Medium-chain acyl-CoA dehydrogenase deficiency (MACD deficiency) represents a genetic metabolic disorder in which medium-chain fatty acids are insufficiently broken down. Under certain conditions, it can lead to dangerous metabolic derailments, which may be fatal. If therapy is started early, the disease can be well controlled.
What is medium-chain acyl-CoA dehydrogenase deficiency?
In medium-chain acyl-CoA dehydrogenase deficiency, the breakdown of medium-chain fatty acids is impaired due to genetic causes. These can no longer be adequately used for energy production. Therefore, the body is forced to break down carbohydrates and amino acids to an increased extent. When energy requirements increase due to higher physical stress, growth processes or infections, the body’s carbohydrate reserves and endogenous proteins are increasingly used for energy production. The same is true during prolonged periods of food abstinence. Normally, under these conditions, fatty acid breakdown is forced by beta oxidation. However, this is not sufficiently possible in the case of MACD deficiency. The resulting increased breakdown of glucose leads to dangerous hypoglycemia. The forced degradation of amino acids simultaneously increases the ammonia content in the blood. Carnitine, which is important for energy metabolism, is reduced because it forms compounds with the accumulating medium-chain fatty acids. The compounds represent intermediates of fatty acid degradation. Since further breakdown of the medium-chain fatty acids is blocked by a defective enzyme in the acyl-hydrogenase complex, a secondary carnitine deficiency develops. A severe deviation of the corresponding values can lead to life-threatening complications. If left untreated, about 25 percent of the metabolic derailments caused by this disorder take a fatal course. Overall, medium-chain acyl-CoA dehydrogenase deficiency is one of the most common metabolic disorders and is part of the examinations performed as part of newborn screening. Timely identification of the responsible genetic defect is necessary for effective therapy. With appropriate therapeutic measures, this disease is readily treatable.
Causes
The cause of medium-chain acyl-CoA dehydrogenase deficiency is due to a malfunction of the MCAD enzyme. An autosomal recessive mutation of the MCAD gene, which is located on chromosome 1, impairs the folding properties of the enzyme. This results in a misfolded enzyme that is secreted and degraded as part of protein quality control. As a result, too little medium-chain acyl-CoA dehydrogenase is present. Medium-chain fatty acids are then poorly degraded. As already mentioned, an autosomal recessive mutation of the MCAD gene is responsible for this disease. In the case of autosomal recessive inheritance, the affected patient has two defective genes, one copy of each transmitted from both parents. Individuals with only one mutated gene do not develop the disease. Therefore, the disease is not inherited from generation to generation. If both parents are heterozygous for one defective gene each, the probability for the offspring to develop MCAD deficiency is 25 percent.
Symptoms, symptoms, and signs
Medium-chain acyl-CoA dehydrogenase deficiency is characterized by a tendency to hypoglycemia, convulsions, and comatose states. The first symptoms usually appear between the second month of life and the fourth year of life. They are triggered by infections or prolonged food deprivation and are manifested by diarrhea, vomiting, impaired consciousness, and seizures. The liver may be enlarged. In any metabolic derangement, blood glucose levels are decreased, blood ammonia levels are increased, and carnitine levels are decreased. The more severe the abnormalities, the greater the risks of falling into a life-threatening coma. However, there are also forms of MCAD deficiency with much milder symptoms. In some cases, there are no symptoms at all. In these cases, only laboratory tests indicate a corresponding genetic defect. Even in the more severely affected patients, there are always symptom-free phases between metabolic derailments.
Diagnosis and course of the disease
Medium-chain acyl-CoA dehydrogenase deficiency can be detected by tandem mass spectroscopy as part of newborn screening.In this method, fractions of acylcarnitines are determined. The concentration of octanoylcarnitine is considered the lead parameter here. If the values are elevated, DNA analysis can help confirm the diagnosis. In the acute phase of the disease, hypoglycemia, elevated ammonia levels, and elevated levels of medium-chain fatty acids in the form of dicarboxylic acids in the urine may be detected. There is also hyperuricemia (elevated uric acid levels in the urine) and signs of liver dysfunction. Sometimes urinary myoglobin levels are also elevated.
Complications
In the worst cases, medium-chain acyl-CoA dehydrogenase deficiency can be fatal for the patient. Therefore, to avoid severe complications and sequelae, early treatment of this disease must occur. In most cases, those affected suffer from severe cramps, which are also associated with pain. Likewise, medium-chain acyl-CoA dehydrogenase deficiency can lead to coma or loss of consciousness, so that the affected person’s everyday life is significantly restricted by the complaint. Disturbances of consciousness occur and the affected person suffers from diarrhea and vomiting. In many cases, there is also an enlargement of the liver, which is also associated with pain. If the affected person is in a coma, this condition can also have a negative effect on the psyche of relatives or parents and children, and lead to depression or other psychological upsets in these people. As a rule, medium-chain acyl-CoA dehydrogenase deficiency can be treated relatively well if it is diagnosed early. This does not result in any particular complications. It is only when it is diagnosed and treated at a late stage that various complications can occur, such that the affected person may have to undergo surgery, for example.
When should one go to the doctor?
Cravings and associated symptoms such as nausea as well as vomiting are signs of a health impairment. If there are disturbances in concentration, a feeling of malaise or a decrease in performance level, a doctor is needed. In case of pain, cramps and a seizure disorder, a visit to the doctor should be made immediately. Lack of drive, loss of appetite or an increased susceptibility to infection should be investigated and treated. Since the disease shows its first symptoms between the ages of six months and four years, young children in particular are at risk of contracting the disease. If those affected show a conspicuous change in their weight, or if there is apathy or behavioral abnormalities, a doctor should be consulted. If there are disturbances of consciousness, increased vigilance is necessary. Since the risk of an accident or injury increases for the affected person due to decreased consciousness, action is required. If a comatose state is evident or a loss of consciousness occurs, an ambulance should be alerted. At the same time, first aid measures are required until their arrival. Swelling of the upper body, fatigue, exhaustion as well as inner restlessness and increased irritability should be presented to a physician. Characteristic of the disease is a phasic regression of all symptoms. Despite the symptom-free period, a visit to the doctor is advisable as soon as signs of health impairment appear repeatedly.
Treatment and therapy
If the diagnosis is made early, the prognosis of the disease is very good. Then prophylactic measures can be initiated in time to prevent metabolic crises, even in difficult and stressful situations. It is important to avoid prolonged food abstinence and infections. Food abstinence should not last longer than two hours. Knowledge of this disease is also necessary for the preparation of possible operations. Many surgeries that are not absolutely necessary should therefore not be performed. If surgery cannot be avoided, artificial nutrition with glucose solution is absolutely necessary to prevent metabolic derailment. Acute metabolic derailment can also be overcome only by infusion with glucose solution. Since carnitine is lacking, oral administration of carnitine is also useful. Furthermore, the administration of riboflavin can lead to an improvement in fat metabolism because it is a coenzyme in the breakdown of fatty acids.
Outlook and prognosis
In the presence of medium-chain acyl-CoA dehydrogenase deficiency, the prognosis is positive if the diagnosis is made as early as possible. However, under certain conditions, this inborn error of metabolism can lead to severe metabolic derailments resulting in death. It is problematic that medium-chain acyl-CoA dehydrogenase deficiency is variable in clinical presentation. Therefore, misdiagnosis cannot be excluded. The symptoms of medium-chain acyl-CoA dehydrogenase deficiency are already noticeable in newborns. To improve the outlook for affected individuals, metabolic screening is now usually performed in newborns. Living conditions are good as long as the affected person avoids prolonged periods of fasting or starvation. He should maintain a low-fat diet in which carbohydrates are present in adequate amounts. In addition, a carnitine deficiency must be taken care of. To prevent impending metabolic derailment, administration of glucose-electrolyte infusions may also be considered. Emergencies and impending metabolic derailments pose a high risk. Therefore, those affected by medium-chain acyl-CoA dehydrogenase deficiency should be admitted immediately for inpatient treatment, if necessary. Those affected by MCAD carry an emergency identification card that identifies them as having medium-chain acyl-CoA dehydrogenase deficiency. The outlook is worse for people with medium-chain acyl-CoA dehydrogenase deficiency when they suffer infections or fast. Fasting before surgery also poses major risks. Metabolic derailment may result in hypoketotic hypoglycemia or metabolic acidosis. Unconsciousness or death may occur if neurologic symptoms such as hypotension or lethargy occur.
Prevention
Because medium-chain acyl-CoA dehydrogenase deficiency is genetic, there is no recommendation for its prevention. In cases of familial clustering, human genetic counseling is useful if there is a desire to have children. DNA testing can detect the defective genes. If both parents each have a mutated gene, the offspring have a 25 percent risk of developing medium-chain acyl-CoA dehydrogenase deficiency. If MCAD deficiency is detected during newborn screening, comprehensive medical control is necessary to prevent infection. Diet must be adjusted to a high-carbohydrate, low-fat diet.
Follow-up
Since peroxisomal disease is based on a genetic defect, therapy can only alleviate a few symptoms without being able to cure the disease completely. For this reason, there is no actual aftercare treatment in this sense, but intensive symptom treatment to alleviate some suffering. In general, patients and their relatives are advised to adopt a healthy lifestyle with a balanced diet to support the immune system. The latter will also suggest certain relaxation and mental techniques for stabilization, as well as advising as many leisure activities as possible. Mental balance makes it easier to deal with the disease and can sometimes promote recovery. If the parents, who have already been affected once, harbor a further desire to have children, they are advised to undergo a detailed genetic examination to determine in advance the likelihood of having another child with the disease.
What you can do yourself
Medium-chain acyl-CoA dehydrogenase deficiency is a metabolic disorder that can be well treated if detected early. An important self-help measure is to regulate metabolism through diet and adequate exercise. People who regularly take medication or engage in activities that negatively affect metabolism should talk to their family doctor. Through appropriate therapy, the metabolism can be optimized and thus MCADD can be treated well. In addition to medical treatment, alternative therapy is also possible. Natural remedies such as valerian or sage can have a good influence on the healing process due to their pain-relieving effect and other positive effects. To minimize any risks and side effects, the use of appropriate preparations should first be discussed with the responsible physician. Parents whose child has died from MCADD should seek trauma therapy.In the event of a new pregnancy, screening should be carried out at an early stage so that any medium-chain acyl-CoA dehydrogenase deficiency can be detected and sudden infant death averted. Affected infants require ongoing observation so that emergency medical services or ambulance services can be contacted immediately in the event of any complications.
