Find information on medical topics, symptoms, drugs, procedures, news and more, written in everyday language.

Disorders of Amino Acid Metabolism

by Lee M. Sanders, MD, MPH

Amino acids are the building blocks of proteins and have many functions in the body. Hereditary disorders of amino acid processing can result from defects either in the breakdown of amino acids or in the body’s ability to get amino acids into cells. Because these disorders cause symptoms early in life, newborns are routinely screened for several common ones. In the United States, newborns are commonly screened for phenylketonuria, maple syrup urine disease, homocystinuria, tyrosinemia, and a number of other inherited disorders, although screening varies from state to state.

Phenylketonuria (PKU)

Phenylketonuria occurs in infants born without the ability to normally break down an amino acid called phenylalanine. Phenylalanine, which is toxic to the brain, builds up in the blood.

  • Phenylketonuria is caused by lack of the enzyme needed to convert phenylalanine to tyrosine.

  • Symptoms include intellectual disability, seizures, nausea, vomiting, an eczema-like rash, and a mousy body odor.

  • The diagnosis is based on a blood test.

  • A strict phenylalanine-restricted diet allows for normal growth and development.

Phenylketonuria (PKU) is a disorder that causes a buildup of the amino acid phenylalanine, which is an essential amino acid that cannot be synthesized in the body but is present in food. Excess phenylalanine is normally converted to tyrosine, another amino acid, and eliminated from the body. Without the enzyme that converts it to tyrosine, phenylalanine builds up in the blood and is toxic to the brain, causing intellectual disability.

Symptoms

Newborns with PKU rarely have symptoms right away, although sometimes they are sleepy or eat poorly. If not treated, affected infants progressively develop intellectual disability over the first few years of life, eventually becoming severe. Other symptoms include seizures, nausea and vomiting, an eczema-like rash, lighter skin and hair than their family members, aggressive or self-injurious behavior, hyperactivity, and sometimes psychiatric symptoms. Untreated children often give off a mousy body and urine odor as a result of a by-product of phenylalanine (phenylacetic acid) in their urine and sweat.


Diagnosis

PKU is usually diagnosed with a routine screening test.

PKU occurs in most ethnic groups. If PKU runs in the family and DNA is available from an affected family member, amniocentesis or chorionic villus sampling with DNA analysis can be done to determine whether a fetus has the disorder.

Parents and siblings of children with PKU can be tested to find out whether they carry the gene that causes the disease. If two carriers conceive a child, that child has a 1 in 4 chance of being born with the disease.


Prognosis

A phenylalanine-restricted diet, if started early and maintained well, allows for normal development. However, if very strict control of the diet is not maintained, affected children may begin to have difficulties in school. Dietary restrictions started after 2 to 3 years of age may control extreme hyperactivity and seizures and raise the child’s eventual intelligence quotient (IQ) but do not reverse intellectual disability. Recent evidence suggests that some intellectually disabled adults with PKU (born before newborn screening tests were available) may function better when they follow the PKU diet.

A phenylalanine-restricted diet should continue for life, or intelligence may decrease and neurologic and mental problems may ensue.


Prevention and Treatment

To prevent intellectual disability, people must restrict phenylalanine intake (but not eliminate it altogether because people need some phenylalanine to live) beginning in the first few weeks of life. Because all natural sources of protein contain too much phenylalanine for children with PKU, affected children cannot have meat, milk, or other common foods that contain protein. Instead, they must eat a variety of processed foods, which are specially manufactured to be phenylalanine-free. Low-protein natural foods, such as fruits, vegetables, and restricted amounts of certain grain cereals, can be eaten. Special nutritional products, including infant formula without phenylalanine, are also available. Future treatments may include cell transplantation and gene therapy.


Maple Syrup Urine Disease

Maple syrup urine disease is caused by lack of the enzyme needed to metabolize amino acids. By-products of these amino acids cause the urine to smell like maple syrup.

Children with maple syrup urine disease are unable to metabolize certain amino acids. By-products of these amino acids build up, causing neurologic changes, including seizures and intellectual disability. These by-products also cause body fluids, such as urine and sweat, to smell like maple syrup. This disease is most common among Mennonite families.

There are many forms of maple syrup urine disease. In the most severe form, infants develop neurologic abnormalities, including seizures and coma, during the first week of life and can die within days to weeks. In the milder forms, children initially appear normal but during infection, surgery, or other physical stress, they can develop vomiting, staggering, confusion, and coma.

Since 2007, nearly every state in the United States has required that all newborns be screened for maple syrup urine disease with a blood test.

Infants with severe disease are treated with dialysis (see see Dialysis). Some children with mild disease benefit from injections of vitamin B 1 (thiamin). After the disease has been brought under control, children must always consume a special artificial diet that is low in three amino acids (leucine, isoleucine, and valine). During times of physical stress or flare-ups, it may be necessary to monitor blood tests and give fluids by vein.

Homocystinuria

Homocystinuria is caused by lack of the enzyme needed to metabolize homocysteine. This disorder can cause a number of symptoms, including decreased vision and skeletal abnormalities.

Children with homocystinuria are unable to metabolize the amino acid homocysteine, which, along with certain toxic by-products, builds up to cause a variety of symptoms. Symptoms may be mild or severe, depending on the particular enzyme defect.

Infants with this disorder are normal at birth. The first symptoms, including dislocation of the lens of the eye, causing severely decreased vision, usually begin after 3 years of age. Most children have skeletal abnormalities, including osteoporosis. Children are usually tall and thin with a curved spine, chest deformities, elongated limbs, and long, spiderlike fingers. Without early diagnosis and treatment, mental (psychiatric) and behavioral disorders and intellectual disability are common. Homocystinuria makes the blood more likely to clot spontaneously, resulting in strokes, high blood pressure, and many other serious problems.

Since 2008, nearly every state in the United States has required that all newborns be screened for homocystinuria with a blood test. A test measuring enzyme function in liver or skin cells confirms the diagnosis.

Some children with homocystinuria improve when given vitamin B 6 (pyridoxine) or vitamin B 12 (cobalamin).

Tyrosinemia

Tyrosinemia is caused by lack of the enzyme needed to metabolize tyrosine. The most common form of this disorder mostly affects the liver and the kidneys.

Children with tyrosinemia are unable to completely metabolize the amino acid tyrosine. By-products of this amino acid build up, causing a variety of symptoms. In some states, the disorder is detected with newborn screening tests.

There are two main types of tyrosinemia: type I and type II.

Type I tyrosinemia is most common among children of French-Canadian or Scandinavian descent. Children with this disorder typically become ill sometime within the first year of life with dysfunction of the liver, kidneys, and nerves, resulting in irritability, rickets, or even liver failure and death. Restriction of tyrosine in the diet is of little help. An experimental drug, which blocks production of toxic metabolites, may help children with type I tyrosinemia. Often, children with type I tyrosinemia require a liver transplant. Since 2007, nearly every state in the United States has required that all newborns be screened for type I tyrosinemia with a blood test.

Type II tyrosinemia is less common. Affected children sometimes have intellectual disability and frequently develop sores on the skin and eyes. Unlike type I tyrosinemia, restriction of tyrosine in the diet can prevent problems from developing.