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Maple Syrup Urine Disease (MSUD)

Maple syrup urine disease, also known as branched chain ketoaciduria is a metabolic disorder caused by the inability to metabolize branched chain amino acids like Isoleucine, Leucine and Valine. This disorder gets its name from the distinctive sweet smell of affected infants' urine, prior to diagnosis. It is an autosomal, recessive disorder.

Historical Background
In 1954, Menkes et al reported a family in which 4 infants died within the first 3 months of their lives because of a neurodegenerative disorder. The urine of these infants had an odor resembling maple syrup (burned sugar). Therefore, this disorder was called maple sugar urine disease and, later, maple syrup urine disease. In the following years, Dancis et al identified the pathogenetic compounds as branched-chain amino acids and their corresponding alpha-keto acids. In 1960, Dancis et al demonstrated that the enzymatic defect in MSUD was at the level of the decarboxylation of the branched-chain amino acids. Snyderman et al initiated the first successful dietary treatment of MSUD by restricting intake of branched-chain amino acids. In 1971, Scriver et al reported the first case of thiamine-responsive MSUD. The branched-chain alpha-keto acid dehydrogenase (BCKD) complex was purified and characterized in 1978.

Causes
Maple syrup urine disease (MSUD) is caused by a gene defect. Mutations in the following genes cause maple syrup urine disease: These four genes produce proteins that work together as the branched-chain alpha-keto acid dehydrogenase complex, essential for breaking down the amino acids leucine, isoleucine, and valine. This leads to a buildup of these chemicals in the blood. These amino acids are mainly present in protein-rich foods such as dairy products, meat, soy, gluten, eggs, nuts, whole grains, beans, and pulses.
 * BCKDHA
 * BCKDHB
 * DLD
 * DBT

Initial Symptoms
Initial symptoms of MSUD include :
 * Lethargy
 * Poor appetite
 * Weight loss
 * Weak sucking ability
 * Irritability
 * A distinctive maple sugar odor in earwax, sweat, and urine
 * Irregular sleep patterns
 * Alternating episodes of hypertonia (muscle rigidity) and hypotonia (muscle limpness)
 * High-pitched cry

Serious symptoms

 * Seizures
 * Coma

Risk Factors
The National Organization for Rare Disorders (NORD) reports that MSUD occurs at the same rate in males and females (about 1 in 185,000 people). The risk for having any form of MSUD depends on whether ythe individual's parents are carriers of the disease. If both parents are carriers, their child has a: If an individual have two normal genes for BCKDC, they cannot pass the disease to their children. When two parents carry the recessive gene for BCKDC, it’s possible for one of their children to have the disease and other children to not have it. However, these children have a 50 percent chance of being carriers. They also may carry a risk later in life of having a child with MSUD.
 * 25 percent chance of receiving two mutated genes and having MSUD
 * 50 percent chance for receiving only one defective gene and being a carrier
 * 25 percent chance of receiving one normal gene from each parent

Effects
When classical MSUD is well managed in the neonatal period, individuals can have normal growth and development and relatively few hospitalizations. Unfortunately, common infections and injuries at any age can result in medical complications which can lead to a decline in neurological functioning. As they grow older, learning and behavioral problems have been identified in children suffering from this disease. While not well studied, Nyhan, Wulfeck, Tallal, and Marsden (1989) found deficits with cognitive and language functioning among children with MSUD. Clearly there is variability, with some children exhibiting significant deficits while others fall within the average range.

Complications
When MSUD is undiagnosed, or metabolic crises are untreated, the following severe complications can occur: When these conditions occur, they can result in: Eventually, life-threatening complications can develop and lead to death, especially if they go untreated.
 * Swelling of the brain
 * Lack of blood flow to the brain
 * Metabolic acidosis — a situation in which the blood contains high levels of acidic substances\
 * Severe neurological damage
 * Intellectual disability
 * Blindness
 * Spasticity, or uncontrolled muscle tightness

Newborn Screening
Many infants with MSUD are identified through newborn screening programs. Tandem mass spectrometry, an advanced newborn screening test that screens for more than 30 different disorders through one blood sample, has aided in the diagnosis of MSUD. Infants with mild or intermittent forms of the disorder may have totally normal blood amino acids after birth and thus can be missed by newborn screening.

Symptomatic Analysis
In places where testing for MSUD is unavailable or where newborn screening fails to detect MSUD, a diagnosis may be suspected based upon symptomatic findings (lethargy, failure to thrive, neurologic signs or, during a metabolic crisis, odor of maple syrup in earwax, sweat or urine). Tests to diagnose MSUD may include urine analysis to detect high levels of keto acids (ketoaciduria) and blood analysis to detect abnormally high levels of amino acids.

Enzymatic Diagnosis
An enzymatic diagnosis may be confirmed through analysis of white blood cells (lymphocytes) or cells taken from an affected individual’s skin. Early diagnosis, especially in suspected individuals, allows for management of asymptomatic infants before the onset of the usual clinical manifestations. Diagnosis through DNA testing is readily available and prenatal diagnosis is available.

Genetic Diagnosis
Molecular genetic testing for mutations in the BCKDHA, BCKDHB and DBT genes is also available to confirm the diagnosis, and is necessary for purposes of carrier testing for at-risk relatives and prenatal diagnosis for at-risk pregnancies.

Treatment
If an infant is diagnosed with MSUD, prompt medical treatment can avoid serious medical problems and intellectual disability. Initial treatment involves reducing the levels of branched chain amino acids (BCAAs) in the baby’s blood. Typically, this involves intravenous (IV) administration of amino acids that don’t contain BCAAs, combined with glucose for extra calories. The treatment promotes the utilization of existing leucine, isoleucine, and valine in the body. At the same time it reduces the BCAA level and provide necessary protein.

Prevention
Since MSUD is an inherited disease, there is no method for prevention. However, a genetic counselor can help to determine one's risk for having a baby with MSUD. Genetic testing can tell if an individual or their partner is a carrier of the disease. DNA testing can identify the disease in a fetus before birth.