Most of the foods and drinks people ingest are complex materials that the body must break down into simpler substances. This process may involve several steps. The simpler substances are then used as building blocks, which are assembled into the materials the body needs to sustain life. The process of creating these materials may also require several steps. The major building blocks are

·                     Carbohydrates

·                     Amino acids

·                     Fats (lipids)

This complicated process of breaking down and converting the substances ingested is called metabolism.

Metabolism is carried out by chemical substances called enzymes, which are made by the body. If a genetic abnormality affects the function of an enzyme or causes it to be deficient or missing altogether, various disorders can occur. The disorders usually result from an inability to break down some substance that should be broken down, allowing some intermediate substance that is often toxic to build up, or from an inability to produce some essential substance. Metabolic disorders are classified by the particular building block that is affected.

Some hereditary disorders of metabolism (such as phenylketonuria and lipidoses) can be diagnosed in the fetus by using amniocentesis or chorionic villus sampling. Usually, a hereditary metabolic disorder is diagnosed by using a blood test or examination of a tissue sample to determine whether a specific enzyme is deficient or missing.

Prenatal Diagnostic Testing


Tests employed



Chorionic villus sampling

        (11-14 weeks)

Chromosomal analysis

DNA analysis


Chromosomal abnormalities, fetal sexing in X-linked




Inborn errors of metabolism




Haemoglobinopathies, Duchenne muscular dystrophy



(15+ weeks)


Chromosomal analysis


As above

As above

As above

Maternal venous

blood sample


AFP, Triple test screening for

Down's syndrome


High incidence of neural tube defects



(10-20 weeks)



Spina bifida, anencephaly, hydrocephaly, cystic renal

disease, renal tract dilatation, exomphalos, gastroschisis,

duodenal atresia, limb abnormalities, cardiac




(>18 weeks)



Chromosomal analysis

Blood testing


As above

As above

Heamoglobin studies, fetal viral infection, rhesus disease,

unexplained hydrops and fetal anaemia pH



·                     Measurement of certain substances in the pregnant woman's blood plus ultrasonography can help estimate the risk of genetic abnormalities in the fetus.

·                     These blood tests and ultrasonography may be done as part of routine care during pregnancy.

·                     If results of these tests suggest an increased risk, tests to analyze the genetic material of the fetus may be done.

·                     These genetic tests are invasive and have certain risks for the fetus.

Prenatal diagnostic testing involves testing the fetus before birth (prenatally) to determine whether the fetus has certain abnormalities, including certain hereditary or spontaneous genetic disorders. Some of these tests, such as ultrasonography and certain blood tests, are often part of routine prenatal care. Ultrasonography and blood tests are safe and sometimes help determine whether more invasive prenatal genetic tests (chorionic villus sampling, amniocentesis, and percutaneous umbilical blood sampling) are needed. Usually, these more invasive tests are done when couples have an increased risk of having a baby with a genetic abnormality (such as a neural tube defect) or a chromosomal abnormality (particularly when the woman is 35 or older). These tests have risks, although very small, particularly for the fetus.

Couples should discuss the risks with their health care practitioner and weigh the risks against their need to know. For example, they should think about whether not knowing the results of testing would cause anxiety and whether knowing that an abnormality was not found would be reassuring. They should think about whether they would pursue an abortion if an abnormality was found. If they would not, they should consider whether they still want to know of an abnormality before birth (for example, to prepare psychologically) or whether knowing would only cause distress. For some couples, the risks outweigh the benefits of knowing whether their baby has a chromosomal abnormality, so they choose not to be tested.

If in vitro fertilization is done, genetic disorders can sometimes be diagnosed before the fertilized egg is transferred from the culture dish to the uterus. These tests are available only in specialized centers and are used primarily for couples with a high risk of certain genetic disorders (such as cystic fibrosis) or chromosomal abnormalities.


Some Genetic Disorders That Can Be Detected Before Birth



Inheritance Pattern

Cystic fibrosis

1 of 3,300 white people

Autosomal recessive

Congenital adrenal hyperplasia

1 of 10,000

Autosomal recessive

Duchenne's muscular dystrophy

1 of 3,500 male births

X-linked recessive

Hemophilia A

1 of 8,500 male births

X-linked recessive

Alpha- and beta-thalassemia

Varies widely by ethnic and racial group

Autosomal recessive

Fragile X syndrome

1 of 2,000 male births

1 of 4,000 female births

X-linked dominant

Polycystic kidney disease (adult type)

1 of 3,000

Autosomal dominant

Sickle cell anemia

1 of 400 blacks in the United States

Autosomal recessive

Tay-Sachs disease

1 of 3,600 Ashkenazi Jews and French Canadians

1 of 400,000 in other groups

Autosomal recessive


First-Trimester Screening

Sometimes blood tests to estimate the risk of Down syndrome are done at about 11 to 14 weeks of pregnancy. These tests involve measuring levels of pregnancy-associated placental protein A (produced by the placenta) and beta-human chorionic gonadotropin in a pregnant woman's blood.

Also, ultrasonography is done to measure a fluid-filled space near the back of the fetus's neck (called fetal nuchal translucency). Abnormal ultrasound measurements indicate an increased risk of Down syndrome or another chromosomal abnormality in the fetus.

First-trimester blood tests plus ultrasonography provide results early. If results are abnormal and the couple wishes, chorionic villus sampling can then be done early to determine whether Down syndrome is present. Amniocentesis can also detect Down syndrome, but it is usually done later in pregnancy.

One advantage of 1st-trimester screening is that with earlier results, abortion, if desired, can be done earlier, when it is safer.

Second-Trimester Screening

During the 2nd trimester, markers in the pregnant woman's blood are measured and sometimes ultrasonography is done to identify women at increased risk of certain problems.

Important markers include the following:

·                     Alpha-fetoprotein: A protein produced by the fetus

·                     Estriol: A hormone formed from substances produced by the fetus

·                     Human chorionic gonadotropin: A hormone produced by the placenta

·                     Inhibin A: A hormone produced by the placenta

Alpha-fetoprotein levels: Alpha-fetoprotein is usually measured in all women, even those who have had 1st-trimester screening or chorionic villus sampling. A high level may indicate an increased risk of having any of the following:

·                     A baby with a neural tube defect of the brain (anencephaly) or spinal cord (spina bifida)

·                     A baby with a birth defect of the abdominal wall

·                     More than one fetus

·                     Pregnancy complications, such as miscarriage, slowed growth or death of the fetus, and premature detachment of the placenta (placental abruption)

If blood tests detect an abnormal alpha-fetoprotein level in a pregnant woman, ultrasonography is done. It can help by doing the following:

·                     Confirming the length of the pregnancy

·                     Determining whether more than one fetus is present

·                     Determining whether the fetus has died

·                     Detecting many birth defects

High-resolution or targeted ultrasonography, which can be done at some specialized centers, provides more detail and may be more accurate than standard ultrasonography, particularly for small birth defects.

If ultrasonography results are normal, a fetal problem is less likely, but certain conditions, such as neural tube defects, are still possible. Thus, whether ultrasonography results are normal or not, amniocentesis to measure the alpha-fetoprotein level in the fluid that surrounds the fetus (amniotic fluid) is recommended by many doctors. Also, the fetus's chromosomes may be analyzed and the amniotic fluid may be tested to determine whether it contains an enzyme called acetylcholinesterase. Levels of alpha-fetoprotein and acetylcholinesterase help doctors better assess risk:

·                     A high alpha-fetoprotein level plus acetylcholinesterase in the amniotic fluid indicates an increased risk of a neural tube defect, such as anencephaly or spina bifida.

·                     A high alpha-fetoprotein level with or without acetylcholinesterase may indicate an increased risk of a neural tube defect and of abnormalities in other organs, such as the esophagus and the abdominal wall.

Sometimes the amniotic fluid sample is contaminated with blood from the fetus, resulting in an abnormal alpha-fetoprotein level. In such cases, the fetus may not have any abnormalities.

Triple and Quad Screening: Measuring other markers (estriol and beta-human chorionic gonadotropin) can help estimate the risk of Down syndrome and other chromosomal abnormalities. This testing may not be necessary for women who have had 1st-trimester screening. Measuring estriol and beta-human chorionic gonadotropin plus alpha-fetoprotein is called triple screening. Inhibin A may also be measured. Measuring these four markers is called quad screening.

Triple or quad screening is done around 15 to 20 weeks of pregnancy. It can help estimate the risk of Down syndrome in the fetus. If risk is high, amniocentesis is considered. Quad screening results are abnormal (positive) in almost 80% of Down syndrome cases. Triple screening detects almost as many cases.

At some medical centers, targeted ultrasonography (a genetic sonogram) is done during the 2nd trimester to help estimate the risk of a chromosomal abnormality. Targeted ultrasonography aims to identify certain structural birth defects that indicate an increased risk of a chromosomal abnormality. This test can also detect certain variations in organs that do not affect function but may indicate an increased risk of a chromosomal abnormality. However, normal results do not necessarily mean that the risk of a chromosomal abnormality is reduced.

Combined 1st- and 2nd-Trimester Screening: For the most accurate results, both groups of tests—1st-trimester tests and 2nd-trimester tests—are done, and results from both are analyzed together. However, if couples want information sooner, they can request a type of screening that provides results during the 1st trimester. Then screening is done in the 2nd trimester only if results of 1st-trimester screening did not require chorionic villus sampling or amniocentesis. Couples should remember that screening tests are not always accurate. They may miss abnormalities, or they may indicate abnormalities when none are present.


Several procedures can be used to detect genetic and chromosomal abnormalities. All, except ultrasonography, are invasive (that is, they require insertion of an instrument into the body) and have a slight risk for the fetus.


Ultrasonography is commonly done during pregnancy. It has no known risks for the woman or fetus. Ultrasonography can do the following:

·                     Confirm the length of the pregnancy

·                     Locate the placenta

·                     Indicate whether the fetus is alive

·                     After the third month, detect certain obvious structural birth defects, including those of the brain, spinal cord, heart, kidneys, stomach, abdominal wall, and bones

·                     In the 2nd trimester, detect findings that tend to indicate a higher-than-normal chance of a chromosomal abnormality in the fetus (targeted ultrasonography)

  • Ultrasonography is often used to check for abnormalities in the fetus when a pregnant woman has abnormal results on a prenatal blood test or a family history of birth defects. However, normal results do not guarantee a normal baby because no test is completely accurate. Results of ultrasonography may suggest chromosomal abnormalities in the fetus, but ultrasonography cannot identify the specific problem. In such cases, amniocentesis may be recommended.

  • Ultrasonography is done before chorionic villus sampling and amniocentesis to confirm the length of the pregnancy so that these procedures can be done at the appropriate time during the pregnancy. During these procedures, ultrasonography is used to monitor the fetus and to guide placement of instruments.

  • At some specialized medical centers, targeted ultrasonography can be done. For this test, experts carefully assess the fetus to check for structural defects that indicate an increased risk of a chromosomal abnormality. This test can provide greater detail than conventional ultrasonography. Thus, this test may detect smaller abnormalities, and abnormalities can be seen earlier, more accurately, or both.

Chorionic Villus Sampling

In chorionic villus sampling, a doctor removes a small sample of the chorionic villi, which are tiny projections that make up part of the placenta. This procedure is used to diagnose some disorders in the fetus, usually between 10 and 12 weeks of pregnancy. Chorionic villus sampling may be used instead of amniocentesis unless a sample of amniotic fluid is needed, as when the alpha-fetoprotein level in amniotic fluid must be measured.

The main advantage of chorionic villus sampling is that its results are available much earlier in the pregnancy than those of amniocentesis. Thus, if no abnormality is detected, the couple's anxiety can be relieved earlier. If an abnormality is detected earlier and if the couple decides to terminate the pregnancy, simpler, safer methods can be used. Also, early detection of an abnormality may enable doctors to treat the fetus appropriately before birth. For example, a pregnant woman may be given a corticosteroid to prevent male characteristics from developing in a female fetus that has congenital adrenal hyperplasia. In this hereditary disorder, the adrenal glands are enlarged and produce excessive amounts of male hormones (androgens).

Before the chorionic villus sampling, ultrasonography is done to determine whether the fetus is alive, to confirm the length of the pregnancy, to check for obvious abnormalities, and to locate the placenta.

A sample of the chorionic villi can be removed through the cervix (transcervically) or the abdominal wall (transabdominally). With both methods, ultrasonography is used for guidance and the tissue sample is suctioned through a needle or catheter with a syringe and then sent for laboratory analysis. Many women have light spotting for a day or two afterward.

·                     Through the cervix: The woman lies on her back with her hips and knees bent, usually supported by heel or knee stirrups, as for a pelvic examination. The doctor inserts a thin, flexible tube (catheter) through the vagina and cervix into the placenta. For most women, the procedure feels very similar to a Papanicolaou (Pap) test, but a few women find it more uncomfortable. This method cannot be used in women who have an active genital infection (such as genital herpes or gonorrhea), chronic inflammation of the cervix, or a placenta that covers the passage between the cervix and uterus.

·                     Through the abdominal wall: The doctor anesthetizes an area of skin over the abdomen and inserts a needle through the abdominal wall into the placenta. Most women do not find this procedure painful. But for some women, the area over the abdomen feels slightly sore for an hour or two afterward.

After chorionic villus sampling, most women who have Rh-negative blood and who do not have antibodies to Rh factor are given an injection of Rh0(D) immune globulin to prevent them from producing antibodies to Rh factor. A woman with Rh-negative blood may produce these antibodies if the fetus has Rh-positive blood and it comes into contact with her blood, as it may during chorionic villus sampling. These antibodies can cause problems in the fetus. The injection is not needed if the father also has Rh-negative blood because in such cases, the fetus always has Rh-negative blood.

The risks of chorionic villus sampling are comparable to those of amniocentesis. The most common risk is that of miscarriage. In specialized centers, the risk of miscarriage is about 1 in 500 procedures. Rarely, the genetic diagnosis is unclear after chorionic villus sampling, and amniocentesis may be necessary. In general, the accuracy of the two procedures is comparable.


One of the most common procedures for detecting abnormalities before birth is amniocentesis. It is often offered to women over 35 to estimate their risk of having a baby with Down syndrome. However, it can be done for any woman who chooses, even if her risk is not higher than normal.

In this procedure, a sample of the fluid that surrounds the fetus (amniotic fluid) is removed and analyzed. Amniocentesis is usually done at 15 weeks of pregnancy or later. The fluid contains cells that have been shed by the fetus. These cells are grown in a laboratory so that the chromosomes in them can be analyzed. Amniocentesis enables doctors to measure the alpha-fetoprotein level in the amniotic fluid. This measurement more reliably indicates whether the fetus has a brain or spinal cord defect than does measurement of this level in the woman's blood.

Detecting Abnormalities Before Birth


Chorionic villus sampling and amniocentesis are used to detect abnormalities in a fetus. During both procedures, ultrasonography is used for guidance.

In chorionic villus sampling, a sample of chorionic villi (part of the placenta) is removed by one of two methods. In the transcervical method, a doctor inserts a thin, flexible tube (catheter) through the vagina and cervix into the placenta. In the transabdominal method, a doctor inserts a needle through the abdominal wall into the placenta. In both methods, a sample of the placenta is suctioned out with a syringe and analyzed.

In amniocentesis, a doctor inserts a needle through the abdominal wall into the amniotic fluid. A sample of fluid is withdrawn for analysis.


Before the procedure, ultrasonography is done to evaluate the heart of the fetus, to confirm the length of the pregnancy, to locate the placenta and amniotic fluid, and to determine how many fetuses are present.

A doctor inserts a needle through the abdominal wall into the amniotic fluid. Sometimes a local anesthetic is first used to numb the site. During the procedure, ultrasonography is done so that the fetus can be monitored and the needle can be guided into place. Fluid is withdrawn, and the needle is removed. Results are usually available in about 1 to 2 weeks.

Percutaneous Umbilical Blood Sampling

Percutaneous umbilical blood sampling is used when rapid chromosome analysis is needed, particularly toward the end of pregnancy when ultrasonography has detected abnormalities in the fetus. Often, results can be available within 48 hours. It is occasionally done for other reasons—for example, when doctors suspect that a fetus has anemia. If the fetus has severe anemia, blood can be transfused to the fetus during percutaneous umbilical blood sampling.

The doctor first anesthetizes an area of skin over the abdomen. Guided by ultrasonography, the doctor then inserts a needle through the abdominal wall into the umbilical cord. A sample of the fetus's blood is withdrawn and analyzed, and the needle is removed.

Percutaneous umbilical blood sampling is an invasive procedure and has risks for the woman and fetus. Loss of the pregnancy as a result of this test occurs in about 1 in 100 procedures.


Carbohydrates are sugars. Some sugars are simple, and others are more complex. Sucrose (table sugar) is made of two simpler sugars called glucose and fructose. Lactose (milk sugar) is made of glucose and galactose. Both sucrose and lactose must be broken down into their component sugars by enzymes before the body can absorb and use them. The carbohydrates in bread, pasta, rice, and other carbohydrate-containing foods are long chains of simple sugar molecules. These longer molecules must also be broken down by the body. If an enzyme needed to process a certain sugar is missing, the sugar can accumulate in the body, causing problems.

Glycogen Storage Diseases

Glycogen storage diseases occur when there is a defect in the enzymes that are involved in the metabolism of glycogen, resulting in growth abnormalities, weakness, and confusion.

·                     Glycogen storage diseases are caused by lack of an enzyme needed to change glucose into glycogen and break down glycogen into glucose.

·                     Typical symptoms include weakness, sweating, confusion, kidney stones, and stunted growth.

·                     The diagnosis is made by examining a piece of tissue under a microscope (biopsy).

·                     Treatment depends on the type of glycogen storage disease and usually involves regulating the intake of carbohydrates.

Glycogen is made of many glucose molecules linked together. The sugar glucose is the body's main source of energy for the muscles (including the heart) and brain. Any glucose that is not used immediately for energy is held in reserve in the liver, muscles, and kidneys in the form of glycogen and is released when needed by the body.

There are many different glycogen storage diseases (also called glycogenoses), each identified by a roman numeral. These diseases are caused by a hereditary lack of one of the enzymes that is essential to the process of forming glucose into glycogen and breaking down glycogen into glucose. About 1 in 20,000 infants has some form of glycogen storage disease.


Some of these diseases cause few symptoms. Others are fatal. The specific symptoms, age at which symptoms start, and their severity vary considerably among these diseases. For types II, V, and VII, the main symptom is usually weakness. For types I, III, and VI, symptoms are low levels of sugar in the blood and protrusion of the abdomen (because excess or abnormal glycogen may enlarge the liver). Low levels of sugar in the blood cause weakness, sweating, confusion, and sometimes seizures and coma. Other consequences for children may include stunted growth, frequent infections, and sores in the mouth and intestines.

Glycogen storage diseases tend to cause uric acid (a waste product) to accumulate in the joints, which can cause gout, and in the kidneys, which can cause kidney stones. In type I glycogen storage disease, kidney failure is common in the second decade of life or later.

Diagnosis and Treatment

The specific type of glycogen storage disease is diagnosed by examining a piece of muscle or liver tissue under a microscope (biopsy).

Treatment depends on the type of glycogen storage disease. For most types, eating many small carbohydrate-rich meals every day helps prevent blood sugar levels from dropping. For people who have glycogen storage diseases that cause low blood sugar levels, levels are maintained by giving uncooked cornstarch every 4 to 6 hours around the clock. For others, it is sometimes necessary to give carbohydrate solutions through a stomach tube all night to prevent low blood sugar levels from occurring at night.


Types and Characteristics of Glycogen Storage Diseases


Affected Organs, Tissues, or Cells


Type O

Liver or muscle

Episodes of low blood sugar levels (hypoglycemia) during fasting if the liver is affected

von Gierke's disease (type IA)

Liver and kidney

Enlarged liver and kidney, slowed growth, very low blood sugar levels, and abnormally high levels of acid, fats, and uric acid in blood

Type IB

Liver and white blood cells

Same as in von Gierke's disease but may be less severe

Low white blood cell count, recurring infections, and inflammatory bowel disease

Pompe's disease (type II)

All organs

Enlarged liver and heart and muscle weakness

Forbes' disease (type III)

Liver, muscle, and heart

Enlarged liver or cirrhosis, low blood sugar levels, muscle damage, heart damage, and weak bones in some people

Andersen's disease (type IV)

Liver, muscle, and most tissues

Cirrhosis, muscle damage, and delayed growth and development

McArdle disease (type V)


Muscle cramps or weakness during physical activity

Hers' disease (type VI)


Enlarged liver

Episodes of low blood sugar during fasting

Often no symptoms

Tarui's disease (type VII)

Skeletal muscle and red blood cells

Muscle cramps during physical activity and red blood cell destruction (hemolysis)



Galactosemia (a high blood level of galactose) is caused by lack of one of the enzymes necessary for metabolizing galactose, a sugar present in lactose (milk sugar). A metabolite that is toxic to the liver and kidneys builds up. The metabolite also damages the lens of the eye, causing cataracts.

·                     Galactosemia is caused by lack of one of the enzymes needed to metabolize the sugar in milk.

·                     Symptoms include vomiting, jaundice, diarrhea, and abnormal growth.

·                     The diagnosis is based on a blood test.

·                     Even with adequate treatment, affected children still develop mental and physical problems.

·                     Treatment involves completely eliminating milk and milk products from the diet.

Galactose is a sugar that is present in milk and in some fruits and vegetables. A deficient enzyme or liver dysfunction can alter the metabolism, which can lead to high levels of galactose in the blood (galactosemia). There are different forms of galactosemia, but the most common and the most severe form is referred to as classic galactosemia.


Newborns with galactosemia seem normal at first but, within a few days or weeks, lose their appetite, vomit, become jaundiced, have diarrhea, and stop growing normally. White blood cell function is affected, and serious infections can develop. If treatment is delayed, affected children remain short and become intellectually disabled or may die.


Galactosemia is detectable with a blood test. This test is done as a routine screening test for newborns in all states in the United States. Before conception, adults with a sibling or child known to have the disorder 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.


If galactosemia is recognized at birth and adequately treated, liver and kidney problems do not develop, and initial mental development is normal. However, even with adequate treatment, children with galactosemia may have a lower intelligence quotient (IQ) than their siblings, and they often have speech problems. Girls often have ovaries that do not function, and only a few are able to conceive naturally. Boys, however, have normal testicular function.


Galactosemia is treated by completely eliminating milk and milk products—the source of galactose—from an affected child's diet. Galactose is also present in some fruits, vegetables, and sea products, such as seaweed. Doctors are not sure whether the small amounts in these foods cause problems in the long term. People who have the disorder must restrict galactose intake throughout life.

Hereditary Fructose Intolerance

Hereditary fructose intolerance is caused by lack of the enzyme needed to metabolize fructose. Very small amounts of fructose cause low blood sugar levels and can lead to kidney and liver damage.

In this disorder, the body is missing an enzyme that allows it to use fructose, a sugar present in table sugar (sucrose) and many fruits. As a result, a by-product of fructose accumulates in the body, blocking the formation of glycogen and its conversion to glucose for use as energy. Ingesting more than tiny amounts of fructose or sucrose causes low blood sugar levels (hypoglycemia), with sweating, confusion, and sometimes seizures and coma. Children who continue to eat foods containing fructose develop kidney and liver damage, resulting in jaundice, vomiting, mental deterioration, seizures, and death. Chronic symptoms include poor eating, failure to thrive, digestive symptoms, liver failure, and kidney damage. For most types of this disorder, early diagnosis and dietary restrictions started early in infancy can help prevent these more serious problems.

The diagnosis is made when a chemical examination of a sample of liver tissue determines that the enzyme is missing. Treatment involves excluding fructose (generally present in sweet fruits), sucrose, and sorbitol (a sugar substitute) from the diet. Severe attacks of hypoglycemia respond to glucose given by vein. Milder attacks are treated with glucose tablets, which should be carried by anyone who has hereditary fructose intolerance.


Mucopolysaccharidoses are a group of hereditary disorders in which complex sugar molecules are not broken down normally and accumulate in harmful amounts in the body tissues. The result is a characteristic facial appearance and abnormalities of the bones, eyes, liver, and spleen, sometimes accompanied by intellectual disability.

·                     Mucopolysaccharidoses occur when the body lacks enzymes needed to break down and store complex sugar molecules (mucopolysaccharides).

·                     Typically, symptoms include short stature, hairiness, stiff finger joints, and coarseness of the face.

·                     The diagnosis is based on symptoms and a physical examination.

·                     Although a normal life span is possible, some types cause premature death.

·                     A bone marrow transplant may help.

Complex sugar molecules called mucopolysaccharides are essential parts of many body tissues. In mucopolysaccharidoses, the body lacks enzymes needed to break down and store mucopolysaccharides. As a result, excess mucopolysaccharides enter the blood and are deposited in abnormal locations throughout the body.

During infancy and childhood, short stature, hairiness, and abnormal development become noticeable. The face may appear coarse. Some types of mucopolysaccharidoses cause intellectual disability to develop over several years. In some types, vision or hearing may become impaired. The arteries or heart valves can be affected. Finger joints are often stiff.

A doctor usually bases the diagnosis on the symptoms and a physical examination. The presence of a mucopolysaccharidosis in other family members also suggests the diagnosis. Urine tests may help but are sometimes inaccurate. X-rays may show characteristic bone abnormalities. Mucopolysaccharidoses can be diagnosed before birth by using amniocentesis or chorionic villus sampling.

Prognosis and Treatment

The prognosis depends on the type of mucopolysaccharidosis. A normal life span is possible. Some types, usually those that affect the heart, cause premature death.

In one type of mucopolysaccharidosis, attempts at replacing the abnormal enzyme have had limited, temporary success. Bone marrow transplantation may help some people. However, death or disability often results, and this treatment remains controversial.

Disorders of Pyruvate Metabolism

Pyruvate metabolism disorders are caused by a lack of the ability to metabolize a substance called pyruvate. These disorders cause a buildup of lactic acid and a variety of neurologic abnormalities.

·                     A deficiency in any one of the enzymes involved in pyruvate metabolism leads to one of many disorders.

·                     Symptoms include seizures, intellectual disability, muscle weakness, and coordination problems.

·                     Some of these disorders are fatal.

·                     Some children are helped by diets that are either high in fat and low in carbohydrates or high in carbohydrates and low in protein.

Pyruvate is a substance that is formed in the processing of carbohydrates and proteins and that serves as an energy source for cells. Problems with pyruvate metabolism can limit a cell's ability to produce energy and allow a buildup of lactic acid, a waste product. Many enzymes are involved in pyruvate metabolism. A hereditary deficiency in any one of these enzymes results in one of a variety of disorders, depending on which enzyme is missing. Symptoms may develop any time between early infancy and late adulthood. Exercise and infections can worsen symptoms, leading to severe lactic acidosis. These disorders are diagnosed by measuring enzyme activity in cells from the liver or skin.

Pyruvate Dehydrogenase Complex Deficiency: This disorder is caused by a lack of a group of enzymes needed to process pyruvate. This deficiency results in a variety of symptoms, ranging from mild to severe. Some newborns with this deficiency have brain malformations. Other children appear normal at birth but develop symptoms, including weak muscles, seizures, poor coordination, and a severe balance problem, later in infancy or childhood. Intellectual disability is common.

This disorder cannot be cured, but some children are helped by a diet that is high in fat and low in carbohydrates.

Absence of Pyruvate Carboxylase: Pyruvate carboxylase is an enzyme. A lack of this enzyme causes a very rare condition that interferes with or blocks the production of glucose from pyruvate in the body. Lactic acid and ketones build up in the blood. Often, this disease is fatal. Children who survive have seizures and severe intellectual disability, although there are recent reports of children with milder symptoms. There is no cure, but some children are helped by eating frequent carbohydrate-rich meals and restricting dietary protein.

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.


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.


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.


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. Some children with mild disease benefit from injections of vitamin B1 (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 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 B6 (pyridoxine) or vitamin B12 (cobalamin).


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.

Disorders of Lipid Metabolism

Fats (lipids) are an important source of energy for the body. The body's store of fat is constantly broken down and reassembled to balance the body's energy needs with the food available. Groups of specific enzymes help the body break down and process fats. Certain abnormalities in these enzymes can lead to the buildup of specific fatty substances that normally would have been broken down by the enzymes. Over time, accumulations of these substances can be harmful to many organs of the body. Disorders caused by the accumulation of lipids are called lipidoses. Other enzyme abnormalities prevent the body from converting fats into energy normally. These abnormalities are called fatty acid oxidation disorders.

Gaucher's Disease

Gaucher's disease is caused by a buildup of glucocerebrosides in tissues. Children who have the infantile form usually die within a year, but children and adults who develop the disease later in life may survive for many years.

In Gaucher's disease, glucocerebrosides, which are a product of fat metabolism, accumulate in tissues. Gaucher's disease is the most common lipidosis. The disease is most common among Ashkenazi (Eastern European) Jews. Gaucher's disease leads to an enlarged liver and spleen and a brownish pigmentation of the skin. Accumulations of glucocerebrosides in the eyes cause yellow spots called pingueculae to appear. Accumulations in the bone marrow can cause pain and destroy bone.





Other Rare Hereditary Disorders of Lipid Metabolism

Wolman's disease results when specific types of cholesterol and glycerides accumulate in tissues. This disease causes enlargement of the spleen and liver. Calcium deposits in the adrenal glands cause them to harden, and fatty diarrhea (steatorrhea) also occurs. Infants with Wolman's disease usually die by 6 months of age.

Cerebrotendinous xanthomatosis occurs when cholestanol, a product of cholesterol metabolism, accumulates in tissues. This disease eventually leads to uncoordinated movements, dementia, cataracts, and fatty growths (xanthomas) on tendons. The disabling symptoms often appear after age 30. If started early, the drug chenodiol helps prevent progression of the disease, but it cannot undo any damage already done.

In sitosterolemia, fats from fruits and vegetables accumulate in blood and tissues. The buildup of fats leads to atherosclerosis, abnormal red blood cells, and xanthomas on tendons. Treatment consists of reducing the intake of foods that are rich in plant fats, such as vegetable oils, and taking

In Refsum's disease, phytanic acid, which is a product of fat metabolism, accumulates in tissues. A buildup of phytanic acid leads to nerve and retinal damage, spastic movements, and changes in the bone and skin. Treatment involves avoiding eating green fruits and vegetables that contain chlorophyll. Plasmapheresis, in which phytanic acid is removed from the blood, may be helpful.


Type 1, the chronic form of Gaucher's disease, is the most common. It results in an enlarged liver and spleen and bone abnormalities. Most commonly diagnosed during adulthood, type 1 Gaucher's disease may lead to severe liver disease, including increased risk of bleeding from the stomach and esophagus and liver cancer. Neurologic problems can also occur.

Type 2, the infantile form, usually causes death in the first year of life. Affected infants have an enlarged spleen and severe neurologic problems.

Type 3, the juvenile form, can begin at any time during childhood. Children with type 3 disease have an enlarged liver and spleen, bone abnormalities, and slowly progressive neurologic problems. Children who survive to adolescence may live for many years.

Many people with Gaucher's disease can be treated with enzyme replacement therapy, in which enzymes are given by vein, usually every 2 weeks. Enzyme replacement therapy is most effective for people who do not have nervous system complications.

Tay-Sachs Disease

Tay-Sachs disease is caused by a buildup of gangliosides in the tissues. This disease results in early death.

In Tay-Sachs disease, gangliosides, which are products of fat metabolism, accumulate in tissues. The disease is most common among families of Eastern European Jewish origin. At a very early age, children with this disease become progressively intellectually disabled and appear to have floppy muscle tone. Spasticity develops and is followed by paralysis, dementia, and blindness. These children usually die by age 3 or 4. The disease cannot be treated or cured.

Before conception, parents can find out whether they carry the gene that causes the disease. During pregnancy, Tay-Sachs disease can be identified in the fetus by chorionic villus sampling or amniocentesis.

Niemann-Pick Disease

Niemann-Pick disease is caused by a buildup of sphingomyelin or cholesterol in the tissues. This disease causes many neurologic problems.

In Niemann-Pick disease, the deficiency of a specific enzyme results in the accumulation of sphingomyelin (a product of fat metabolism) or cholesterol. Niemann-Pick disease has several forms, depending on the severity of the enzyme deficiency, which determines how much sphingomyelin or cholesterol accumulates. The most severe forms tend to occur in Jewish people. The milder forms occur in all ethnic groups.

In the most severe form (type A), children fail to grow normally and have several neurologic problems. These children usually die by age 3. Children with type B disease develop fatty growths in the skin, areas of dark pigmentation, and an enlarged liver, spleen, and lymph nodes. They may be intellectually disabled. Children with type C disease develop symptoms during childhood, with seizures and neurologic deterioration.

Some forms of Niemann-Pick disease can be diagnosed in the fetus by chorionic villus sampling or amniocentesis. After birth, the diagnosis can be made by a liver biopsy (removal of a tissue specimen for examination under a microscope). None of the types of Niemann-Pick disease can be cured, and children tend to die of infection or progressive dysfunction of the central nervous system. Currently, some therapies that may slow or halt the progression of symptoms in types B and C are being studied.

Fabry's Disease

Fabry's disease is caused by a buildup of glycolipid in tissues. This disease causes skin growths, pain in the extremities, poor vision, recurrent episodes of fever, and kidney or heart failure.

In Fabry's disease, glycolipid, which is a product of fat metabolism, accumulates in tissues. Because the defective gene for this rare disorder is carried on the X chromosome, the full-blown disease occurs only in males. The accumulation of glycolipid causes noncancerous (benign) skin growths (angiokeratomas) to form on the lower part of the trunk. The corneas become cloudy, resulting in poor vision. A burning pain may develop in the arms and legs, and children may have episodes of fever. Children with Fabry's disease eventually develop kidney failure and heart disease, although most often, they live into adulthood. Kidney failure may lead to high blood pressure, which may result in stroke.

Fabry's disease can be diagnosed in the fetus by chorionic villus sampling or amniocentesis. The disease cannot be cured or even treated directly, but researchers are investigating a treatment in which the deficient enzyme is replaced by transfusion. Treatment consists of taking analgesics to help relieve pain and fever or anticonvulsants. People with kidney failure may need a kidney transplant.

Fatty Acid Oxidation Disorders

Fatty acid oxidation disorders are caused by a lack or deficiency of the enzymes needed to break down fats, resulting in delayed mental and physical development.

Several enzymes help break down fats so that they may be turned into energy. An inherited defect or deficiency of one of these enzymes leaves the body short of energy and allows breakdown products, such as acyl-CoA, to accumulate. The enzyme most commonly deficient is medium chain acyl-CoA dehydrogenase (MCAD). Other enzyme deficiencies include short chain acyl-CoA-dehydrogenase deficiency (SCAD), long chain-3-hydroxyacyl-CoA-deficiency (LCHAD), and trifunctional protein deficiency (TFP).

MCAD Deficiency: This disorder is one of the most common inherited disorders of metabolism, particularly among people of Northern European descent.

Symptoms usually develop between birth and age 3. Children are most likely to develop symptoms if they go without food for a period of time (which depletes other sources of energy) or have an increased need for calories because of exercise or illness. The level of sugar in the blood drops significantly, causing confusion or coma. Children become weak and may have vomiting or seizures. Over the long term, children have delayed mental and physical development, an enlarged liver, heart muscle weakness, and an irregular heartbeat. Sudden death may occur.

Since 2007, nearly every state in the United States has required that all newborns be screened for MCAD with a blood test. Immediate treatment is with glucose given by vein. For long-term treatment, children must eat often, never skip meals, and consume a diet high in carbohydrates and low in fats. Supplements of the amino acid carnitine may be helpful. The long-term outcome is generally good.