Maple syrup urine disease

Maple syrup urine disease (MSUD), also called branched-chain ketoaciduria, is an autosomal recessive metabolic disorder affecting branched-chain amino acids. It is one type of organic acidemia. The condition gets its name from the distinctive sweet odor of affected infants' urine.

Diagnosis and symptoms
MSUD is caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), leading to a buildup of the branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products in the blood and urine.

The disease is characterized in an infant by the presence of sweet-smelling urine, with an odor similar to that of maple syrup. Infants with this disease seem healthy at birth but if left untreated suffer severe brain damage and eventually die.

From early infancy, symptoms of the condition include poor feeding, vomiting, dehydration, lethargy, hypotonia, seizures, hypoglycaemia, ketoacidosis, opisthotonus, pancreatitis, coma and neurological decline.

Classification
Maple syrup urine disease can be classified by its pattern of signs and symptoms, or by its genetic cause. The most common and severe form of the disease is the classic type, which appears soon after birth. Variant forms of the disorder may appear later in infancy or childhood and are typically less severe, but still involve mental and physical problems if left untreated.

There are several variations of the disease:


 * Classic Severe MSUD
 * Intermediate MSUD
 * Intermittent MSUD
 * Thiamine-responsive MSUD
 * E3-Deficient MSUD with Lactic Acidosis

Management
Keeping MSUD under control requires careful monitoring of blood chemistry and involves both a special diet and frequent testing.

A diet with minimal levels of the amino acids leucine, isoleucine, and valine must be maintained in order to prevent neurological damage. As these three amino acids are required for proper metabolic function in all people, specialized protein preparations containing substitutes and adjusted levels of the amino acids have been synthesized and tested, allowing MSUD patients to meet normal nutritional requirements without causing harm.

Usually, patients are also monitored by a dietitian. Their diet must be adhered to strictly and permanently. However, with proper management those afflicted are able to live healthy, normal lives and not suffer the severe neurological damage associated with the disease.

Genetic prevalence


Maple syrup urine disease affects approximately 1 out of 180,000 infants. Due in part to the founder effect, however, MSUD has a much higher prevalence in children of Amish, Mennonite, and Jewish descent.

Mutations in the following genes cause maple syrup urine disease:


 * BCKDHA
 * BCKDHB
 * DBT
 * DLD

These four genes produce proteins that work together as the branched-chain alpha-keto acid dehydrogenase complex. The 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 genes reduce or eliminate the function of the enzyme complex, preventing the normal breakdown of isoleucine, leucine, and valine. As a result, these amino acids and their by-products build up in the body. Because high levels of these substances are toxic to the brain and other organs, this accumulation leads to the serious medical problems associated with maple syrup urine disease. This condition has an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome, and two copies of the gene - one from each parent - must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder.