Acetylcholinesterase (Ache) Deficiency - Causes, Symptoms, Diagnosis, Treatment

What Is Acetylcholinesterase (AChE)?

It is a cholinergic enzyme found at the postsynaptic neuromuscular junction of muscles and glands. The term cholinergic enzyme is used for a substance that hydrolyzes (breaks down) acetylcholine-a neurotransmitter. AChE is responsible for terminating neuronal transmission and signaling by breaking down acetylcholine.

Acetylcholine is an excitatory neurochemical released by the neurons in the brain and acts as a chemical message. The neurons use it to communicate with one another and with specialized cells of the muscles and glands, which in turn stimulates them to perform a number of physiological functions like intestinal peristalsis, glandular secretion, regulating heartbeat, etc.

Although acetylcholine plays a key role in the above-mentioned functions, its mode of action is regulated by the body with the help of AChE, because if left uninhibited it will continuously excite the muscles and glands leading to conditions like cramps, muscular weakness, paralysis, etc.

AChE terminates the transmission of acetylcholine at the neuromuscular junction (junction between the terminal end of the nerve and a muscle or gland) by hydrolyzing it into acetic acid and choline.

AChE is present at all cholinergic junctions, it is bound to the basement membrane in the synaptic clefts (space between the nerve terminal and the plasma membrane of the muscle) where it hydrolyses and releases acetylcholine. The deficiency of this enzyme will lead to a cholinergic crisis that will cause life-threatening conditions.

What Causes Deficiency of Acetylcholinesterase (AChE)?

It is a rare occurrence and when present is always mistaken for myasthenia gravis-which is also a neuromuscular condition with a different cause but similar symptoms. AChE deficiency can be present at birth or can be acquired, based on this is divided into two types:

• Congenital End-Plate Deficiency - This is a genetic condition that is present since birth, the individual will have no or reduced AChE due to mutations in the gene COLQ or COL13A1.

Mutations are changes in the structure of a gene that will deviate the gene from expressing its normal traits. The amount of AChE deficiency caused due to mutations in the COLQ and COL13A1 genes varies from patient to patient.

Often patients born with AChE deficiency are coupled with other genetic conditions with similar symptoms under the name congenital myasthenia syndrome. It is an umbrella term that contains conditions characterized by muscle weakness that worsen with physical exertion.

• Acquired or Relative AChE deficiency- This is a reversible condition where the individual has a normal plasma AChE (4000 units/liter to 13500 units/liter), but the deficiency is the result of excess AChE inhibitors in the bloodstream.

The common clinical conditions with the excess presence of AChE inhibitors are:

1. Overmedication With AChE Inhibitors - Certain medications are given as part of the treatment for conditions like myasthenia gravis and Alzheimer's to inhibit the action of AChE. These medications are known as acetylcholinesterase inhibitors (AChEI).

Some of the well-known AChEI prescribed for myasthenia gravis are Edrophonium, Neostigmine, Pilocarpine, etc, and for Alzheimer’s are Rivastigmine and Donepezil.

Excess use of these AChEI for the treatment of both conditions will lead to a cholinergic crisis (excess acetylcholine).

2. Exposure to Organophosphates - Organophosphates are naturally occurring AChEI which are extensively used in pesticides, insecticides, herbicides, and as nerve gas.

These enter the body by inhalation (vapors of the nerve gas), ingestion (of food containing pesticides and insecticides), or by direct contact with the chemical with the skin or mucus membrane.

Examples of such chemicals are Sarin (nerve gas), Malathion (insecticide), Carbamate (pesticide), etc.

These compounds inhibit the action of AChE leading to excess stimulation of nicotinic and muscarinic receptors by acetylcholine causing nausea, vomiting, bronchospasm, miosis, blurry vision, etc.

3. Reversal of Neuromuscular Blockage - In patients with convulsion or electric shock, the clinician will prescribe nondepolarizing agents like Vecuronium, Rocuronium, etc to interrupt transmission by essentially blocking the neuromuscular junction.

Once the patient has stabilized, to reverse the effects of these nondepolarizing agents, a reversal agent like Neostigmine or Pyridostigmine is given which are essentially AChE inhibitors. If given in excess doses, it will also lead to relative AChE deficiency.

What Are the Symptoms of AChE Deficiency?

Symptoms are nonspecific and are similar to myasthenia gravis, some of them are:

• General muscle weakness.

• Slow pupillary light response.

• Respiratory distress and dysphagia.

• Recurrent apnea triggered by infections.

• Bilateral nonfatigable ptosis.

• Marked axial weakness.

• Eye miosis and blurry vision.

• Flaccid paralysis.

• Tachycardia progress to bradycardia.

• Nausea, vomiting, and diarrhea.

• Urinary frequency and urgency.

• Seizures.

• Coma.

• Ataxia.

• Agitation and restlessness.

• Ataxia and slurred speech.

If the underlying cause of the deficiency is congenital there is no guarantee that the symptoms will be present at the birth of the patient, depending on the extent of the mutation they can manifest at birth or as late as their thirties.

How Is AChE Deficiency Treated?

Treatment depends on the cause of the deficiency, for congenital end-plate AChE deficiency, Ephedrine, and Albuterol have shown promising results, however, if the symptoms are severe and indicative of a cholinergic crisis, the treatment is mentioned below:

• Emergency Management - The core principle is stabilization by ABC (airway, breathing, and circulation). Care should be taken that the airway is patent and the patient is breathing spontaneously. Intravenous fluid should be started immediately to maintain adequate circulation and the patient should be monitored for stable vital signs

• Inpatient Management - This is done to reduce the effects of excess acetylcholinesterase inhibitors which automatically will increase the availability of AChE. The drug of choice is either Pralidoxime or Obidoxime. They act as molecular crowbars that separate the bonded nerve gas, organophosphate, and other AChEI from the acetylcholinesterase.

The separated AChE can then continue the process of chemical breakdown of the neurotransmitter acetylcholine. Pralidoxime should be given to patients with signs of respiratory muscle weakness until there is an improvement. The downside of this drug is it does not cross the blood-brain barrier, so it does not neutralize the organophosphate poisoning effect in the central nervous system, however, this can be neutralized with Atropine.

Conclusion:

Diagnosis of AChE deficiency is difficult because the symptoms of AChE deficiency mimic myasthenia gravis. The clinician should run comprehensive investigations before treatment to prevent mismanagement. This includes a physical examination, laboratory testing, and molecular genetic testing. Once the diagnosis is established, it is important that the patient and their family members receive genetic counseling if the deficiency is congenital which will help them to understand the nature, mode of inheritance, and implications of the genetic disorder.