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Mysterious Metabolic Disorder: How Medium-Chain Fatty Acids Play a Key Role in Our Bodies?
Medium-chain fatty acid dehydrogenase deficiency (MCAD deficiency or MCADD) is a disorder that affects fatty acid oxidation, impairing the body's ability to convert medium-chain fatty acids into acetyl-CoA. The condition is characterized by hypoglycemia and possible sudden death if no timely intervention is given, usually after fasting or vomiting. Before the advent of expanded newborn screening, MCADD was an underdiagnosed cause of sudden infant death. Those who are identified before symptoms develop have a good prognosis. The condition is most common in white northern European populations, with an incidence rate ranging from 1:4,000 to 1:17,000, depending on the population.
The mainstay of treatment for MCADD is prevention, through avoidance of fasting and other situations in which the body does not rely on fatty acid oxidation for energy.
Symptoms and Signs
MCADD presents during childhood with hypoketosis, hypoglycemia, and liver dysfunction, often following prolonged fasting or infection with vomiting. Babies who are exclusively breastfed may develop these symptoms soon after birth because of poor feeding. In some cases, the first manifestation of MCADD may be a mild illness followed by sudden death. Many people with MCADD may remain completely asymptomatic if they never encounter conditions that stress their metabolism.
With the advent of expanded newborn screening, some mothers are being found to have MCADD in their infants following newborn screening due to low carnitine levels.
Medium-chain fatty acid desaturase (MCAD) is responsible for the dehydrogenation of fatty acids between 6 and 12 carbons in length during their β-oxidation. Beta-oxidation of fatty acids provides energy after the body has exhausted its glucose and glycogen stores, a process that typically occurs during prolonged fasting or illness when caloric intake is reduced and energy demands are increased.
Genetics
MCADD is inherited in an autosomal recessive manner, meaning that an affected individual must inherit the mutant allele from both parents. The gene involved is ACADM, located at 1p31, contains 12 exons and encodes a protein of 421 amino acids. In northern European whites, there is a common mutation that replaces adenine with guanine at position 985, resulting in a substitution of lysine with glutamic acid at position 304 of the protein. As newborn screening has expanded, other mutations have been found to be more common.
The clinical manifestation of MCADD depends not only on the mutation in the ACADM gene, but also on whether the body is facing environmental or physiological stress that requires reliance on fatty acid oxidation for energy.
There is no strong correlation between an individual's genotype and their clinical manifestations. Some mutations identified through newborn screening programs are not seen in clinically symptomatic individuals, even though they correspond to higher enzyme activity. Nonetheless, treatment that avoids fasting remains the mainstream for all people diagnosed with MCADD.
Diagnosis
Clinically, suspicion of MCADD or other fatty acid oxidation disorders is often seen in individuals with concurrent lethargy, seizures, coma, and hypoketotic hypoglycemia, particularly when triggered by mild illness. MCADD may also be associated with acute liver disease and hepatomegaly, which may lead to a misdiagnosis of Reye's syndrome. In some cases, the only manifestation of MCADD is sudden, unexplained death, often preceded by minor illness.As part of expanded newborn screening, doctors will use mass spectrometry to analyze blood samples to detect MCADD and confirm the diagnosis as early as possible.
Typical biochemical features of MCADD include propionic acid amino acid profiles, which are represented by hexacarnitine (C6), octacarnitine (C8), decacarnitine (C10), or decaenoic acid carnitine (C10: 1) The level is increased, with C8 content greater than C6 and C10. Urine organic acid analysis can also aid in the diagnosis, showing dicarboxylic acid urine with low ketone bodies. In asymptomatic individuals, specialized analyses can help detect cyanine amino acids and can be used to confirm the diagnosis.
TreatmentAs with most other fatty acid oxidation disorders, patients with MCADD need to avoid prolonged fasting. During illness, careful management is necessary to avoid metabolic deregulation, which can lead to death. During an illness, simple carbohydrate or glucose supplementation is essential to prevent protein breakdown. Patients diagnosed with MCADD should have an "emergency letter" so that medical staff can intervene appropriately in an emergency.
MCADD is often misdiagnosed by pediatricians as Reye's syndrome, making a correct diagnosis more difficult.
Prognosis and epidemiology
According to a study of the entire population of New South Wales, Australia, about 25% of patients died within 30 months, while a 2006 Dutch study found that 17% of individuals died at a young age. Has died. The incidence of MCADD is most common in northern European white populations and is significantly lower in other populations. Common mutations for this condition have not yet been identified in Asian populations.
As awareness of MCADD increases, this and other fatty acid oxidation disorders are being considered as one of the recently discovered undiagnosed causes of sudden infant death syndrome. Do you understand the impact of dysregulated fatty acid metabolism on our body and its possible long-term consequences?
