Have you ever heard of metabolic disorders? Metabolism is the process where our body breaks down substances we consume as food (fats, carbohydrates, and proteins), into their basic units and utilises them for energy. This happens in the form of thousands of reactions catalysed by specialised proteins called enzymes. Each enzyme is highly specific to the reaction it catalysed. MCAD is one such enzyme. 

MCAD deficiency is an inherited disorder where the body produces less of an enzyme called MCAD (Medium-Chain Acetyl-Coenzyme A Dehydrogenase). This is an enzyme that breaks down medium-chain fatty acids, which allows fat to be used for energy. Due to reduced production of this enzyme, an accumulation of medium-chain fatty acids occurs, which can cause a medical emergency known as a metabolic crisis.

Metabolic crises are of particular concern for babies and infants, as this is the period when MCAD deficiency becomes evident. The symptoms range from fatigue and reduced responsiveness, to more severe conditions including vomiting, seizures, and coma. Continue reading to learn more about how to diagnose, manage and treat this condition.

Overview 

MCAD Deficiency, also known as MCADD, stands for Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. While the name may sound pretty daunting, it is actually quite simple to understand. Our body’s metabolism consists of a series of reactions that break down the main components of our diet (fats, carbohydrates, and proteins) into their constituent simpler molecules. This process is called catabolism. These basic molecules, like amino acids, nucleotides, and other small molecules are used to build bodily components like muscle tissue, blood cells, and various other components the body requires in a process called anabolism. Each of these reactions can only be carried out in the presence of certain proteins called enzymes, and MCAD is a prime example of such enzymes. 

This enzyme is a very important component of fatty acid metabolism (a process which utilises the stored fats in the body as an energy source). As the name suggests, MCAD deficiency is a condition where the production of this enzyme is highly reduced.This means that the long-chain fats consumed by the person are not completely broken down, and they are instead broken into medium-chain fats and metabolites which can be toxic upon accumulation.

It is a genetic disorder that is inherited, and it is a lifelong condition, however, treatments exist which will be discussed in the coming sections.¹ 

Causes and risk factors 

The main cause of MCAD deficiency is genetic. Each protein produced in the body is coded by a segment of DNA called a gene. The MCAD enzyme is encoded by the ACADM gene. Certain people have an altered ACADM gene which causes too less of a functional MCAD enzyme to be produced, leading to MCAD deficiency. Therefore, this condition is passed from parent to child in an autosomal recessive inheritance pattern-  that is, one copy of the faulty gene is inherited from each parent.² Having only one copy of the gene will not cause the disorder but the person will be a carrier for the condition. There is a 25% chance for a child with two carrier parents to be born with MCAD deficiency.

The primary risk factor for MCAD deficiency is a family history of the condition. If a parent, grandparent, or other close relative has the condition, one’s risk of being a carrier or having MCADD significantly increases. If anyone in your immediate family suffers from MCAD deficiency, contact a qualified genetic counsellor for a proper risk assessment.

People of certain ethnicities are at a higher risk of MCAD deficiency than average as concluded from observed patterns- notably people of Northern European descent show higher rates (1 in 6400 individuals). People from Portugal and Native American communities in California also show higher incidence rates. 

Symptoms and manifestations

MCAD deficiency symptoms are usually observed in infants showing their first metabolic crisis- a condition where an accumulation of toxic metabolites due to deficiency of the MCAD enzyme causes a collection of symptoms that can prove lethal or severely damaging if not treated early. A metabolic crisis is also known as metabolic decompensation.

Symptoms include:

• Fatigue
• Non-responsiveness and sleepiness 
• Poor feeding
• Seizures 
• Coma  

These symptoms can be mitigated by ensuring that the child or baby is fed at regular intervals, and in emergency cases, glucose supplements can be administered. 

Diagnosis 

As MCAD deficiency is an inherited condition, genetic testing is the most frequent form of diagnosis. The extent of the deficiency of the MCAD enzyme is gauged with further testing. The following diagnostic procedures may be carried out if a medical professional suspects MCAD deficiency in a patient.

Newborn screening

As it is a congenital condition (present since birth), screening may be carried out in newborns if they exhibit symptoms. This screening takes the form of blood tests that test for a specific type of chemical called octanoyl carnitine. A high level of octanoylcarnitine coupled with other symptoms of MCADD can let a practitioner arrive at a diagnosis.

Genetic testing

Genetic testing may be carried out to examine if the patient has one or two abnormal copies of the ACADM gene causing MCAD Deficiency. One copy would indicate that the person is a carrier that can potentially transmit this condition to a child, and two copies indicate that the person is suffering from MCAD deficiency. Genetic counselling may be carried out for such individuals to discuss the probability of passing on the condition to their children. 

Biochemical tests

The cells of a patient are cultured in-vitro and the ability of these cells to break down fat is analysed. If toxic medium-chain fatty acids indicative of MCAD deficiency are found, it can indicate a diagnosis.

Treatment and management 

As MCADD is a genetic disorder, there is no specific treatment for it. The aim of treatment in this case becomes symptom management. A few options to mitigate symptoms are:

• Avoid fasting and eat balanced meals at regular intervals
• Avoid alcohol
• Feed children formulas that do not contain high levels of medium-chain fatty acids
• Consult a metabolic specialist for a customised diet chart and surveillance of MCAD levels in the body

Consumption of alcohol or fasting can lead to a metabolic crisis, in this case, glucose supplements need to be consumed as soon as possible. Glucose may also be administered through IV.  If a child with MCAD deficiency is ill, consuming high-sugar drinks can help.  In association with a metabolic specialist, find the “safe fasting time” for the patient, which is the longest time the patient can stay without food safely.

FAQs

How can I prevent MCAD deficiency? 

As MCAD Deficiency is an inherited genetic disorder, it cannot be prevented. However, if you or anyone in your family is suffering from MCAD Deficiency, it is advisable to undergo genetic counselling before planning a baby as you may be a carrier even if not necessarily suffering from MCAD, and the baby may inherit the condition. It can also be managed by consulting a metabolic specialist to formulate a special diet and management strategies for a potential metabolic crisis. 

How common is MCAD deficiency? 

MCAD deficiency is one of the most common metabolic disorders and affects 1 in 50,000 individuals in the general population. However, as mentioned above, certain ethnicities and descents show higher rates of incidence- people of Northern European descent show a 1 in 6400 rate for instance. Native Americans in California are also at a higher risk.

Who is at risk of MCAD deficiency?

Anyone with a family member suffering from MCAD deficiency is at a higher risk for the condition. As it is an autosomal recessive condition, it will only manifest if both parents are carriers (have one copy of the gene) or one is a carrier and at least one parent is suffering from MCAD (two copies of the faulty gene). 

When should I see a doctor?

If your infant is showing any symptoms described as a part of a metabolic crisis described above, contact a medical professional as soon as possible.

Summary

MCAD deficiency, also known as MCADD, stands for Medium-Chain Acyl-Coenzyme A Dehydrogenase deficiency. It is a genetically inherited disorder that follows an autosomal recessive mode of inheritance, that is, for a person to suffer from the condition two alleles of the faulty gene need to be present. A person with only one allele of this condition is termed a carrier. MCAD is an enzyme that is essential in fat metabolism to break down medium-chain fatty acids in a form that is usable by the body for energy. As there is a deficiency in this enzyme, medium-chain fatty acids build up, which causes toxicity in the form of a metabolic crisis. This metabolic crisis causes symptoms including fatigue, seizures, reduced responsiveness, and more in children with this condition. It can be prevented by avoiding fasting, and mitigated by administering glucose via supplements or IV. MCADD is diagnosed by blood screening in newborns, genetic sequencing, or biochemical testing. In families where members are suffering from MCAD deficiency, it is advised to carry out genetic counselling in the case of pregnancy or planning a baby for a proper risk assessment and precautions that need to be taken. The condition can be managed by consuming a balanced diet, eating at regular intervals, and preventing alcohol intake- things which reduce the chances of a metabolic crisis occurring.