Carnitine Deficiency

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Background

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.

Pathophysiology

Primary carnitine deficiency is caused by a deficiency in the plasma membrane carnitine transporter, with urinary carnitine wasting causing systemic carnitine depletion.[1] 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) is also 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).

SLC22A5 mutations can affect carnitine transport by impairing maturation of transporters to the plasma membrane.[2]

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 CNS, 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 are also 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.

Epidemiology

Frequency

United States

No studies have estimated the incidence of primary carnitine deficiency in the United States, however; it may be similar to the incidence in Japan from the cases already reported.

International

In a Japanese study, primary systemic carnitine deficiency was estimated to occur in 1 per 40,000 births.[3] In Australia, the incidence has been estimated to be between 1:37,000-1:100,000 newborns. The frequency of this condition in adults is not known. However, in the United Kingdom, a previous report identified 4 affected mothers in 62,004 infants screened, with a frequency of 1:15,500.

Mortality/Morbidity

In order to abate the mortality and morbidity of undiagnosed primary carnitine deficiency, this condition has been included in the expanded newborn screening program in several states within the United States.[4] Primary carnitine deficiency can be identified in infants by expanded newborn screening using tandem mass spectrometry.[5] Low levels of free carnitine (C0) are detected. However, low carnitine levels in newborns may also reflect maternal primary carnitine deficiency.

A significant cohort of patients with primary carnitine deficiency do not present in infancy or early childhood as previously thought but remain asymptomatic into adulthood. These observations are derived from the experience of expanded newborn screening programs that identified maternal primary carnitine deficiency in mothers who were for the most part minimally symptomatic or asymptomatic. One mother with primary carnitine deficiency was reported to have a history of syncope that worsened during pregnancy, when plasma carnitine levels are physiologically lower.[6]

Race

Overall, this disorder is panethnic, and, in some families, consanguinity is present in cases of primary carnitine deficiency.

Sex

No sex predilection is observed in primary carnitine deficiency.

Age

The mean age at onset for primary carnitine deficiency not detected or ascertained by a newborn screening program 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.

History

The following may be associated with carnitine deficiency:

Physical

The following may be associated with carnitine deficiency:

Causes

Causes of carnitine deficiency include the following:

Laboratory Studies

If the patient is suspected of having primary carnitine deficiency or other metabolic disorders associated with secondary carnitine deficiency and is presenting with a metabolic emergency, the following studies are indicated:

Imaging Studies

The following imaging studies may be indicated:

Other Tests

The following other tests may be indicated:

Procedures

Skin biopsy can be performed to confirm diagnosis of primary carnitine deficiency by demonstrating reduced carnitine transport in fibroblasts that express the transporter. Fibroblasts may be used for fatty acid oxidation studies or enzyme assay. However, with the clinical availability of SLC22A5 sequencing, it may not be strictly necessary to perform a skin biopsy for the transport assay on cultured fibroblasts.

Muscle biopsy may be necessary to confirm the diagnosis of some conditions that may cause secondary carnitine deficiency (eg, respiratory chain defect) or to measure the carnitine concentration in muscle in cases of myopathic carnitine deficiency.

Histologic Findings

Biopsy of the liver may show microvesicular lipid steatosis that, along with the rest of the clinical picture, may lead to a diagnosis of Reye syndrome. If muscle biopsy is performed, very low fatty infiltration may be seen.

Medical Care

In infants with carnitine deficiency ascertained via newborn screen program, oral carnitine supplementation is followed by a slow increase of plasma carnitine levels. If the infants’ levels reflect maternal primary carnitine deficiency, the rise in plasma levels is fast and this should prompt the work-up towards the diagnosis of maternal primary carnitine deficiency. Guidelines for the management of carnitine deficiency and other fatty acid mitochondrial disorders have been established.[12]

Consultations

The following consultations may be indicated:

Diet

The following may be indicated in patients with carnitine deficiency:

Activity

The following may be noted in patients with carnitine deficiency:

Medication Summary

Use of L-carnitine in primary carnitine deficiency restores plasma carnitine levels to nearly normal, but muscle carnitine levels rise slightly. Muscle function can be normalized in patients with carnitine deficiency when muscle carnitine levels remain less than 10% of controls. Cardiomyopathy often responds well to carnitine supplementation. Carnitine supplementation in fatty acid oxidation disorders and other organic acidurias is to correct carnitine deficiency and to allow removal of toxic intermediates. The other goal of therapy is to restore CoA levels. Carnitine therapy for long-chain fatty acid oxidation defects has become questionable because it promotes formation of long-chain acylcarnitines that may cause arrhythmogenesis and membrane dysfunction. Carnitine supplementation in total parenteral nutrition (TPN) prevents secondary carnitine deficiency in preterm newborns.

Levocarnitine (Carnitor, L-Carnitine)

Clinical Context:  An amino acid derivative synthesized from methionine and lysine, required in energy metabolism. Can promote excretion of excess fatty acids in patients with defects in fatty acid metabolism or specific organic acidopathies, which bioaccumulate acyl CoA esters. Normal levels occur in liver, and mild level increases occur in skeletal muscle. May cause reversal of skeletal and heart muscle abnormalities.

Dextrose (D10W, D-glucose)

Clinical Context:  Monosaccharide absorbed from intestines and distributed, stored, and used by tissues.

Parenterally injected dextrose is used in patients unable to sustain adequate PO intake. Direct PO absorption results in a rapid increase in blood glucose concentrations. Dextrose is effective in small doses. Concentrated dextrose infusions provide higher amounts of glucose and increased caloric intake in a small volume of fluid.

Riboflavin (Vitamin B-2)

Clinical Context:  Essential in activation of pyridoxine and conversion of tryptophan to niacin; component of flavoprotein enzymes, which are necessary for tissue respiration. Riboflavin functions as a cofactor for electron transport in complex I, complex II, and in the electron transfer of flavoprotein. It has proven useful for the treatment of some patients with SCAD deficiency, riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency, and milder forms of glutaric aciduria type II.

Betaine (Cystadane)

Clinical Context:  Methyl group donor used in the treatment of homocystinuria. Decreases elevated homocysteine blood levels. Used for conditions that can cause hyperhomocysteinemia and secondary carnitine deficiency (ie, cobalamin C deficiency).

Hydroxocobalamin (Vitamin B-12, Hydro cobex)

Clinical Context:  Deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B-12 in humans. Vitamin B-12 synthesized by microbes but not humans or plants. Vitamin B-12 deficiency may result from intrinsic factor deficiency (pernicious anemia), partial or total gastrectomy, or diseases of the distal ileum. Used to treat conditions caused by altered cobalamin metabolism that may cause secondary carnitine deficiency (ie, cobalamin C deficiency).

Ubidecarenone (CoQ-10, Coenzyme Q, Ubiquinone)

Clinical Context:  Coenzyme involved in mitochondrial energy production. Controls flow of oxygen within individual cells. Has essential antioxidant and membrane-stabilizing properties.

Glycine (Aminoacetic acid)

Clinical Context:  The simplest amino acid that helps improve glycogen storage is used in the synthesis of hemoglobin, collagen, and glutathione, and it facilitates the amelioration of high blood fat and uric acid levels. Glycine is primarily used for the treatment of isovaleric acidemia, which is an organic acidemia that causes secondary carnitine depletion.

Biotin

Clinical Context:  Water-soluble vitamin, generally classified as a B-complex vitamin. An essential coenzyme in fat metabolism and in other carboxylation reactions. Used for the treatment of biotin responsive propionic acidemia, which can lead to secondary carnitine deficiency.

Class Summary

At high doses, L-carnitine corrects severe carnitine depletion and associated metabolic abnormalities observed in primary carnitine deficiency and enables the production of ketone bodies during fasting. In secondary carnitine deficiency, carnitine enhances excretion of toxic metabolites and generation of free CoA.

Further Inpatient Care

Admit patients with carnitine deficiency for medical management of acute metabolic decompensation.

Prescribe 10% dextrose in water at rates of 10 mg/kg/min or higher to achieve normal glucose concentrations. If the rate of glucose infusion is based on blood glucose level alone, it may underestimate carbohydrate demand because tissues are depleted of glycogen stores.

Provide intravenous (IV) carnitine if the patient is known to have carnitine deficiency and a defect affecting the oxidation of long chain fatty acids has been excluded.

Further Outpatient Care

Carefully monitor adequate carnitine dose in primary and secondary carnitine deficiencies by evaluating plasma carnitine levels during follow-up visits. Carefully review diet compliance in secondary carnitine deficiency, considering avoidance of fasting, intake of fat-restricted, high-carbohydrate diet, and other dietary supplements that may be needed, such as riboflavin or glycine. Treat infections aggressively.

Inpatient & Outpatient Medications

Medications include carnitine for primary and secondary carnitine deficiency, as well as other cofactors that may be needed for different conditions associated with secondary carnitine deficiency (eg, riboflavin, coenzyme Q, biotin, hydroxocobalamin, betaine, glycine). If a seizure disorder has developed secondary to a past episode of hypoglycemia, valproic acid should not be used as an anticonvulsant.

Transfer

Patients may require transfer to a tertiary care center in which a more specialized metabolic workup for further diagnostic evaluation can be performed.

Deterrence/Prevention

The following are indicated in patients with carnitine deficiency:

Complications

The following complications may occur:

Prognosis

The prognosis of patients with carnitine deficiency is as follows:

Author

Fernando Scaglia, MD, FACMG, Associate Professor of Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Christian J Renner, MD, Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany

Disclosure: Nothing to disclose.

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lois J Starr, MD, FAAP, Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center; Director of the Multidisciplinary Diagnostic Autism Clinic, Clinical Geneticist, Craniofacial Clinic, Children's Hospital and Medical Center

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Disclosure: Nothing to disclose.

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