Carnitine deficiency has a variable presentation depending on the cause of the disease. Some common manifesting signs, symptoms and processes include hypoglycemia, fatty liver disease, hyperammonemia associated with muscle pain, altered mental status, cardiomyopathy open link, fatigue and muscle abnormalities that include necrosis, myoglobinuria and myopathy.

Primary carnitine deficiency may be completely asymptomatic or can sometimes present acutely with sudden death. Patients can be generally categorized into two subtypes, those presenting with mainly hypoglycemia and those who are more likely to develop cardiomyopathy. Muscular pathology can occur in both subtypes. In addition, early signs and symptoms include but are not restricted to heart enlargement, cardiomyopathy, depletion of carnitine in tissue and the plasma, high levels of carnitine in the urine, hypoketotic hypoglycemia as well as muscle pathology manifesting with weakness.

Screening for primary carnitine deficiency can be established right after birth. Infants with the disease exhibit decreased levels of carnitine and other associated compounds such as acylcarnitine [9]. Nonetheless, it is important to point out that decreased levels of carnitine do not necessarily underline primary carnitine deficiency. They may be caused by secondary factors such as a deficiency in maternally transferred carnitine. Patients who are found to have low carnitine levels necessitate good follow-up and monitoring. The latter includes the performance of appropriate laboratory testing on the mother to identify any possible carnitine deficiency as well as the cause of the deficiency. It is interesting to note that maternal carnitine deficiency can be completely asymptomatic in the mother and was found to be more common than initially expected. In some cases, heart problems affecting the mother have been identified after the screening of the newborns. It remains unknown whether asymptomatic individuals diagnosed with the condition require the same level of treatment as symptomatic patients who were diagnosed early in their lives.

Diagnosis of carnitine deficiency depends on the age of the patient and the type of deficiency. Diagnosis of carnitine palmitoyltransferase deficiency is established with mass spectrometry. Prenatal diagnosis can also be preformed through sampling of fetal cells present in the amniotic fluid. In adults, the condition can be diagnosed by measuring the serum, urinary and tissue levels of acylcarnitine. In systemic deficiency, carnitine levels are low both in the muscle and in the liver whereas in myopathic deficiency, carnitine is only decreased in the muscle.

Treatment of carnitine deficiency varies, depending on the age of the patient and the subtype of the disease. Diagnosed newborns are generally treated with oral carnitine therapy. This is usually followed by a gradual elevation of carnitine levels in the plasma. Rapid and sudden elevations of serum carnitine may indicate that the underlying cause is of maternal origin and should prompt the physician to investigate the presence of the disease in the mother [10].

Diagnosis and management does not necessitate inpatient admission, unless in case there is a sudden and acute deterioration. Patients may then be admitted for urgent laboratory testing, treatment and stabilization. Hypoketotic hypoglycemic encephalopathy is a particularly urgent medical condition that requires the stabilization of the patient. This is achieved by an intravenous infusion of 10% dextrose in water, given at a rate of 10 mg/kg/min. The rate of the infusion needs to be adjusted depending on the concentrations of glucose in the blood.

In addition to oral therapy, carnitine supplementation through the intravenous route may also be necessary, especially in primary carnitine deficiency. This provides urgent assistance in fatty acid transport to the mitochondria. It also aids the body in getting rid of toxic compounds such as carnitine esters. IV carnitine administration is generally not recommended in patients suffering from carnitine deficiency subsequent to abnormalities in fatty acid oxidation. In fact, this treatment may lead to the accumulation of acylcarnitines, with potential arrhythmogenic effect. Patients diagnosed with organic acidemias such as isovaleric acidemia, methylmalonic acidemia and propionic acidemia and who are unable to tolerate oral supplementation with carnitine also benefit from treatment with IV carnitine.

In addition to carnitine supplementation, patients may require treatment for the various complications of the disease, particularly those involving the heart. Nonetheless, oral carnitine therapy can on its own improve the function of the heart as well as other processes such as intellectual ability, growth and fasting ketogenesis.

Secondary carnitine deficiency is approached in a dual fashion to first target carnitine depletion and then limit the damage of the underlying primary metabolic abnormality by instituting a specific diet. Patients should be very strongly recommended to avoid any sort of fasting. It may also be helpful to include in the physician team a nutritionist and a genetic counselor.
Diet modification is not necessary in primary carnitine deficiency, although patients are still required to avoid any fasting period. On the other hand, patients diagnosed with metabolic abnormalities in fatty acid oxidation necessitate a diet that is poor in fat and rich in carbohydrates. Only 30% of total calories should be generated from fat digestion. Patients are also advised to eat frequent meals. Other important dietary advice includes supplementation with medium-chain triglycerides and linoleic acids and ingestion of uncooked cornstarch before sleeping. Essential fatty acid supplementation is important in preventing skin abnormalities as well as in improving growth. Carbohydrate intake before bedtime can help in reducing morning hypoglycemia.

Dietary modifications in other forms of carnitine deficiency depend on the type of the disease. For example, patients are recommended to avoid specific protein products in certain organic acidemias and aminoacidopathies.

It is generally not recommended to limit physical activity in patients with primary carnitine deficiency undergoing treatment, particularly when there are noticeable improvements in heart function and overall growth and strength. On the other hand, patients with a secondary carnitine deficiency due to fatty acid oxidation metabolic abnormalities generally necessitate a reduction of physical activity in particular circumstances. Patients diagnosed with CPT-II deficiency or very long-chain acyl-CoA dehydrogenase deficiency are at a higher risk for rhabdomyolysis and myoglobinuria, and thus require decreased strenuous activity. In addition, patients with long-chain 3-hyroxyacyl-CoA dehydrogenase (LCHAD) deficiency and VLCAD deficiency are more prone to cardiomyopathies and may also require less physical activity.

In general, all patients with carnitine deficiency are advised to avoid very strenuous exercise and keep excellent hydration when performing physical activity.

Prognosis for primary carnitine deficiency is excellent for patients who are on carnitine therapy. Nonetheless, untreated disease can lead to severe complications such as arrhythmias, heart failure or sudden death. It is important for patients to commit to their treatment for the duration of their lives as noncompliance at any stage can result in severe hypoglycemia and sudden death due to arrhythmia, even in the absence of cardiomyopathy.

Prognosis for secondary carnitine deficiency is dependent on the underlying cause. Treatment is usually completely inefficient in patients suffering from translocase deficiency or carnitine palmitoyltransferase II deficiency that particularly targets infants [8]. Secondary carnitine deficiency caused by metabolic abnormalities in fatty acid oxidation necessitates changes in diet and avoidance of any fasting for the entirety of the patient's life. Organic acidemias also require supplementation with the appropriate minerals and nutrients and diet modifications to avoid the intake of harmful materials.

Carnitine deficiency can be categorized into primary, secondary or muscular deficiency. Primary carnitine deficiency is caused by a mutation in the SLC22A5 gene, with subsequent defective OCTN2 transport channel.

On the other hand, secondary carnitine deficiency can result from a number of causes, including genetic, iatrogenic and environmental factors. The most common form involves a defect in fatty acid oxidation.

Some forms of carnitine deficiency are restricted to muscular tissue. These are associated with a significant decrease in the levels of carnitine only in the muscle. The biochemical processes underlying such deficiency are still unknown.

Incidence of primary carnitine deficiency in the United States is still undetermined, although it is thought to be similar to Japan's, where it is found at a rate of 1 in 40,000 births [1]. Mortality and morbidity have significantly improved with the institution of regular screening procedures with tandem mass spectrometry in newborns [2] [3]. Although the disorder is more commonly diagnosed among children, it can be also encountered in adults [4]. Carnitine deficiency is not associated with any particular gender predilection but can be particularly common among subpopulations due to consanguinity and genetic isolation. For example, incidence in the Faroe Islands can reach 1:200 [5].

Primary carnitine deficiency results from an abnormal carnitine transport protein and affects especially kidney and muscle tissue. An absence of a transport protein results in greater excretion of carnitine in the urine and reduced concentrations within the cells [6]. This eventually leads to disruption of critical biochemical pathways such as pyruvate oxidation, metabolism of amino acids and the Krebs cycle [7].

Secondary carnitine deficiency, on the other hand, can be caused by a multitude of factors. Abnormalities within the metabolic pathway of fatty acid oxidation are the main contributors. In particular, fatty acid oxidation blockage results in the buildup of acyl-CoA compounds. This is turn leads to excessive esterification of carnitine and the formation of acylcarnitine. Acylcarnitines are then excreted into the urine and lead to a decrease in carnitine entry into kidney cells through the transporter protein. The ultimate result is a depletion of cellular carnitine levels.

Genetic conditions such as Lowe Syndrome and cystinosis that are linked with Fanconi syndrome can also present with a secondary deficiency in carnitine. This is largely due to excessive excretion of carnitine. Furthermore, intolerance to lysine can result in elevated lysine levels in the urine, decreasing the systemic levels of lysine and consequently carnitine, as the latter is required for the biosynthesis of carnitine. Diseases that may also be associated with carnitine deficiency include methylmalonic acidemia, propionic acidemia and defects within the respiratory chain.

Although treatment can prevent the occurrence of many complications of carnitine deficiency, the disease itself is not preventable. In general, it is important to avoid fasting and strenuous exercise, treat infections vigorously and assure good hydration.

Carnitine deficiency is a metabolic disorder that mainly manifests itself with low levels of carnitine. It can be primary or secondary. Primary carnitine deficiency is caused by a defective membrane transport protein due to a genetic mutation. Secondary carnitine deficiency has a multitude of causes that include various metabolic and iatrogenic conditions. With the advance of screening methods, patients are usually diagnosed at birth although some may be diagnosed later in life or incidentally. If untreated, carnitine deficiency can lead to growth failure, severe hypoglycemia, hyperammonemia and muscular weakness. The heart is particularly at risk and its involvement may lead to heart failure, arrhythmias and even sudden death. Treatment depends on the underlying cause but all forms of carnitine deficiency require supplementation with carnitine. Other recommendations include an avoidance of fasting and very strenuous physical activity. Some forms of carnitine deficiency may also require additional supplementation and a special diet.

Carnitine deficiency is a condition in which the quantity of carnitine, a small compound that participates in the biochemical reactions within the cell, is depleted in the body. Carnitine plays a very important role in energy metabolism and its absence can disrupt the normal body functioning. Primary carnitine deficiency is a genetic disorder caused by an absence of a protein that is normally present on the external membrane of the cell. This protein helps in transporting carnitine to the inside of the cell. Patients usually are screened at birth, although some may present signs very late in life, either due to a sudden appearance of symptoms or accidental diagnosis. Without treatment, patients can develop serious complications in various organ systems. The heart is especially targeted and its involvement can lead to heart failure and disruption of its electrical rhythm, which may sometimes result in sudden death. Carnitine deficiency is treated with oral carnitine supplementation, although some forms of the disease require IV therapy or supplementation with other compounds. Patients are generally advised to avoid fasting and very strenuous physical activity.

1. Koizumi A, Nozaki J, Ohura T, et al. Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency. Hum Mol Genet. 1999 Nov; 8(12):2247-54. 
2. Schimmenti LA, Crombez EA, Schwahn BC, Heese BA, Wood TC, Schroer RJ. Expanded newborn screening identifies maternal primary carnitine deficiency. Mol Genet Metab. 2007 Apr;90(4):441-5.
3. Wilcken B, Wiley V, Sim KG, Carpenter K. Carnitine transporter defect diagnosed by newborn screening with electrospray tandem mass spectrometry. J Pediatr. 2001 Apr; 138(4):581-4. 
4. Vijay S, Patterson A, Olpin S, Henderson MJ, Clark S, Day C. Carnitine transporter defect: diagnosis in asymptomatic adult women following analysis of acylcarnitines in their newborn infants. J Inherit Metab Dis. 2006 Oct; 29(5):627-30.
5. Lund AM, Joensen F, Hougaard DM, et al. Carnitine transporter and holocarboxylase synthetase deficiencies in The Faroe Islands. J Inherit Metab Dis. 2007 Jun;30(3):341-9.
6. Magoulas PL, El-Hattab AW. Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2012 Sep 18; 7(1):68. 
7. Tamai I. Pharmacological and pathophysiological roles of carnitine/organic cation transporters (OCTNs: SLC22A4, SLC22A5 and Slc22a21). Biopharm Drug Dispos. 2013 Jan;34(1):29-44.
8. Angelini C, Semplicini C. Metabolic myopathies: the challenge of new treatments. Curr Opin Pharmacol. 2010 Mar 29. Curr Opin Pharmacol. 2010 Jun;10(3):338-45.
9. Lee NC, Tang NL, Chien YH, et al. Diagnoses of newborns and mothers with carnitine uptake defects through newborn screening. Mol Genet Metab. 2010 May;100(1):46-50.
10. Angelini C, Federico A, Reichmann H, Lombes A, Chinnery P, Turnbull D. Task force guidelines handbook: EFNS guidelines on diagnosis and management of fatty acid mitochondrial disorders. Eur J Neurol. 2006 Sep; 13(9):923-9.