CASE STUDY- CARNITINE DEFICIENCY

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 metabolise 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.

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

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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 acyl transferase 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.

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Pathogenesis

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 metabolise 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.

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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.

Diagnosis

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

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 highcarbohydrate, low-fat diet.