme that catalyzes this reaction.
7. The enzyme carnitine palmitoyltransferase-1 converts long-chain fatty acids-coenzyme A to acylcarnitine in the presence of carnitine after they have diffused past the outer mitochondrial membrane (carnitine palmitoyltransferase-1).
8. In healthy conditions, acylcarnitine production lowers the percentage of acyl residues associated with coenzyme A and raises the proportion of free coenzyme A to acyl-coenzyme A.
9. Acylcarnitine crosses the inner mitochondrial membrane by the carnitine-acylcarnitine translocase via the carnitine shuttle.
10. In the mitochondrial matrix, acylcarnitine is converted back to long-chain fatty acids-CoAs and free carnitine by the carnitine palmitoyltransferase-2 (CPT-II).
11. When acylcarnitine crosses the inner mitochondrial membrane, simultaneously, the free carnitine released by the carnitine palmitoyltransferase-2 leaves the mitochondrial matrix by the action of carnitine-acylcarnitine translocase, termed the carnitine shuttle.
12. Once they are inside the mitochondrial matrix, long-chain fatty acids-coenzyme A are readily oxidized, resulting in acetyl-coenzyme A production.
13. Acetyl-coenzyme A is subsequently used for energy and ketone body production.
14. Acetyl-coenzyme A is also an allosteric activator of pyruvate carboxylase that catalyzes the gluconeogenesis pathway, which is active during catabolic states such as fasting.
15. When carnitine levels are low, long-chain fatty acids cannot be delivered to the mitochondrial matrix for oxidation and subsequent use in the Krebs cycle and ketone body synthesis.
16. During fasting periods, poor fatty acid consumption hinders gluconeogenesis and typically results in nonketotic or hypoketotic hypoglycemia (producing no or little ketone bodies, respectively).
17. When fatty acid oxidation is compromised, glucose is quickly consumed and not replaced by gluconeogenesis.
18. A number of intermediary metabolic processes, including the Krebs cycle, amino acid metabolism, and beta-oxidation of fatty acids, are also impacted in circumstances of carnitine shortage.
What Are the Treatment Modalities to Be Followed for Treating Carnitine Deficiency?
A large dose of oral L-carnitine (100 to 200 mg/kg daily in three separate doses) is the basis of treatment for primary carnitine insufficiency. L-carnitine has a 5 percent to 18 percent oral bioavailability. L-carnitine is a rather safe drug, and the most common side effects at high doses are diarrhea and abdominal pain. In addition, trimethylamine, which has an odd, fishy odor, is produced by bacterial breakdown of oral L-carnitine that was not absorbed in the gut. Reduced L-carnitine dosage or a seven to ten-day course of oral Metronidazole treatment, eliminating intestinal bacterial overgrowth, could reduce these side effects.
Plasma levels can be raised using L-carnitine maintenance therapy, and the dose is adjusted based on both the response and the plasma levels. L-carnitine supplementation is continued to reduce myopathic symptoms and prevent hypoglycemia episodes. Due to the defective OCTN2 (organic cation transporter novel family member 2), which cannot sufficiently boost the carnitine uptake into the myocyte, the carnitine levels in the muscle increase only a little (up to 5 percent to 10 percent of controls). Most carnitine enters the body passively by plasma diffusion and low-affinity transporters, and this slight increase is sufficient to stop muscle problems.
Children with primary carnitine insufficiency who experience acute episodes of hypoglycemia are rapidly treated with intravenous ten percent dextrose, therapy of any concomitant metabolic abnormalities (such as acid-base abnormalities), and urgent carnitine supplementation. In primary carnitine insufficiency, frequent feedings and avoiding fast states are essential to preventing hypoglycemic episodes.
Conclusion
Most primary carnitine deficiency cases in developed nations are found through neonatal screening testing. Testing plasma carnitine levels is the initial step when a carnitine deficit is suspected. Low plasma-free carnitine levels ( 5 mol/L vs. typical 20 to 50 mol/L) are present in primary carnitine deficiency patients. Genetic testing is done to confirm the diagnosis, and an immediate referral to a metabolic specialist should be made. The prognosis has improved due to early diagnosis and immediate L-carnitine treatment. As long as L-carnitine therapy is continued, most primary carnitine deficiency cases have a favorable outcome. If untreated, this illness could be lethal. Undiagnosed patients may exhibit sudden death. Patients with primary carnitine deficiency can differ in their clinical presentations and symptom intensity. Primary carnitine deficiency that is undiagnosed or inadequately managed might cause serious problems. Convulsions and brain damage can result from hypoglycemic episodes.
