HEREDITARY METABOLIC DISEASES

1. HEREDITARY METABOLIC DISEASES

2. 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.

3. Particular risk factors are: •Advanced maternal age (e.g. Down's syndrome) • Family history of inherited diseases (e.g. fragile X syndrome, Huntington's chorea) • Previous child with genetic disorder (e.g. Tay-Sachs disease)

4. 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.

5. 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.

6. 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.

7. Second-Trimester Screening 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

8. 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)

9. 2. A baby with a birth defect of the abdominal wall 3. Morethanonefetus 4. Pregnancy complications, such as miscarriage, slowed growth or death of the fetus, and premature detachment of the placenta (placental abruption)

10. 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.

11. Triple and Quad Screening • Measuring estriol and beta-human chorionic gonadotropin plus alpha-fetoprotein is called triple screening. • InhibinA 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.

12. 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.

13. 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.

14. 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).

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

22. PHENYLKETONURIA • 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 mental retardation.

24. SYMPTOMS mentalretardationoverthefirstfewyears oflife, whicheventuallybecomessevere. Othersymptomsincludeseizures, nauseaandvomiting, an eczema-like rash, lighterskinandhairthantheirfamilymembers, aggressiveor self-injuriousbehavior, hyperactivity, andsometimespsychiatricsymptoms.

25. 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.

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

28. MAPLE SYRUP URINE DISEASE • Maple syrup urine disease is caused by lack of the enzyme needed to metabolize amino acids. • By-productsoflecine, isoleucine and valinebuildup, causingneurologicchanges, includingseizuresandmentalretardation. These by-productsalsocausebodyfluids, suchasurineandsweat, tosmelllikemaplesyrup

29. 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 develop vomiting, staggering, confusion, coma, and the odor of maple syrup particularly during physical stress, such as infection or surgery

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

31. HOMOCYSTINURIA • Childrenwithhomocystinuriaareunabletometabolizetheaminoacidhomocysteine, which, alongwithcertaintoxic by-products, builds up to cause a variety of symptoms.

32. 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; the child is usually tall and thin with a curved spine, elongated limbs, and long, spiderlike fingers.

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

34. TYROSINEMIA Tyrosinemia is caused by lack of the enzyme needed to metabolize tyrosine. Therearetwomaintypesoftyrosinemia: I and II. Type I tyrosinemiaismostcommoninchildrenof French-Canadian orScandinaviandescent. Childrenwiththisdisordertypicallybecomeillsometimewithinthefirstyearoflifewithdysfunctionoftheliver, kidneys, andnerves, resultinginirritability, rickets, orevenliverfailureanddeath.

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

36. GLYCOGEN STORAGE DISEASES • 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.

37. 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.

39. 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.

40. GALACTOSEMIA Galactosemia (a highbloodlevelofgalactose) iscausedbylackofoneoftheenzymesnecessaryformetabolizinggalactose, a sugarpresentinlactose (milksugar). A metabolitebuildsupthatistoxictotheliverandkidneysandalsodamagesthelensoftheeye, causingcataracts.

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

42. 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.

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

44. A normal diet provides between 10-20 mg of iron daily, of which the body absorbs only 1.0 to 1.5 mg through the intestinal tract. The rest of the iron not absorbed during digestion is excreted in the stool.

45. Normally, the body has about 4,000 mg of iron, of which about 3,000 mg is contained in hemoglobin in the red blood cells. About 500 mg is bound to the storage protein ferritin, and 300 mg is stored in the liver. Transferrin, the protein that carries the iron from organ to organ around the body, helps regulate how and when iron is stored and transferred to bone marrow and other cells when needed for body processes.

46. In hereditary hemochromatosis (HHC), the feedback signal within this complex system is not working properly. The gut continues to absorb iron at 2-4 times the normal rate, despite the body already being overloaded with iron. It takes time for iron overload to reach a level that will cause organ damage and failure. Men typically develop disease between 40 and 60 years of age, and women after menopause.

47. 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.

48. In Gaucher's disease, glucocerebrosides, which are a product of fat metabolism, accumulate in tissues. Gaucher's disease is the most common lipidosis. Gaucher'sdisease 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.

49. 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.

50. 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.