Elevated Acylcarnitine compounds and associated hypoglycemia- What is the defect?

Case details

A 5- year-old boy suffered gastroenteritis for two days and was brought to emergency in the semiconscious state. Blood glucose at the time of admission was 45 mg/dl and his urine was negative for glucose and ketone bodies. Glucose was administered intravenously and his condition improved within 10 minutes. Subsequent laboratory investigations revealed elevated acylcarnitine residues. The child was diagnosed with an enzyme deficiency. The parents were instructed to feed the child more frequently.

Which of the following enzymes might be deficient?

A. Acyl Co A synthetase

B. Carnitine Acyl transferase-1

C. Translocase

D. Carnitine Acyl transferase-2

E. Acyl co A dehydrogenase

The correct answer is-E- Acyl co A dehydrogenase.

In the given options-

Acyl co A synthetase catalyzes the activation of fatty acid to Fatty acyl co A. The activation of fatty acid is required prior to its oxidation in the mitochondrial matrix (figure-1).

Carnitine Acyl transferase-1(CAT-1), Translocase and Carnitine Acyl transferase-2(CAT-2) are the components of carnitine shuttle (figure-1) which is required for the transportation of fatty acyl co A across the inner mitochondrial membrane.

a) CAT-1 catalyzes the conversion of Acyl co A to Acyl carnitine.

b) Translocase transports acyl carnitine across the inner mitochondrial membrane in exchange for carnitine.

c) CAT-2 catalyzes the conversion of Acyl carnitine back to Acyl co A, the form that is required for the beta oxidation by the enzymes present in the mitochondrial matrix (figure-1)

Carnitine shuttle

Figure-1- Role of carnitine in the transport of long-chain fatty acids through the inner mitochondrial membrane. Long-chain acyl-CoA cannot pass through the inner mitochondrial membrane, but its metabolic product, acyl carnitine, can cross through with the help of carnitine shuttle. CPT (Carnitine palmitoyl transferase), is specific for Palmitic acid, which is the most abundant fatty acid, Acyl is a general term for a fatty acid.

Mitochondrial beta oxidation is a cyclic process. In each cycle, the fatty acyl co A is subjected to four chemical processes. Two carbons are removed  as Acetyl co A from the parent compound in each cycle. The chemical processes involved in each cycle are :

1) Dehydrogenation

2) Hydration

3) Dehydrogenation, and

4) Thiolytic cleavage.

These cycles are repeated, till the fatty acid is completed broken down to final two carbon compounds.

Acyl co A dehydrogenase  is the first enzyme in the cyclic process of beta oxidation. It catalyzes the conversion of acyl co A to α,β Unsaturated Acyl co A or Δ2 trans enoyl co A (figure-2).


Steps of beta oxidation

Figure-2 – Long-chain acyl-CoA is cycled through reactions 2–5, each time acetyl-is split off through each cycle, by thiolase (reaction 5). When the acyl radical is only four carbon atoms in length, two acetyl-CoA molecules are formed in reaction 5.

There are chain specific acyl co A dehydrogenases- Short chain, medium and long chain acyl co A dehydrogenases.

The deficiency of Acyl co A dehydrogenase causes impairment of beta oxidation of fatty acids.

The impaired fatty acid oxidation results in impaired synthesis of ketone bodies, thus the body has to fulfill the energy demands through glucose. The glucose requirement is increased, and it is the imbalance between the demand and supply of glucose that leads to hypoglycemia in acyl co A dehydrogenase deficiency.

Due to the similar reasons, the hypoglycemia is also observed in the carnitine deficiency. In that case it is impaired internalization of fatty acids across the inner mitochondrial membrane that leads to inhibition of fatty acid oxidation.

In the present clinical state, since there is elevation of acylcarnitine compounds, the deficiency of Acyl co A synthetase and the components of carnitine shuttle can be ruled out, the most probable cause of hypoglycemia is deficiency of acyl co A dehydrogenase.

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