What is Medium-Chain Acyl-CoA Dehydrogenase Deficiency?
Fatty acid oxidation disorders (FAODs) are a type of rare genetic condition that disrupt the normal process of breaking down fats in the body to produce energy, especially during periods of fasting or stress. This process happens in the mitochondria, the “power generators” of our cells, and requires several enzymes to function correctly. FAODs are categorized based on the size of the fat molecules impacted by the disorder. An especially common type of FAOD is called Medium-chain acyl-CoA dehydrogenase deficiency (MCADD), which specifically affects medium-sized fat molecules.
MCADD is a recessive genetic disorder, which means a child needs to inherit two copies of the defective gene, one from each parent, to develop the condition. This disorder is due to changes in a specific gene called acyl-CoA dehydrogenase medium chain (ACADM). When MCADD is present, the body can struggle to produce sufficient energy when its normal energy stores, known as glycogen, run out.
This energy shortage can cause a variety of symptoms, including a specific kind of low blood sugar called hypoketotic hypoglycemia, vomiting, seizures, and even falling into a coma. It’s also believed that MCADD might be responsible for a small number of cases of unexplained infant deaths, also known as Sudden Infant Death Syndrome (SIDS). The disease typically presents symptoms during early childhood, often within the first two years, but sometimes it can stay hidden and not cause symptoms until adulthood.
Thanks to newborn screening (NBS), it is now easier to identify people with MCADD even before they show symptoms; however, there is still a need for more research into the condition and how to manage it best. It’s crucial that doctors stay knowledgeable about the causes, detection tools, and treatment options for MCADD because diagnosing and treating the disorder early can greatly improve a person’s outlook.
What Causes Medium-Chain Acyl-CoA Dehydrogenase Deficiency?
Mutations or changes in the ACADM gene, located on one segment of our DNA called chromosome 1p31, lead to a specific disorder. These mutations cause the resulting protein to misfold, or take an incorrect shape, which results in the MCAD enzyme not working properly or not working at all. The ACADM gene is quite large, containing 44 kb of DNA and 12 introns. To date, over 400 different variations of the ACADM gene have been identified, with 68 classified as disease-causing, 82 likely to cause disease, and around 165 still uncertain.
The most common mutation is one called c.985A>G. This specific mutation causes a major change in the protein, leading to a total loss of function. This mutation is found in up to 80% of people showing symptoms of the disorder. It’s important to note that this mutation can be present in two copies in the same person (homozygous) causing a more severe form of the disease. However, sometimes it occurs in combination with other variants, resulting in a milder form of the disease. Another mutation, called c.199 T>C, is known to cause less severe symptoms.
For people of Japanese descent, the mutations c.1085G>A, c.50G>A, c.157C>T, and c.843A>T are frequently seen and account for 60% of the disease-causing mutations in this group. For the Chinese population, a mutation called c.727C >T has been identified, but it’s unclear how often this mutation occurs in this population. According to recent studies in China, the most common disease-causing mutation in people with this disorder, is one called c.449_452delCTGA, which is found in 27.7% of patients. Interestingly, this mutation has also been reported in the Japanese population.
Risk Factors and Frequency for Medium-Chain Acyl-CoA Dehydrogenase Deficiency
Fatty Acid Oxidation Disorders (FAODs) are diseases that affect between 0.9 and 15.2 out of every 100,000 individuals. The rate is notably high in Europe and the United States, where it’s between 6 and 16.4 people per 100,000 individuals. This is mainly due to the significant number of Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) cases in these regions.
MCADD is quite common, with a global occurrence of 1 in 50,000 live births. In North America and Northern Europe, it’s even more prevalent, affecting between 1 in 5,000 and 1 in 20,000 individuals. Certain European countries around France report occurrences ranging from 1 in 10,000 to 1 in 27,000 people. Interestingly, about 1 in every 70 people may carry the gene for this disorder. It affects both males and females equally.
However, MCADD is less common in Asian populations. The rate of occurrence in Japan is roughly 1 in 100,000 people. In China, it is between 1 in 80,332 and 1 in 282,591. However, these figures are probably underestimates, as the data only includes symptomatic patients who went for diagnostic testing. For instance, in Saudi Arabia, the estimated prevalence of symptomatic MCADD is 1 in 18,000.
Newborn screening (NBS) has revealed that MCADD may actually be more common than we used to believe, as it has led to the discovery of milder cases. In a large UK study involving several ethnicities, NBS found MCADD in about 1 in 10,000 babies. Most of these babies were Caucasian, while those with an “uncertain phenotype” were largely of Asian descent. These findings emphasize the importance of considering ethnic diversity in MCADD diagnosis.
Signs and Symptoms of Medium-Chain Acyl-CoA Dehydrogenase Deficiency
MCADD, or Medium-Chain Acyl-CoA Dehydrogenase Deficiency, is a condition that most people are born with but typically don’t show symptoms right away. Symptoms usually start within the first two years of life when the child has an illness or goes a long period without eating, like when parents start to reduce overnight feedings. The most common symptoms include severe low blood sugar, throwing up, seizures related to low blood sugar, sluggishness, and coma.
Just because someone has a “milder” type of MCADD doesn’t mean they won’t show severe symptoms. For example, even those with a type of MCADD that might appear less severe based on their biochemistry can still experience severe low blood sugar and related symptoms.
Some people with MCADD might also experience symptoms of non-inflammatory brain disease, liver dysfunction, and accumulation of fat in the liver. Sometimes these symptoms might be confused with Reye syndrome. This is another condition that can cause such symptoms, usually following a viral illness. People with MCADD might also experience low muscle tone. A significant symptom to watch for in a physical exam is an enlarged liver, which could indicate a serious, possibly life-threatening illness.
Some babies with MCADD might show symptoms of a fast, irregular heartbeat caused by a buildup of medium-chain acylcarnitines. There have also been reports of an irregular heartbeat coming from the upper chambers of the heart. Also, MCADD can be associated with sudden and unexplained death in infants. Some reports suggest that MCADD could be a factor in up to 1% of all such cases. Autopsies of patients who died suddenly from MCADD often show brain swelling and fatty infiltration in the liver, heart, and kidneys.
Newborn screening for fatty acid oxidation disorders, which includes MCADD, didn’t become widespread until the 2000s, and some countries still haven’t added it to their screening processes. Combined with the rarity of the disorder and the chance of inaccurate testing, this makes it difficult to diagnose MCADD reliably. Some people may not receive treatment, despite showing symptoms in infancy. Over time, with repeated periods of low blood sugar and metabolic crises these individuals could develop persistent, often drug-resistant, forms of epilepsy and cognitive delays.
Because different genetic mutations can cause MCADD, some patients might only have a modest reduction in MCAD activity and may not show symptoms until adulthood. Adults usually show symptoms during periods of severe catabolic stress, which can be life-threatening. Adults with symptomatic MCADD often report drinking alcohol followed by vomiting. Unlike younger patients, adults are more likely to show symptoms related to the heart. This likely happens because undiagnosed adults have medium-chain fatty acids accumulating in their heart muscle cells for many years during childhood and adolescence.
Testing for Medium-Chain Acyl-CoA Dehydrogenase Deficiency
Identifying a disease like Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) early can greatly improve a patient’s health and future medical costs. Otherwise, there’s a 20% to 25% chance that the undetected disease could lead to serious harm or even death.
The majority of MCADD cases currently are detected during newborn screening tests (NBS). These tests measure certain substances, namely octanoyl-carnitine (C8) and decanoyl-carnitine (C10), in a baby’s blood sample. If the level of C8 is above 0.40 μmol/L, it suggests something might be off and extra tests are needed. A multiple-repeated test done on the blood samples can validate the results, reducing chances of a false positive.
However, this test isn’t perfect. Some individuals with MCADD might slide under the radar, especially those who don’t have the common c.985A>G mutation in its usual form. Newborns with low birth weight can also pose a challenge, as their results may not accurately represent their MCADD status.
If the initial test suggests a high C8 level, further confirmatory tests should be done. These include repeating the level checks for other substances, like acylcarnitine and organic acids in the urine, and also determine the degree of activity of a particular enzyme (MCAD) in the body. The DNA can also be checked for mutations in a gene called ACADM.
The results from these tests are used together to confirm if a newborn has MCADD. If a newborn originally tested positive but the follow-up tests don’t match up, the initial result is regarded as a false positive, and no additional testing is needed.
Later, if necessary, genetic testing can be done. While DNA or exosome sequencing can detect possible mutations, the meaning of such variants isn’t always clear. Medical professionals use other biochemical markers as well to help differentiate between patients with MCADD and those without it.
Overall, the extent of enzyme activity in the body and the presence of certain genetic variants can hinder or improve the accuracy of MCADD diagnosis. Therefore, these factors should be taken into account during testing in order to provide necessary medical care to those who need it.
Treatment Options for Medium-Chain Acyl-CoA Dehydrogenase Deficiency
MCADD is a condition that affects the body’s ability to convert certain fats into energy. While there is no definitive cure for MCADD, it is managed mostly through diet to prevent long periods of fasting and ensure the person receives enough nutrients, especially during times of stress.
When symptoms of MCADD appear, the main treatments are about halting the breakdown of stored energy in the body (catabolism) and treating low blood sugar (hypoglycemia). For those who can eat and drink normally, consuming simple carbohydrates is one common approach. Some specialists suggest at-home blood glucose monitoring during illness or if hypoglycemia is suspected, although any further management should be done with the guidance of a specialist. It’s important to educate caregivers about glucose needs during illness.
If a patient cannot intake enough carbohydrates by mouth, a glucose solution, specifically dextrose, might have to be administered intravenously. It’s important to note that some doctors strongly advise against using a 5% dextrose solution. In any case, the actual patient’s needs must dictate the approach, so the specific type and amount of these solutions can differ.
In addition to MCADD-specific treatments, any illnesses or conditions that might have triggered the symptoms should also be addressed. Frequently seen triggers include gastrointestinal issues, ear infections, and throat inflammation. In teenagers and adults, alcohol consumption might have to be checked too.
The primary goal of long-term management for MCADD is to prevent long fasting periods. Generally, the younger the patient, the shorter the time they should go without food. However, as patients with MCADD exhibit varying degrees of MCAD function, individual fasting schedules are usually more effective, especially for severe cases.
Other long-term preventive measures include avoiding some types of foods and formulas with medium-chain fatty acids, which can cause problems in people with MCADD. Certain foods, like raw cornstarch, are recommended for slow glucose release overnight. A diet rich in complex carbohydrates and low in fat is encouraged, while avoiding meals with medium-chain triglycerides. Some patients might experience muscle weakness and fatigue, at which point physical therapy is recommended.
Currently, there isn’t consistent evidence supporting the effectiveness of L-carnitine supplementation, which was theorized to treat secondary carnitine deficiency. Furthermore, restrictive fat diets are not recommended, while consumption of fruits, vegetables, and complex carbohydrates is suggested.
An emergency protocol letter is recommended for all patients, outlining pertinent findings of this disorder, giving detailed management instructions and providing contact information for the patient’s metabolic specialist. A medical alert tag or bracelet might be considered for school-age children and adults to speed up emergency response, should they need it.
Several potential future therapies are also in the works such as nitrogen scavengers, gene therapy, and proteomics testing. However, these are yet to be proven effective and safe for human use.
What else can Medium-Chain Acyl-CoA Dehydrogenase Deficiency be?
The symptoms of MCADD, a certain metabolic disorder, can resemble the symptoms of several other metabolic diseases. Consider these diseases when diagnosing MCADD:
- Short-chain acyl-CoA dehydrogenase deficiency
- Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and trifunctional protein deficiency
- Very-long-chain acyl-CoA dehydrogenase deficiency
- Multiple acyl-CoA dehydrogenase deficiency
- 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency
- Ornithine transcarbamylase (OTC) deficiency
Additionally, Reye syndrome has similar symptoms to MCADD and it’s important to take it into account. It’s usually found in older kids who have taken aspirin. The key differences that set Reye syndrome apart from MCADD is that it features higher enzyme levels in the liver and certain changes that can be seen under the microscope.
What to expect with Medium-Chain Acyl-CoA Dehydrogenase Deficiency
Patients diagnosed early with MCADD (Medium-chain acyl-CoA dehydrogenase deficiency, a rare genetic disorder that affects how the body processes fat to produce energy) and given proper care during sudden illnesses have an excellent chance of recovery. Early diagnosis through newborn screening (NBS) and follow-up care provided by centers specializing in metabolic disorders have reduced the disease’s health complications and death rates to nearly zero. Without a diagnosis, children have a mortality rate as high as 25% after experiencing the first symptoms. Moreover, many survivors can develop severe problems with brain function after this initial episode.
Recently, a study showed that the occurrence of acute symptomatic MCADD episodes was reduced from a previous rate of 66% to 95%, down to between 0% and 13% due to newborn screening. Furthermore, the death rate linked with the first episode of symptoms was lowered to between 3% and 4% from the previous rate of 14% to 21%. The study also reported a decrease in the occurrence and severity of cognitive impairment in patients with MCADD, from 67% to 11% after implementing expanded newborn screening. The authors found that their higher rates of cognitive impairment, both before and after screening when compared to other studies, were likely due to including mild cognitive impairment within their results. After factoring out mild cognitive impairment and considering only moderate to severe intellectual disabilities, they found results similar to previous studies, with a 13% prevalence before and 0% after newborn screening.
Possible Complications When Diagnosed with Medium-Chain Acyl-CoA Dehydrogenase Deficiency
One of the main concerns with this disease is that it can lead to problems with brain function, such as learning difficulties, speech problems, and attention deficit disorder. Research shows that when a person has a more severe form of the disease, it often goes hand in hand with these cognitive difficulties. To lessen this complication, it’s crucial to avoid going long periods without eating and to manage symptoms during illnesses.
The good news is that with early diagnosis and proper treatment, the chances of brain function problems are greatly reduced.
Something else to look out for is weight gain and obesity. This can occur when caregivers, concerned about blood sugar levels, give the patient too many carbohydrates. Obesity can lead to other health problems like diabetes and difficulties with processing sugar. For this reason, it’s important for caregivers and individuals with this disease to learn about the right amount of calories needed to usually from a dietician who specializes in metabolic disorders.
It’s also worth mentioning that the risk of gaining weight is even higher for those who take L-carnitine supplements. Other possible complications include chronic kidney failure, likely due to fat buildup in the kidneys causing scarring. Regular check-ups for kidney function are recommended.
Possible Complications:
- Problems with brain function (such as learning difficulties, speech problems, and attention deficit disorder)
- Obesity and weight gain, leading to other health problems like diabetes
- Chronic kidney failure due to fat buildup
Preventing Medium-Chain Acyl-CoA Dehydrogenase Deficiency
Living with MCADD (Medium-Chain Acyl-CoA Dehydrogenase Deficiency), a rare genetic disorder that affects the body’s ability to convert certain fats into energy, means that patients have to adapt to a lifestyle that is different from their peers. This could mean following a strict diet and continually monitoring their health, which can cause significant stress for the family. A study found that almost 75% of parents who care for a child with a metabolic disorder, such as MCADD, feel a great deal of burden in their day-to-day lives. This burden can be felt even before a confirmed diagnosis and can bring on high levels of anxiety in parents and caregivers.
Even when newborn screening (NBS) tests prove to be inaccurately positive, this anxiety can persist and can even lead to higher health care use in the child’s first year of life. Patients with MCADD often visit the emergency department more frequently and are more likely to need hospital treatment from the age of 6 to 12 months. A recent study from Canada also indicated that children diagnosed with MCADD use healthcare services at a significantly higher rate during the early years of childhood compared to children who screened negative for MCADD.
Because of this, providing caregivers with support and education is a vital part of treating MCADD. These interventions are aimed to reassure parents and to teach them how to recognize the signs of a possible metabolic crisis. Dieticians and nurses specialized in metabolic disorders are crucial in helping families understand and manage the disorder. They do this through extended teaching sessions that complement the information given by physicians. With this understanding, caregivers can better manage their child’s condition and are more likely to seek timely medical evaluation if a health issue arises. This support is particularly important in the first year of life, a time when parents often feel physically and mentally overwhelmed.
As children with MCADD grow, their caregivers may continue to feel increased levels of anxiety, particularly when altering the child’s diet or when fasting periods are required. In their fear of the child developing low blood sugar (hypoglycemia), parents might overcompensate, often adhering to stricter dietary routines than what is recommended. This behavior, known as a “risk-averse approach,” is common among parents of children with MCADD. So providing caregiver support, repeated reminders about care plans, and encouraging open discussions about their fears are important steps in ensuring child’s growth and minimizing the impact of the diagnosis.
