Maple syrup urine disease
Description, Causes and Risk Factors:
An inborn error of metabolism caused by defective oxidative decarboxylation of alpha-keto acids of leucine, isoleucine, and valine; these branched-chain amino acids are present in the blood and urine in high concentrations; manifestations of disease include feeding difficulties, physical and mental retardation, and a urine odor similar to that of maple syrup; neonatal death is common. Autosomal recessive inheritance, caused by mutation in the E1, E2 or E3 subunit of the branched-chain alpha-keto acid dehydrogenase gene (BCKDH) on 19q. There are various forms differentiated by the subunit of BCKDH mutated.
Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. The condition gets its name from the distinctive sweet odor of affected infants' urine. Beginning in early infancy, this condition is characterized by poor feeding, vomiting, lack of energy (lethargy), and developmental delay. If untreated, maple syrup urine disease can lead to seizures, coma, and death.
Maple syrup urine disease is often classified by its pattern of signs and symptoms. The most common and severe form of the disease is the classic type, which becomes apparent soon after birth. Variant forms of the disorder become apparent later in infancy or childhood and are typically milder, but they still involve developmental delay and other medical problems if not treated.
There are several variations of the disease:
Classic Severe MSUD.
- Intermediate MSUD.
- Intermittent MSUD.
- Thiamine-responsive MSUD.
- E3-Deficient MSUD with Lactic Acidosis.
Mutations in the BCKDHA, BCKDHB, DBT, and DLD genes cause maple syrup urine disease. These four genes provide instructions for making proteins that work together as a complex. The protein complex is essential for breaking down the amino acids leucine, isoleucine, and valine, which are present in many kinds of food (particularly protein-rich foods such as milk, meat, and eggs).
Mutations in any of these four genes reduce or eliminate the function of the protein complex, preventing the normal breakdown of leucine, isoleucine, and valine. As a result, these amino acids and their byproducts build up in the body. Because high levels of these substances are toxic to the brain and other organs, their accumulation leads to the serious medical problems associated with maple syrup urine disease.
Maple syrup urine disease affects an estimated 1 in 185,000 infants worldwide. The disorder occurs much more frequently in the Old Order Mennonite population, with an estimated incidence of about 1 in 380 newborns.
A baby who has the disorder may appear normal at birth. But within three to four days, the symptoms appear. These may include: loss of appetite, fussiness, and sweet-smelling urine. The elevated levels of amino acids in the urine generate the smell, which is reminiscent of maple syrup.
Plasma amino acids should be evaluated to assess the elevation of branched-chain amino acids and to detect alloisoleucine. The detection of alloisoleucine is diagnostic for maple syrup urine disease (MSUD). Alloisoleucine may not appear until the sixth day of life, even when leucine levels are elevated. Transient elevations of branched-chain amino acids (without the presence of alloisoleucine) may develop in patients with ketotic hypoglycemia and in patients in the postabsorptive state.
Measure urine organic acids using gas chromatography-mass spectrometry (GC-MS) to detect alpha-hydroxyisovalerate, lactate, pyruvate, and alpha-ketoglutarate.Newborn screening for MSUD is performed with tandem mass spectrometry using concentrations of leucine and isoleucine and the Fisher Ratio (branch-chain amino acids/phenylalanine and tyrosine) as diagnostic measures. Immediate treatment should follow the identification of affected newborn infants.
Enzyme activity can be measured in lymphocytes, cultured fibroblasts, or both, although this test is not necessary for diagnosis.
Prenatal diagnosis can be performed by measuring enzyme activity in cultured amniocytes or chorion villus cells, mutation analysis, or by measuring branch-chain amino acid concentrations in amniotic fluid.
Treatment involves dietary restriction of the amino acids leucine, isoleucine, and valine. This treatment must begin very early to prevent brain damage. Babies with the disease must eat a special formula that does not contain the amino acids leucine, isoleucine, and valine. As the person grows to adulthood, he or she must always watch their diet, avoiding high protein foods such as meat, eggs, and nuts.
If levels of the three amino acids still get too high, patients can be treated with an intravenous solution that helps the body use up excess leucine, isoleucine, and valine for protein synthesis.
Gene therapy is also a potential future treatment for patients with MSUD. This would involve replacing the mutated gene with a good copy, allowing the patient's cells to generate a functional BCKD protein complex and break down the excess amino acids.
NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.