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A teenage girl was brought to the medical centre because of her complaints that she used to get too tired when asked to participate in gym classes. A consulting neurologist found muscle weakness in girl’s arms and legs. When no obvious diagnosis could be made, biopsies of her muscles were taken for test.

Biochemistry revealed greatly elevated amounts of triglycerides  esterified with primary long chain fatty acids. Pathology reported the presence of significant numbers of lipid vacuoles in the muscle biopsy

What is the probable diagnosis?

What is the cause for these symptoms?

Case details

The most likely cause of these symptoms is carnitine deficiency.

Carnitine deficiency

 The amino acid carnitine is required for the transport of long-chain fatty acyl coenzyme  esters into myocyte mitochondria, where they are oxidised for energy. Carnitine is obtained from foods, particularly animal-based foods, and via endogenous synthesis.

Carnitine deficiency results from inadequate intake of or inability to metabolize the amino acid carnitine. It can cause a heterogeneous group of disorders. Muscle metabolism is impaired, causing myopathy, hypoglycemia, or cardiomyopathy.Infants typically present with hypoglycemic, hypoketotic encephalopathy. Most often, treatment consists of dietary l-carnitine.





Basic concept

Fatty acids are activated on the outer mitochondrial membrane, whereas they are oxidised in the mitochondrial matrix. The activation is brought by converting the fatty acid into Acyl co A ester under the activity of Acyl co A synthetase (1). A special transport mechanism is needed to carry long-chain acyl CoA molecules across the inner mitochondrial membrane.Activated long-chain fatty acids are transported across the membrane by conjugating them to carnitine. The acyl group is transferred from the sulphur atom of CoA to the hydroxyl group of carnitine to form acyl carnitine. This reaction is catalysed by carnitine acyl transferase I (also called carnitine palmitoyl transferase I), which is bound to the outer mitochondrial membrane.(2)

Acyl carnitine is then shuttled across the inner mitochondrial membrane by a translocase. (3)

 The acyl group is transferred back to CoA on the matrix side of the membrane. This reaction, which is catalyzed by carnitine acyltransferase II (carnitine palmitoyl transferase II) (4),  is simply the reverse of the reaction that takes place in the cytosol.

Finally, the translocase returns carnitine to the cytosolic side in exchange for an incoming acyl carnitine (See figure).


Figure showing the role of carnitine in transporting the activated fatty acids in to the mitochondria.


A number of diseases have been traced to a deficiency of carnitine, the transferase or the translocase. The symptoms of carnitine deficiency range from mild muscle cramping to severe weakness and even death.The muscle, kidney, and heart are the tissues primarily affected. Muscle weakness during prolonged exercise is an important characteristic of a deficiency of carnitine acyl transferase because muscle relies on fatty acids as a long-term source of energy. Medium-chain (C8-C10) fatty acids, which do not require carnitine to enter the mitochondria, are oxidised normally in these patients. These diseases illustrate that the impaired flow of a metabolite from one compartment of a cell to another can lead to a pathological condition.

Causes of carnitine deficiency

Causes of carnitine deficiency include the following:

·        Inadequate intake (e.g., due to fad diets,lack of access, or long-term TPN)

·        Inability to metabolize carnitine due to enzyme deficiencies (e.g., carnitine palmitoyl Transferase deficiency.

·        Decreased endogenous synthesis of carnitine due to a severe liver disorder

·        Excess loss of carnitine due to diarrhoea,diuresis, or hemodialysis

·        A hereditary disorder in which carnitine leaks from renal tubules (Primary carnitine deficiency)

·        Increased requirements for carnitine when ketosis is present or demand for fat oxidation is high (eg, during a critical illness such as    sepsis or major burns; after major surgery of the GI tract)

·        Decreased muscle carnitine levels due to mitochondrial impairment

Primary Carnitine deficiency The underlying defect involves the plasma membrane sodium gradient–dependent carnitine transporter that is present in heart, muscle, and kidney. This transporter is responsible both for maintaining intracellular carnitine concentrations 20- to 50-fold higher than plasma concentrations and for renal conservation of carnitine.Primary carnitine deficiency has an Autosomal recessive pattern of inheritance.Mutations in the gene lead to the production of defective carnitine transporters. As a result of reduced transport function, carnitine is lost from the body and cells are not supplied with an adequate amount of carnitine.

Clinical manifestations of Carnitine deficiency

 Symptoms and the age at which symptoms appear depend on the cause. Carnitine deficiency may cause muscle necrosis, myoglobinuria, hypoglycemia, fatty liver, muscle aches, fatigue, and cardiomyopathy.

 1) The most common presentation is progressive cardiomyopathy with or without skeletal muscle weakness beginning at 2–4 yr of age.Energy deprived muscle cells are damaged.

 2) A smaller number of patients may present with fasting hypoketotic hypoglycemia during the 1st yr of life before the cardiomyopathy becomes symptomatic.Blockage of the transport of long chain fatty acids into mitochondria deprives the patient of energy production, as the fatty acid oxidation is impaired; all the energy needs are fulfilled by glucose oxidation. The resultant imbalance between demand and supply causes hypoglycemia. The compensatory ketosis in carnitine  induced hypoglycemia is not observed as the precursor, Acetyl co A is not available for ketone body production. The main source of Acetyl co is fatty acid oxidation  and that is impaired in carnitine deficiency.

3) Serious complications such as heart failure, liver problems, coma, and sudden unexpected death are also a risk.

Deficiencies in the Carnitine Acyl Transferase enzymes I and II can cause similar symptoms.


1)  Diagnosis of the carnitine transporter defect is aided by the fact that patients have extremely reduced carnitine levels in plasma and muscle (1–2% of normal).

2)  Fasting ketogenesis may be normal if liver carnitine transport is normal, but it may be impaired if dietary carnitine intake is interrupted.

3)  Hypoglycemia is a common finding. It is precipitated by fasting and strenuous exercise.

4) Muscle biopsy reveals significant lipid vacuoles.


Treatment of this disorder with pharmacological doses of oral carnitine is highly effective in correcting the cardiomyopathy and muscle weakness as well as any impairment in fasting ketogenesis. All patients must avoid fasting and strenuous exercise. Some patients require supplementation with medium-chain triglycerides and essential fatty acids (eg, Linoleic acid, Linolenic acid). Patients with a fatty acid oxidation disorder require a high-carbohydrate, low-fat diet.

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