HEREDITARY HEREDITARY METABOLIC METABOLIC DISEASESDISEASES

Hereditary metabolic disorders form a wide class of human hereditary disorders, which includes more than 600 different forms. Some of them are rare or even extremely rare. However, their summarized incidence is fairly high, 1:3000 to 1:5000 live births.

Particular risk factors Particular risk factors are:are:

••Advanced maternal age (e.g. Advanced maternal age (e.g. Down's syndrome)Down's syndrome)

• • Family history of inherited Family history of inherited diseases (e.g. fragile X diseases (e.g. fragile X syndrome, Huntington's chorea)syndrome, Huntington's chorea)

• • Previous child with genetic Previous child with genetic disorder (e.g. Tay-Sachs disease)disorder (e.g. Tay-Sachs disease)

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.

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.

Second-Trimester Screening

Important markers include the following:Alpha-fetoprotein: A protein produced by the fetusEstriol: A hormone formed from substances produced by the fetusHuman chorionic gonadotropin: A hormone produced by the placentaInhibin A: A hormone produced by the placenta

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

2. A baby with a birth defect of the abdominal wall

3. More than one fetus

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

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.

Triple and Quad ScreeningMeasuring 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.

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.

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).

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.

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.

Amniocentesis

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.

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.

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.

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.

PHENYLKETONURIAPHENYLKETONURIA

Excess phenylalanine is normally Excess phenylalanine is normally converted to tyrosine, another converted to tyrosine, another amino acid, and eliminated from amino acid, and eliminated from the body. Without the enzyme that the body. Without the enzyme that converts it to tyrosine, converts it to tyrosine, phenylalanine builds up in the phenylalanine builds up in the blood and is toxic to the brain, blood and is toxic to the brain, causing mental retardation.causing mental retardation.

SYMPTOMSSYMPTOMS mental retardation over the first few mental retardation over the first few

yearsyears

of life, which eventually becomes of life, which eventually becomes severe. Other symptoms include severe. Other symptoms include seizures, nausea and vomiting, an seizures, nausea and vomiting, an eczema-like rash, lighter skin and hair eczema-like rash, lighter skin and hair than their family members, than their family members, aggressive or self-injurious behavior, aggressive or self-injurious behavior, hyperactivity, and sometimes hyperactivity, and sometimes psychiatric symptoms. psychiatric symptoms.

Untreated children often give Untreated children often give off a "mousy" body and urine off a "mousy" body and urine odor as a result of a by-odor as a result of a by-product of phenylalanine product of phenylalanine (phenylacetic acid) in their (phenylacetic acid) in their urine and sweat.urine and sweat.

A phenylalanine-restricted diet, if started early and maintained well, allows for normal development.

MAPLE SYRUP URINE DISEASEMAPLE SYRUP URINE DISEASEMaple syrup urine disease is caused by lack of the enzyme needed to metabolize amino acids. By-products of By-products of lecine, isoleucine lecine, isoleucine and valineand valine build up, causing build up, causing neurologic changes, including neurologic changes, including seizures and mental retardation. seizures and mental retardation. These by-products also cause These by-products also cause body fluids, such as urine and body fluids, such as urine and sweat, to smell like maple syrupsweat, to smell like maple syrup

infants develop neurologic infants develop neurologic abnormalities, including seizures and abnormalities, including seizures and coma, during the first week of life coma, during the first week of life and can die within days to weeksand can die within days to weeks

In the milder forms, children initially In the milder forms, children initially appear normal but develop vomiting, appear normal but develop vomiting, staggering, confusion, coma, and the staggering, confusion, coma, and the odor of maple syrup particularly odor of maple syrup particularly during physical stress, such as during physical stress, such as infection or surgeryinfection or surgery

Infants with severe disease are Infants with severe disease are treated with dialysis. Some treated with dialysis. Some children with mild disease benefit children with mild disease benefit from injections of the vitamin B1 from injections of the vitamin B1 (thiamin). After the disease has (thiamin). After the disease has been brought under control, been brought under control, children must always consume a children must always consume a special artificial diet that is low in special artificial diet that is low in the particular amino acids that are the particular amino acids that are affected by the missing enzyme.affected by the missing enzyme.

HOMOCYSTINURIAHOMOCYSTINURIA

Children with Children with homocystinuria are unable homocystinuria are unable to metabolize the amino to metabolize the amino acid homocysteine, which, acid homocysteine, which, along with certain toxic by-along with certain toxic by-productsproducts, builds up to cause a variety of symptoms.

The first symptoms, including The first symptoms, including dislocation of the lens of the eye, dislocation of the lens of the eye, causing severely decreased causing severely decreased vision, usually begin after 3 vision, usually begin after 3 years of age. Most children have years of age. Most children have skeletal abnormalities, including skeletal abnormalities, including osteoporosis; the child is usually osteoporosis; the child is usually tall and thin with a curved spine, tall and thin with a curved spine, elongated limbs, and long, elongated limbs, and long, spiderlike fingers. spiderlike fingers.

Some children with homocystinuria improve when given vitamin B6 (pyridoxine) or vitamin B12 (cobalamin).

TYROSINEMIATYROSINEMIA

Tyrosinemia is caused by lack of the enzyme needed to metabolize tyrosine.

There are two main types of tyrosinemia: I There are two main types of tyrosinemia: I and II. Type I tyrosinemia is most common and II. Type I tyrosinemia is most common in children of French-Canadian or in children of French-Canadian or Scandinavian descent. Children with this Scandinavian descent. Children with this disorder typically become ill sometime disorder typically become ill sometime within the first year of life with dysfunction within the first year of life with dysfunction of the liver, kidneys, and nerves, resulting of the liver, kidneys, and nerves, resulting in irritability, rickets, or even liver failure in irritability, rickets, or even liver failure and death. and death.

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

GLYCOGEN STORAGE GLYCOGEN STORAGE DISEASESDISEASES

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

Types and Characteristics of Glycogen Storage Diseases

Name Affected Organs Symptoms

Type O Liver, muscle Enlarged liver with accumulation of fat inside the liver cells (fatty liver); episodes of low blood sugar levels (hypoglycemia) when fasting

von Gierke's disease (Type IA)

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

Type IB Liver, white blood cells

Same as in von Gierke's disease but may be less severe; low white blood cell count; recurring mouth and intestinal infections or Crohn's disease

Pompe's disease (Type II)

All organs Enlarged liver and heart, muscle weakness

Forbes' disease (Type III)

Liver, muscle, heart, white blood cells

Enlarged liver or cirrhosis; low blood sugar levels; muscle damage and heart damage in some people

Andersen's disease (Type IV)

Liver, muscle, most tissues

Cirrhosis in juvenile type; muscle damage and heart failure in adult (late-onset) type

McArdle's disease (Type V)

Muscle Muscle cramps or weakness during physical activity

Hers' disease (Type VI)

Liver Enlarged liver; episodes of low blood sugar when fasting; often no symptoms

Tarui's disease (Type VII)

Skeletal muscle, red blood cells

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

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.

GALACTOSEMIAGALACTOSEMIA

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

A newborn with galactosemia A newborn with galactosemia seems normal at first but within a seems normal at first but within a few days or weeks loses his few days or weeks loses his appetite, vomits, becomes appetite, vomits, becomes jaundiced, has diarrhea, and stops jaundiced, has diarrhea, and stops growing normally. White blood cell growing normally. White blood cell function is affected, and serious function is affected, and serious infections can develop. If infections can develop. If treatment is delayed, affected treatment is delayed, affected children remain short and become children remain short and become mentally retarded or may die.mentally retarded or may die.

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

Hereditary hemochromatosis Hereditary hemochromatosis is is a a genetic, metabolic disorder that genetic, metabolic disorder that results in iron overloadresults in iron overload; the body ; the body absorbs and retains too much absorbs and retains too much dietary iron. It is a primary disorder dietary iron. It is a primary disorder of iron metabolism that can affect of iron metabolism that can affect many organ systems including the many organ systems including the liver, pancreas, heart, endocrine liver, pancreas, heart, endocrine glands and joints. It is glands and joints. It is potentially potentially fatal, but easily treated if fatal, but easily treated if diagnosed earlydiagnosed early, before the excess , before the excess iron causes irreversible damageiron causes irreversible damage

A normal diet provides between A normal diet provides between 10-20 mg of iron daily10-20 mg of iron daily, of which , of which the body absorbs only 1.0 to 1.5 mg the body absorbs only 1.0 to 1.5 mg through the intestinal tract. through the intestinal tract.

The rest of the iron not absorbed The rest of the iron not absorbed during digestion is excreted in the during digestion is excreted in the stool.stool.

Normally, the body has about 4,000 mg of Normally, the body has about 4,000 mg of iron, of which about 3,000 mg is iron, of which about 3,000 mg is contained in hemoglobin in the red blood contained in hemoglobin in the red blood cells.cells.

About 500 mg is bound to the storage About 500 mg is bound to the storage protein ferritin, and 300 mg is stored in protein ferritin, and 300 mg is stored in the liver. Transferrin, the protein that the liver. Transferrin, the protein that carries the iron from organ to organ carries the iron from organ to organ around the body, helps regulate how and around the body, helps regulate how and when iron is stored and transferred to when iron is stored and transferred to bone marrow and other cells when bone marrow and other cells when needed for body processes.needed for body processes.

In hereditary hemochromatosis (HHC), In hereditary hemochromatosis (HHC), the feedback signal within this complex the feedback signal within this complex system is not working properly. The gut system is not working properly. The gut continues to absorb iron at 2-4 times the continues to absorb iron at 2-4 times the normal rate, despite the body already normal rate, despite the body already being overloaded with iron.being overloaded with iron.

It takes time for iron overload to reach a It takes time for iron overload to reach a level that will cause organ damage and level that will cause organ damage and failure. failure. Men typically develop disease Men typically develop disease between 40 and 60 years of age, and between 40 and 60 years of age, and women after menopause.women after menopause.

GAUCHER'S DISEASEis 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. 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.

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.

TAY-SACHS DISEASE is caused by a buildup of gangliosides in

the tissues. This disease results in early death.

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.

NIEMANN-PICK DISEASE is caused by a buildup of sphingomyelin

or cholesterol in the tissues. This disease causes many neurologic problems.

Niemann-Pick disease has several forms, depending on the severity of the enzyme deficiency, which determines how much sphingomyelin or cholesterol accumulates.

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.

FABRY'S DISEASE 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 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.