Chemical Name: (R)-3-Carboxy-2-hydroxy-N,N,N-trimethyl-1- propanaminium hydroxide,
inner salt /
(R)-(3-Carboxy-2-hydroxypropyl) trimethyl ammonium hydroxide, inner salt
L-Carnitine forms white crystals or a white crystalline hygroscopic powder. It has a slight characteristic odor.
L-Carnitine is extremely hygroscopic and even deliquescent and it can liquefy on exposure to air.
L-Carnitine melts above 200ˇćunder decomposition.
L-Carnitine is highly soluble in water, in alcohol, in alkaline solutions, and in dilute mineral acids. It is practically insoluble in acetone or ethyl acetate.
L-Carnitine is a natural, vitamin-like nutrient responsible for promoting the ¦Â-oxidation process of long- chain fatty acids. In other words, it helps the body convert fatty acids into energy. L-Carnitine is often used in medicine and health food, sports drinks, infant nutrition and animal nutrition
Carnitine is a naturally occurring hydrophilic amino acid derivative, produced endogenously in the kidneys and liver and derived from meat and dairy products in the diet. It plays an essential role in the transfer of long-chain fatty acids into the mitochondria for beta-oxidation. Carnitine binds acyl residues and helps in their elimination, decreasing the number of acyl residues conjugated with coenzyme A (CoA) and increasing the ratio between free and acylated CoA.
Carnitine deficiency is a metabolic state in which carnitine concentrations in plasma and tissues are less than the levels required for normal function of the organism. Biologic effects of low carnitine levels may not be clinically significant until they reach less than 10-20% of normal. Carnitine deficiency may be primary or secondary.
Primary carnitine deficiency is caused by a deficiency in the plasma membrane carnitine transporter, with urinary carnitine wasting causing systemic carnitine depletion. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for beta-oxidation and energy production, and the production of ketone bodies (which are used by the brain) also is impaired.
Regulation of the intramitochondrial free CoA also is affected, with accumulation of acyl-CoA esters in the mitochondria. This, in turn, affects the pathways of intermediary metabolism that require CoA (eg, Krebs cycle, pyruvate oxidation, amino acid metabolism, mitochondrial and peroxisomal beta oxidation).
The 3 areas of involvement include (1) the cardiac muscle, which is affected by progressive cardiomyopathy (by far, the most common form of presentation), (2) the central nervous system, which is affected by encephalopathy caused by hypoketotic hypoglycemia, and (3) the skeletal muscle, which is affected by myopathy.
Muscle carnitine deficiency (restricted to muscle) is characterized by depletion of carnitine levels in muscle with normal serum concentrations. Evidence indicates that the causal factor is a defect in the muscle carnitine transporter.
In secondary carnitine deficiency, which is caused by other metabolic disorders (eg, fatty acid oxidation disorders, organic acidemias), carnitine depletion may be secondary to the formation of acylcarnitine adducts and the inhibition of carnitine transport in renal cells by acylcarnitines.
In disorders of fatty acid oxidation, excessive lipid accumulation occurs in muscle, heart, and liver, with cardiac and skeletal myopathy and hepatomegaly. Long-chain acylcarnitines also are toxic and may have an arrhythmogenic effect, causing sudden cardiac death.
Encephalopathy may be caused by the decreased availability of ketone bodies associated with hypoglycemia. Preterm newborns also may be at risk for developing carnitine deficiency because immature renal tubular function combined with impaired carnitine biosynthesis renders them strictly dependent on exogenous supplies to maintain normal plasma carnitine levels.
Valproic acid may cause an acquired type of secondary carnitine deficiency by directly impairing renal tubular reabsorption of carnitine. The effect on carnitine uptake and the existence of an underlying inborn error involving energy metabolism may be fatal; in other cases, it may primarily affect the muscle, causing weakness.
- In the US: No studies have estimated the incidence of primary carnitine deficiency in the United States. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, the most common fatty acid oxidation disorder and a cause of secondary carnitine deficiency, has been estimated to occur in 1 per 10,000 population of Northern European ancestry. In a study involving 165 children who were thought to be at risk for carnitine deficiency because of their presenting symptoms, 31% had positive test results.
- Internationally: In a Japanese study, primary systemic carnitine deficiency was estimated to occur in 1 per 40,000 births. No frequency has been estimated overall for secondary carnitine deficiency; however, in a prospective surveillance study conducted in the United Kingdom, MCAD deficiency was estimated to occur in 4.5 per 100,000 population.
- Sudden death: Unfortunately, the first clinical manifestation in asymptomatic individuals with primary carnitine deficiency may be sudden death. This also may occur in patients with secondary carnitine deficiency as a consequence of ventricular tachycardia or fibrillation.
- Heart failure: Patients with primary carnitine deficiency develop a progressive cardiomyopathy that usually presents at a later age. The cardiac function does not respond to inotropes or diuretics. If the condition is not diagnosed correctly and no carnitine is supplemented, progressive heart failure eventually leads to death. Heart failure caused by dilated cardiomyopathy may be the presenting syndrome in patients with secondary carnitine deficiency caused by defects in beta-oxidation, such as long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.
- Hypoglycemic hypoketotic encephalopathy: Acute encephalopathy accompanied by hypoketotic hypoglycemic episodes usually presents in younger infants with primary carnitine deficiency. Periods of fasting in association with viral illness trigger these acute episodes. Some patients have developmental delay and central nervous system dysfunction associated with these episodes. If no carnitine replacement is given, recurrent episodes of encephalopathy may ensue.
Race: Ethnic origins vary, and, in some families, consanguinity is present in cases of primary carnitine deficiency. Regarding fatty acid oxidation disorders as a cause of secondary carnitine deficiency, the most frequent cause of these disorders is MCAD deficiency, with an estimated frequency of 1 in 17,000 population of Northern European ancestry.
Sex: No sexual predilection exists for primary carnitine deficiency (an autosomal recessive disorder) or secondary carnitine deficiency.
- The mean age at onset for primary carnitine deficiency is 2 years, with onset ranging from 1 month to 7 years. Infants typically present with hypoketotic hypoglycemia, whereas older children present with skeletal or heart myopathy.
- Symptoms of muscle carnitine deficiency may appear early yet generally occur later (ie, second or third decade of life).
- In secondary carnitine deficiency caused by fatty acid oxidation disorders, the age of onset varies. Metabolic decompensation triggered by viral illness, associated with encephalopathy, and accompanied by liver involvement, hypotonia, or cardiomyopathy tends to occur in infancy. Cardiomyopathy or skeletal myopathy tends to present later. Carnitine deficiency also may occur in preterm newborns receiving total parenteral nutrition (TPN) with no carnitine supplementation.
- Primary carnitine deficiency
- One classic initial presentation of primary carnitine deficiency is hypoketotic hypoglycemic encephalopathy, accompanied by hepatomegaly, elevated liver transaminases, and hyperammonemia.
- Cardiomyopathy is the other classic presentation (affecting older children); onset may occur with rapidly progressive heart failure.
- Muscle weakness, the third manifestation of the disease, may accompany the heart failure or present by itself.
- Carnitine deficiency may be a cause of gastrointestinal dysmotility, with recurrent episodes of abdominal pain and diarrhea.
- Hypochromic anemia and recurrent infections are other manifestations of the disease.
- Muscle carnitine deficiency
- Severe reduction in muscle carnitine levels and normal serum carnitine concentrations characterize muscle carnitine deficiency. This disorder is restricted to muscle, with no renal leak of carnitine or signs of liver involvement.
- Symptoms of muscle carnitine deficiency can appear in the first years of life, but they may occur later during the second or third decade. Patients may experience proximal muscular weakness of varying degree, exercise intolerance, or myalgia.
- Secondary carnitine deficiency
- Fatty acid oxidation defects: Breastfed infants may experience a catabolic state shortly after birth, when the production of milk is not adequate to meet nutritional requirements. Acute metabolic decompensation with hypoketotic or nonketotic hypoglycemia usually occurs in infancy, whereas cardiac and skeletal muscle disease manifest later. The episodes of metabolic decompensation, triggered by fasting or common viral illness, consist of altered consciousness that can be complicated by seizures, apnea, or cardiorespiratory arrest. Patients may have a history of failure to thrive, developmental delay, or nonspecific abdominal problems.
- Patients with organic acidemias causing secondary carnitine deficiency may present with crises consisting of hypoglycemia, ketoacidosis, and hyperammonemia.
- Patients with respiratory chain defects or mitochondrial disorders and secondary carnitine deficiency may present with abnormal fatigability and lactic acidosis associated with exertion. These children also may present with encephalopathy and/or lipid storage myopathy and carnitine depletion. Carnitine deficiency has been observed in children with urea cycle defects, and it may exacerbate episodes of hyperammonemia.
- Carnitine deficiency in the preterm newborn: Signs and symptoms related to carnitine deficiency are not completely defined in the newborn. Apnea, cardiac death, and sudden death have been found in infants with carnitine depletion.
- Carnitine deficiency can develop in children with renal Fanconi tubulopathy; it may be idiopathic and present with renal tubular acidosis or secondary to acquired or inherited conditions.
- Carnitine deficiency may present in children being treated with valproic acid and may be associated with fulminant liver failure and presentation similar to that in Reye syndrome. It also may present with a myopathy and increased lipid storage in patients with AIDS who are being treated with zidovudine.
- In primary carnitine deficiency, physical findings may vary depending on the form of presentation.
- CNS: If the presentation is encephalopathy caused by hypoketotic hypoglycemia, the patient may present limp, unresponsive, and comatose after a prolonged fast. Pyramidal movements or minimal athetoid movements can persist after this type of presentation. Modest hepatomegaly also can be appreciated.
- Skeletal muscle: In the myopathic presentation, patients may have mild motor delays, hypotonia, or progressive proximal weakness.
- Cardiac muscle: Patients with primary carnitine deficiency may present with cardiomyopathy. Onset may occur with rapidly progressive heart failure or murmur. Cardiomegaly may be found on the physical examination, associated with the presence of a heart murmur. A gallop rhythm can be found, associated with a dilated cardiomyopathy.
- Muscle carnitine deficiency findings are limited to muscle and can be associated with proximal weakness and signs of exercise intolerance and cardiomyopathy.
- Secondary carnitine deficiency presents with clinical manifestations of fatty acid oxidation disorders.
- Episodes of metabolic decompensation triggered by infection or fasting may present with lethargy that may be accompanied by seizures or apnea.
- This encephalopathy also may present with hypotonia and hepatomegaly.
- Signs of cardiac hypertrophy may be evident, with gallop or heart murmur on the cardiac examination.
- Less frequently, these patients may have other findings, such as pigmentary retinopathy, peripheral neuropathy, cardiac arrhythmias, or myoglobinuria.
- Disorders such as glutaric aciduria type II or carnitine palmitoyltransferase II (CPT-II) deficiency can present with dysmorphic features, such as mid-facial hypoplasia and frontal bossing (Zellwegerlike phenotype) and congenital abnormalities of the abdominal wall.