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Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 2 - M-Z - I

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toms of a compound heterozygote may be more mild than those of either homozygote, because the two mutant PPCA proteins can complement, or compensate, for each other’s abnormalities.

Demographics

As an autosomal recessive disorder, neuraminidase deficiency with beta-galactosidase deficiency occurs with equal frequency among males and females. Since it requires two defective copies of the PPGB gene, one inherited from each parent, it is much more common in the offspring of couples who are related to each other (consanguineous marriages), such as first or second cousins.

Galactosialidosis appears to occur with the highest frequency among Japanese. The juvenile/adult form is particularly common among Japanese and specific mutations in the PPGB gene occur with a high frequency in this population.

Signs and symptoms

Although the features of galactosialidosis vary greatly, they are very similar to those of neuraminidase deficiency (sialidosis). These progressive symptoms include red spots in the eyes, known as cherry-red macules. Eventually, the corneas may be become cloudy and cataracts and blindness may develop. Hearing loss is also common with galactosialidosis.

Myoclonus are sudden involuntary muscle contractions, which may eventually develop into myoclonic seizures. The myoclonus may become debilitating. Tremors and various other neurological conditions may develop. There may be a progressive loss of muscle coordination, called ataxia, and walking and standing may become increasingly difficult.

Small red skin lesions called angiokeratoma are signs of galactosialidosis. Swollen liver and spleen (hepatosplenomegaly) may develop. Cardiac disease can be one of the major consequences of the disorder.

Symptoms of the more severe forms of galactosialidosis include coarse or malformed facial features and a variety of skeletal malformations (dysostosis multiplex), including short stature. Mental retardation also may be present. Galactosialidosis is one cause of nonimmune hydrops fetalis, the excessive accumulation of fluid in the fetus.

Diagnosis

Early-infantile onset

Some findings of the disorder, including facial and skeletal abnormalities, may be apparent at birth. Skeletal

K E Y T E R M S

Dysostosis multiplex—A variety of bone and skeletal malformations.

Fibroblast—Cells that form connective tissue fibers like skin.

Galactosialidosis—The inherited disorder known as neuraminidase deficiency with beta-galactosi- dase deficiency.

Ganglioside—A complex membrane lipid made up of a long-chain fatty acid, a long-chain amino alcohol, and an oligosaccharide containing sialic acid.

Glycoprotein—A protein with at least one carbohydrate group.

Heterozygote—Having two different versions of the same gene.

Homozygote—Having two identical copies of a gene or chromosome.

Lysosome—Membrane-enclosed compartment in cells, containing many hydrolytic enzymes; where large molecules and cellular components are broken down.

Myoclonus—Twitching or spasms of a muscle or an interrelated group of muscles.

Oligosaccharide—Several monosaccharide (sugar) groups joined by glycosidic bonds.

Polysaccharide—Linear or branched macromolecule composed of numerous monosaccharide (sugar) units linked by glycosidic bonds.

Recessive—Genetic trait expressed only when present on both members of a pair of chromosomes, one inherited from each parent.

Sialic acid—N-acetylneuraminic acid, a sugar that is often at the end of an oligosaccharide on a glycoprotein.

Sialidosis—An inherited disorder known as neuraminidase deficiency.

Vacuolation—The formation of multiple vesicles, or vacuoles, within the cytosol of cells.

x rays may be used to diagnose dysostosis multiplex. Magnetic resonance imaging (MRI) or computer tomography (CT) scans may be used to determine brain atrophy. An electroencephalogram (EEG) may indicate epileptic activity.

deficiency galactosidase-beta with deficiency Neuraminidase

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Neuraminidase deficiency with beta-galactosidase deficiency

Neuraminidase activity

Typically, neuraminidase deficiency is diagnosed by measuring the activity of the enzyme in cultures of fibroblast cells (connective tissue cells) that have been grown from cells obtained by a skin biopsy. Neuraminidase activity usually is measured by testing the ability of fibroblast cell preparations to hydrolyze, or cleave, a synthetic compound such as 4-methylumbellif- eryl-D-N-acetylneuraminic acid. Hydrolysis by neuraminidase liberates 4-methylumbelliferone, which is a compound with a fluorescence that can be measured accurately. The normal range of neuraminidase activity in fibroblasts is 95–653 picomoles per min per mg of protein. With galactosialidosis, neuraminidase activity in fibroblasts may be less than 4% of normal.

Beta-galactosidase activity

Beta-galactosidase activity in blood cells is measured in much the same way as neuraminidase activity in fibroblasts. Using the substrate 4-methylumbelliferyl- alpha-D-galactopyranoside, the fluorescence of 4-methy- lumbelliferone that is liberated through the action of beta-galactosidase is measured.

In severe forms of galactosialidosis, beta-galactosi- dase activity is less than 15% of normal and neuraminidase activity is less than 1% of normal. The combination of low beta-galactosidase and low neuraminidase in fibroblasts, with normal levels of other lysosomal enzymes, is diagnostic for galactosialidosis.

PPCA activity

The enzymatic activity of PPCA also can be measured in fibroblasts. In the early-infantile form of galactosialidosis, PPCA activity may be completely lacking. A small amount of PPCA activity (2–5% of normal) usually is present in the lysosomes of individuals with other forms of galactosialidosis. The highest levels of PPCA activity are associated with the least severe and lateronset forms of the disorder. Carriers with a single mutated PPGB gene may have only half of the normal level of PPCA activity, although they are without symptoms of the disorder.

Histology

In neuraminidase deficiency with beta-galactosidase deficiency, the lysosomes fill with sialyloligosaccharides and sialylglycopeptides (partially degraded proteins with sialyloligosaccharides still attached). These swollen lysosomes may form inclusion bodies and give cells a vacuolated appearance that is diagnostic of lysosomal storage disease.

Neuraminidase deficiency may be diagnosed by histological, or microscopic, examination of a number of different types of cells that may show this cytosolic vacuolation. These cells include the Kupffer cells of the liver, lymphocytes (white blood cells that produce antibodies), bone marrow cells, epithelial skin cells, fibroblasts, and Schwann cells, which form the myelin sheaths of nerve fibers.

Urine tests

Neuraminidase deficiency may be diagnosed by screening the urine for the presence of sialyloligosaccharides, using chromatography to separate the components of the urine on the basis of size and charge. In unaffected individuals, sialyloligosaccharides are cleaved by neuraminidase and, therefore, are present in the urine in only very low amounts. With neuraminidase deficiency, urine levels of sialyloligosaccharides may be three to five times higher than normal.

Sialylglycopeptides can be detected in the urine under conditions of neuraminidase deficiency. In neuraminidase deficiency with beta-galactosidase deficiency, keratan sulfate, which accumulates because of the low activity of GALNS, also can be identified in the urine.

Prenatal diagnosis

Galactosialidosis may be diagnosed prenatally. In atrisk fetuses, cultured fetal cells from the amniotic fluid (amniocytes), obtained by amniocentesis, or cultured chorionic villi cells, obtained by chorionic villi sampling (CVS) in the early weeks of pregnancy, may be tested for neuraminidase and beta-galactosidase activities. Furthermore, the enzymatic activities of PPCA can be measured in amniocytes and chorionic villi. PPCA activity is normally very high in these cells and low activity is an indication of an affected fetus. However, since carriers of a single mutated PPGB gene do not have symptoms of galactosialidosis, it may be difficult to recognize an atrisk fetus unless there is a family history of the disorder.

Treatment and management

At present, there is no treatment for neuraminidase deficiency with beta-galactosidase deficiency. Rather, attempts are made to manage individual symptoms. Myoclonic seizures, in particular, are very difficult to control. Bone marrow transplantation is being studied as a treatment for severe galactosialidosis.

Prognosis

The prognosis for individuals with this disorder varies greatly depending on the specific genetic mutation,

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which determines the age of onset and severity of the disease. Individuals with mild forms of galactosialidosis may have nearly normal life expectancies. However, the early-infantile form of galactosialidosis usually results in death shortly after birth.

Resources

BOOKS

Saito, M., and R. K. Yu. “Biochemistry and Function of Sialidases.” In Biology of the Sialic Acids. Edited by A. Rosenberg, 7–67. New York: Plenum Press, 1995.

Thomas, G. H., and A. L. Beaudet. “Disorders of Glycoprotein Degradation and Structure: Alpha-mannosidosis, Betamannosidosis, Fucosidosis, Sialidosis, Aspartylglucosaminuria and Carbohydrate-deficient Glycoprotein Syndrome.“ In The Metabolic and Molecular Bases of

Inherited Disease. Edited by C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, 2529–61. New York: McGraw Hill, Inc., 1995.

PERIODICALS

Hiraiwa, M. “Cathepsin A/Protective Protein: An Unusual

Lysosomal Multifunctional Protein.” Cellular and

Molecular Life Sciences 56 (December 1999): 894–907.

ORGANIZATIONS

The International Society for Mannosidosis and Related Diseases. 3210 Batavia Avenue, Baltimore, MD 21214. (410) 254-4903. info@mannosidosis.org. http://www

.mannosidosis.org .

United Leukodystrophy Foundation. 2304 Highland Drive, Sycamore, IL 60178. (815) 895-3211. (800) 728-5483. ulf@tbcnet.com. http://www.ulf.org/ .

WEBSITES

Murphy, Paul. “Lysosomal Storage Diseases: A Family Sourcebook.” Human Genetic Disease: A Layman’s Approach. http://mcrcr2.med.nyu.edu/murphp01/ lysosome/bill1a.htm .

Margaret Alic, PhD

I Neurofibromatosis

Definition

Neurofibromatosis (NF), or von Recklinghausen disease, is a disorder which causes development of multiple soft tumors (neurofibromas). These tumors occur under the skin and throughout the nervous system (cells which control body movement and sensation).

Description

Neural crest cells are primitive cells which exist during fetal development. These cells eventually turn into

K E Y T E R M S

Chromosome—A microscopic thread-like structure found within each cell of the body and consists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromosomes or their shape and size (structure) may lead to physical or mental abnormalities.

Mutation—A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring.

Neurofibroma—A soft tumor usually located on a nerve.

Tumor—An abnormal growth of cells. Tumors may be benign (noncancerous) or malignant (cancerous).

cells that form nerves throughout the brain, spinal cord, and body. Collectively, this system of nerve cells is called the nervous system, which coordinates movement and sensation. Some nerve cells carry impulses from the brain to muscles or other peripheral structures, hence the name peripheral nervous system. Another group of nerve cells called the central nervous system are capable of transmitting sensation back to the brain for interpretation (such as feeling cold or hot).

In neurofibromatosis, a genetic defect causes these neural crest cells to develop abnormally. This results in numerous tumors and malformations of the nerves, bones, and skin.

Genetic profile

Both forms of neurofibromatosis are caused by a defective gene. NF-1 is due to a defect on chromosome 17; NF-2 results from a defect on chromosome 22. Both of these disorders are inherited as a dominant trait. This means that anybody who receives just one defective gene will have the disease. However, a family pattern of NF is only evident for about half of all cases of NF. The other cases of NF occur due to a spontaneous mutation (a spontaneous and permanent change in the structure of a specific gene). Once a spontaneous mutation has been established in an individual it is then possible to be passed on to any offspring. The chance of a person with NF passing on the NF gene to their child is 50%. There are different pathologic alleles (variations of the mutant gene). The frequency of spontaneous (new) mutations is very high and causes for this are still unknown.

Neurofibromatosis

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Neurofibromatosis

The large and small protrudings growths on the back of this patient are characteristic of neurofibromatosis.

(Custom Medical Stock Photo, Inc.)

Demographics

Neurofibromatosis-I occurs in about one of every 4,000 births. Neurofibromatosis-I is one of the most common genetic disorders that is dominantly inherited. Two types of NF exist, NF-1 (90% of all cases), and NF-2 (10% of all cases).

Signs and symptoms

NF-1 has a number of possible signs and can be diagnosed if any two of the following are present:

The presence of café-au-lait (French for coffee-with- milk) spots. These are patches of tan or light brown skin, usually about five to 15 mm in diameter. Nearly all patients with NF-1 will display these spots.

Multiple freckles in the armpit or groin area.

Ninty percent of patients with NF-1 have tiny tumors called Lisch nodules in the iris (colored area) of the eye.

Neurofibromas. These soft tumors are the hallmark of NF-1. They occur under the skin, often located along nerves or within the gastrointestinal tract. Neurofibromas are small and rubbery, and the skin overlying them may be somewhat purple in color.

Skeletal deformities, such as a twisted spine (scoliosis), curved spine (humpback), or bowed legs.

Tumors along the optic nerve (the nerve cells which transmit a visual stimulus to the back part of the brain called the occipital lobe, for intrepretation), which cause vision disturbance occurs in about 20% of patients.

The presence of NF-1 in a patient’s parent, child, or sibling.

• Hypertension, or elevated blood pressure.

There are very high rates of speech impairment, learning disabilities, and attention deficit disorder in children with NF-1. Other complications include the development of a seizure disorder (an abnormal firing of nerve cells in muscles, causing severe contractions, sometimes involving the whole body), or abnormal accumulation of fluid within the brain (a condition called hydrocephalus). A number of cancers are more common in patients with NF-1. These include a variety of types of malignant brain tumors, as well as leukemia, and cancerous tumors of certain muscles (rhabdomyosarcoma), the adrenal glands (pheochromocytoma), or the kidneys (Wilms’ tumor).

Patients with NF-2 do not necessarily have the same characteristic skin symptoms (café-au-lait spots, freckling, and neurofibromas of the skin) that appear in NF-1. The characteristic symptoms of NF-2 are due to tumors along the acoustic nerve. Interfering with the function of this nerve results in the loss of hearing; and the tumor may spread to neighboring nervous system structures, causing weakness of the muscles of the face, headache, dizziness, poor balance, and uncoordinated walking. Cloudy areas on the lens of the eye (called cataracts) frequently develop at an unusually early age. As in NF-1, the chance of brain tumors developing is unusually high.

Diagnosis

Diagnosis is based on the broad spectrum of clinical signs previously described, which usually can be detected by careful physical examination, ophthalmologic evaluation (visualizing the structures in the eye) and audiogram (test to measure hearing ability). Diagnosis of NF-1 requires that at least two of the listed signs are present. Diagnosis of NF-2 requires the presence of either a mass on the acoustic nerve or another distinctive nervous system tumor. An important diagnostic clue for either NF-1 or NF-2 is the presence of the disorder in a patient’s parent, child, or sibling. A test to detect a protein (the end-products of a gene) relevant to NF-1 mutagenesis has been created, but accuracy for this procedure has not been established.

Monitoring the progression of neurofibromatosis involves careful testing of vision and hearing. X ray studies of the bones are frequently indicated to detect for the development of deformities. CT scans and MRI scans are performed to track the development/progression of tumors in the brain and along the nerves. Auditory evoked potentials (the electric response evoked in the cerebral cortex by stimulation of the acoustic nerve) may be helpful to determine acoustic nerve involvement, and EEG (electroencephalogram, a record of electrical

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impulses in the brain) may be required for patients with suspected seizures. Regular blood pressure monitoring is also advised.

Treatment

There are no available treatments for the disorders which underlie either type of neurofibromatosis. To some extent, the symptoms of NF-1 and NF-2 can be treated individually. Skin tumors can be surgically removed. Some brain tumors, and tumors along the nerves, can be surgically removed, or treated with drugs (chemotherapy) or x-ray treatments (radiation therapy). Twisting or curving of the spine and bowed legs may require surgical treatment, or the wearing of a special brace.

Prognosis

Prognosis varies depending on the tumor type which develops. As tumors grow, they begin to destroy surrounding nerves and structures. Ultimately, this destruction can result in blindness, deafness, increasingly poor balance, and increasing difficulty with the coordination necessary for walking. Deformities of the bones and spine can also interfere with walking and movement. When cancers develop, prognosis worsens according to the specific type of cancer.

Prevention

There is no known way to prevent the approximately 50% of all NF cases that occur due to a spontaneous change in the genes (mutation). New cases of inherited NF can be prevented with careful genetic counseling. A person with NF can be made to understand that each of his or her offspring has a 50% chance of also having NF when a parent has NF. Special tests can be performed on the fetus (developing baby) during pregnancy to determine if the fetus will be born with this disorder. Amniocentesis (where a needle is passed through the mother’s abdomen into the amniotic sac which contains the amniotic fluid and cushions the developing fetus) or chorionic villus sampling (a procedure involving extraction of a tissue sample from the placenta, the structure which connects the fetal blood with the mother, necessary for nutrient and waste exchange) are two techniques which allow small amounts of fetal DNA (deoxyribonucleic acid, the chemical which contains specific codes which determine genetic makeup of an individual) removed for analysis. The tissue can then be examined for the presence of the parent’s genetic defect. Some families choose to use this information in order to prepare for the arrival of a child with a serious medical condition. Other families may choose not to continue the pregnancy.

Resources

BOOKS

Haslam, Robert H. A. “Neurocutaneous Syndromes.” In Nelson Textbook of Pediatrics, edited by Richard Behrman. Philadelphia: W. B. Saunders Co., 1996.

PERIODICALS

“Health Supervision for Children with Neurofibromatosis.” Pediatrics 96, 2 (August 1995): 368+.

Heim R. A., et al. “Distribution of 13 truncating mutations in the neurofibromatosis 1 gene.” Human Molecular Genetics 4 (1995): 975-81.

Levy, Charles E. “Physiatry and Care of Patients with Neurofibromatosis.” The Journal of the American Medical

Association 278, 18 (November 12, 1997): 1493 . Waller, Amy L., and James E. Baumgartner. “Current Concepts

in the Management of Neurofibromatosis Type 1.” Physician Assistant 21, 8 (August 1997): 103+.

ORGANIZATIONS

March of Dimes Birth Defects Foundation. National Office, 1275 Mamaroneck Ave., White Plains, NY 10605. (888) 663-4637. resourcecenter@modimes.org. http://222

.modimes.org .

The National Neurofibromatosis Foundation, Inc. 95 Pine St., 16th Floor, New York, NY 10005. (800)323-7938.http://nf.org .

Neurofibromatosis, Inc. 8855 Annapolis Rd., #110, Lanham, MD 20706-2924. (800) 942-6825.

Laith Farid Gulli, MD

I Niemann-Pick disease

Definition

Niemann-Pick disease (NPD) is a disorder of fat metabolism that causes abnormalities of the skin, eyes, musculoskeletal system, nervous system, liver, and lymphoid organs. It is named for German pediatricians Albert Niemann (1880-1921) and Ludwig Pick (18981935). Six types of the disease have been identified (A, B, C, D, E, and F).

Description

Niemann-Pick disease is inherited through an autosomal recessive trait. The different types of NPD are characterized by an abnormal accumulation of sphingomyelin. A sphingomyelin is any group of sphingolipids (consists of a lipid and a sphingosine) containing phosphorus. It occurs primarily in the tissue of the nervous system.

disease Pick-Niemann

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Niemann-Pick disease

K E Y T E R M S

Hepatosplenomegaly—Enlargement of the liver and spleen.

Macula—Abnormal pigmentation in the tissue of the eye.

Sphingomyelin—A group of sphingolipids containing phosphorus.

Sphingomyelinase—Enzyme required to breakdown sphingomyelin into ceramide.

Some characteristics of Niemann-Pick disease may be common for all types. Common symptoms include jaundice, hepatosplenomegaly (enlargement of the liver and spleen), physical and mental impairment, and feeding difficulties. Symptoms for most types of NPD (A, B, C, and D) are seen in infancy or early childhood.

Alternate names associated with the NPD disorder are lipid histiocytosis, sphingomyelin lipidosis, and sphingomyelinase deficiency.

Genetic profile

Niemann-Pick disease is caused by an autosomal recessive genetic trait, therefore the condition will not appear unless a person receives the same defective gene for fat metabolism from each parent. This means that if a person is heterozygous for the trait then they will be a carrier and if they are homozygous then they will show the trait. There is a 25% chance for each pregnancy that the disorder will passed onto the child (ren) if both parents are heterozygous for the trait and a 100% chance if both parents are homozygous for the trait.

The gene for Niemann-Pick disease types A and B has been located on the short arm (p) of chromosome 11. The gene for types C and D has been located on chromosome 18. NPD types C and D are believed to be allelic disorders. This term means that the two types are due to different mutations (a change in building block sequences) of the same gene. Type E is similar to type C and may be a variant form. It is possible that type F is a mild form of type B but as of 2000 there is no supportive research.

Demographics

Niemann-Pick disease affects males and females equally and has been identified in all races. Type A is the most common form of the disease and is responsible for about 80% of NPD cases.

Types A and B occur mainly in families of eastern European Jewish descent (Ashkenazi). It is estimated that one in 75 may be carriers. Type B is also common in individuals from Tunisia, Morocco, and Algeria. Type C is more common in Spanish-Americans in southern New Mexico and Colorado. As of 2000, it is believed that over 300 people in the United States are affected with type C and an estimated one million worldwide. Type D occurs in French-Canadian descendents from Nova Scotia. Type F has been found to affect people of Spanish descent. As of 2000, it is not clear as to which populations are affected by type E.

Signs and symptoms

Type A

This is the infantile or acute form of Niemann-Pick disease. Abnormal accumulation of sphingomyelin is seen in the developing fetus. Sphingomyelin accumulation could represent 2-5% of the total body weight in individuals with type A. Symptoms may progress rapidly and include the following:

Hepatosplenomegaly. Enlargement of the liver and spleen is due to the low levels of the enzyme sphingomyelinase. This enzyme is required to breakdown sphingomyelin in the body. The decreased levels of this enzyme cause sphingomyelin content of the liver and spleen to be abnormally high. This occurs between the ages of six and 12 months. Accurance of liver enlargement is seen more commonly than that of the spleen.

Musculoskeletal abnormalities. Degenerative muscle weakness and floppiness may occur due to a decline in motor and intellectual functioning. This is caused by increased accumulation of sphingomyelin in the nervous system. Seizures and muscular spasms may also occur.

Macula. Pigmentation in the tissue of the eyes may occur. Formation of cherry-red spots may be seen in approximately 50% of patients diagnosed with NPD type A. This is not visible and can only be detected using special instrumentation.

Additional abnormalities. These include jaundice, fever, and gastrointestinal (GI) problems such as vomiting, diarrhea, and abdominal distention.

Type B

This is the chronic form of Niemann-Pick disease. Symptoms progress slowly and begin during infancy or early childhood. Like type A, type B occurs due to a deficiency of the enzyme sphingomyelinase. Neurological involvement is minimal and usually absent. Symptoms are as follows:

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Hepatosplenomegaly. Abnormal enlargement of the liver and spleen occur due to the accumulation of sphingomyelin.

Macula. The formation of cherry-red spots on the eyes may be seen in some affected individuals.

Additional abnormalities. These include a slow growth rate and increased incidence of respiratory infections.

Type C

This type of Niemann-Pick disease occurs due to the inability to breakdown cholesterol. This may lead to a secondary deficiency of acid sphingomyelinase. Studies have shown that there may be two types of NPD type C, NPC1 and NPC2. NPC2 is believed to be caused by a deficiency of HE1 (human epididymis-1), which is a cho- lesterol-binding protein. NPD type C can occur at anytime between infancy and adulthood but is usually seen in children between the ages of three and 10. The progression of symptoms in NPD type C is slow and the loss of mental and motor function usually occur in early adulthood. Symptoms are as follows:

Hepatosplenomegaly. The liver and spleen may be moderately enlarged due to the inability to breakdown cholesterol.

Musculoskeletal. Psychomotor dysfunction, seizures, tremors, and spasticity of the muscles result due to excessive accumulation of cholesterol in the brain. An individual with NPD type C may also exhibit extreme muscle weakness due to emotional excitement and ataxia. Ataxia is the inability to coordinate voluntary muscle movements.

Eyes. Type C is characterized by vertical gaze palsy. This results in the difficulty or loss of up and down movement. Some individuals may experience opththalmoplegia (loss of muscle ability to move eyes). This is an impaired function of the muscles of the eyes and may cause the eyes to become stuck or fixed in an upward position.

Additional abnormalities. These include dysarthria and jaundice. Dysarthria is the inability to form and speak words clearly. Jaundice is a yellow discoloration of the skin, eyes, and possibly the mucous membranes.

Type D

This is the Nova Scotia variant of Niemann-Pick disease. Like NPD type C, individuals with type D are unable to metabolize cholesterol properly. Individuals with type D do not suffer from a deficiency of acid sphingomyelinase. The symptoms of type D are very similar to type C but vary from case to case.

Type E

As of 2000, many researchers consider this to be a variant form of type C. NPD type E does not usually begin until adulthood and neurological impairment is rare. Symptoms include the following:

Hepatosplenomegaly. Enlargement of the liver and spleen may occur due to the accumulation of cholesterol.

Dementia. This is characterized by confusion, disorientation, deterioration of intellectual capacity and function, and impairment of the memory. Dementia is progressive and irreversible.

Ataxia. Individuals may have an inability to coordinate voluntary muscle movements.

Opththalmoplegia. Individuals with type E may have an inability to control the muscle movement of the eyes. This may cause the eyes to become stuck in a certain position.

Type F

This type of Niemann-Pick disease is characterized by a finding of sea-colored blue cells in the blood and/or bone marrow of individuals and therefore may be called Sea-Blue histocyte disease. It affects people of Spanish descent and may be a mild form of type B. Symptoms may include:

Hepatosplenomegaly. Abnormal enlargement of the liver and spleen may occur in individuals with NPD type F.

Cirrhosis. The lobes of the liver may become covered with fibrous tissue (thickened tissue). This fibrous tissue obstructs blood flow through the liver.

Mild thrombocytopenia. Individuals with NPD type F may suffer from a decrease in the number of platelets found in the blood. Platelets are necessary for coagulation of the blood.

Macula. Pigmentation in the tissue of the eyes may occur. Individuals may develop a white ring around the maculae of the eyes.

Hair. Individuals may have an absence of hair in the axillary (armpit) area of the body.

Diagnosis

As of 2000, there is no objective diagnostic test for Niemann-Pick disease types D, E, and F. Types A and B are diagnosed through DNA testing or by a blood test. Blood tests for individuals with types A and B will show low levels of the enzyme sphingomyelinase in white blood cells and elevated sphingomyelin and free cholesterol.

disease Pick-Niemann

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Nijmegen breakage syndrome

Type C can be diagnosed by prenatal testing of fibroclastic cells to determine their ability to process and store cholesterol. This is done by testing the amniotic fluid (liquid which bathes and cushions the fetus). Formation of foam cells occurs in all types of NPD and can be determined through a biopsy of bone marrow tissue. Diagnosis of all types is made possible by taking a detailed family history and a thorough examination of the individual.

Symptoms of Niemann-Pick disease may be similar to those of Refsum syndrome (disorder of fat metabolism associated with abnormal accumulation of phytanic acid in the blood and other body tissues), Tay-Sachs disease (disorder found in Eastern European Jewish descendents that results in deterioration of the central nervous system), Sandhoff disease (lipid storage disorder due to a deficiency of the enzyme hexosaminidase), Gaucher’s disease (lipid storage disease), and Sialidosis (metabolic disorder due to a deficiency of the enzyme alpha-neu- raminidase).

Treatment and management

As of 2000, there is no specific treatment available for any type of Niemann-Pick disease. Individuals are treated on a symptomatic basis. As of 2000, individuals with NPD types A and B have not benefited from enzyme replacement therapies or organ transplants. Cholesterol lowering drugs and low cholesterol diets are often used for individuals with NPD types C and D. As of 2000, these have not been effective in slowing the progress of types C and D.

Investigational therapies are being tested for types A, B, C, and D. The possibility of treatment by bone marrow transplantation is being tested for types A and B. Studies have also been completed on the use of stem cell (a cell which produces usable tissues) transplantation as treatment for types A and B. Researchers at the National Institutes of Health are studying combinations of cholesterol lowering drugs for treatment of NPD types C and D.

Social and lifestyle issues

Individuals diagnosed with Niemann-Pick disease may want to seek counseling or attend support groups that focus on the psychological, physical, and social issues that may result due to the illness.

Parents may want to seek counseling or attend support groups that focus on the lifestyle changes associated with having a child diagnosed with Niemann-Pick disease.

Prognosis

The prognosis for all types of Niemann-Pick disease varies. In type A, death usually results in early childhood.

In individuals with types C and D, death usually results in adolescence or early adulthood. Individuals with type B have a prolonged survival due to the decrease of neurological involvement. As of 2000 the prognosis for types E and F has not been adequately researched.

Affected individuals and their families may want to seek genetic counseling. Pregnant women can receive prenatal testing for NPD type C. Pregnant women that are carriers and have a partner that is a carrier should receive genetic counseling regarding the 25 percent chance of the child having Niemann-Pick disease.

Early diagnosis is important. Due to advances in medicine an early diagnosis may increase life expectancy.

Resources

BOOKS

Bowden, Vickey R., Susan B. Dickey, and Cindy Smith Greenberg. Children and Their Families: The continuum of care. Philadelphia: W. B. Saunders Company, 1998.

Emery, Alan E. H., MD, and David L. Rimoin, MD, eds. “Sphingomylin Lipidoses (Niemann-Pick disease).” In

Principle and Practice of Medical Genetics, Volume 2, New York: Churchhill Livingstone, 1983.

Laith F. Gulli, MD

Tanya Bivins, BS

Niikawa-Kuroki syndrome see Kabuki syndrome

I Nijmegen breakage syndrome

Definition

Nijmegen breakage syndrome (NBS) is a condition in which chromosomes are susceptible to breakage and symptoms include short stature, small head size, and increased risk for learning disabilities/mental retardation, infections, and cancer.

Description

Nijmegen breakage syndrome gets its name from the fact that the first patient was described in Nijmegen in the Netherlands. A registry of patients is maintained there, and patients with the syndrome are susceptible to having their chromosomes break. These breaks result in rearrangements of chromosomes called translocations, in which two chromosomes exchange pieces, and inversions, in which a section of a chromosome breaks off and

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rejoins the chromosome upside down. Chromosome rearrangements in NBS most commonly involve chrmosomes 7 and 14. Genes involved in the immune system, which fights infection, are located on these chromosomes; as a result of disruptions of these genes, most patients with NBS have an increased rate of infections, particularly those involving the respiratory system and the urinary tract. The chromosome breaks also increase susceptibility to cancer. People with NBS are more prone to chromosome breaks when exposed to radiation as well. Other defining features of NBS are short stature and small head size.

Genetic profile

NBS is an autosomal recessive disease, which means that one abnormal gene from each parent must be inherited to develop symptoms. A person with only one defective gene copy is called a carrier and will not show signs of NBS but has a 50% chance of passing along the gene to offspring with each pregnancy. Couples in which both parents are carriers of NBS have a 25% chance in each pregnancy of conceiving an affected child. The gene for NBS is on chromosome 8 and is called the NBS1 gene, coding for a protein called nibrin, which is found in all cells throughout the body. Normal nibrin is believed to be important in the repair of DNA which has been damaged by breaks in both strands.

Most patients have a specific change in both copies of the nibrin gene in which a string of five DNA bases, ACAAA, is missing from a specific area of the gene, leading to a shortened, or truncated, version of nibrin. A few other mutations have been reported in single patients. All of these mutations also result in a shortened, nonfunctional version of nibrin.

Demographics

NBS is extremely rare. Approximately 70 patients have been reported. A total of 55 patients from 44 families had been reportedly enrolled in the Nijmegen registry as of 2001. Most patients have been of Slavic or other European descent, with a few patients reported from New Zealand, Mexico, and the United States.

Signs and symptoms

Virtually all patients with NBS have microcephaly, or a small head size (in the lower 3%), with about 75% having this feature present at birth. Young children with NBS show impaired growth. Babies with NBS are either born small or begin to experience growth delay during their first two years. The growth rate is normal after that, but the children always remain small for their ages.

K E Y T E R M S

Balanced chromosome translocation—A rearrangement of the chromosomes in which two chromosomes have broken and exchanged pieces without the loss of genetic material.

Chromosome inversion—Rearrangement of a chromosome in which a section of a chromosome breaks off and rejoins the chromosome upside down.

Microcephaly—An abnormally small head.

According to data available in 2001, approximately 40% have normal intelligence, 50% have borderline to mild mental retardation (IQ of 55 to 70), and 10% have moderate mental retardation (IQ of 40 to 54). As of 2001, the 55 patients studied in detail showed no correlation between head circumference at birth and IQ. There is a characteristic facial appearance, which includes a receding forehead, long nose, receding chin, extra folds of skin underneath the eyes, freckles on the nose and cheeks, large ears, and thin hair. Patients frequently have café au lait spots (areas of skin that are the color of coffee with milk), and other pigment changes in the skin and eyes.

The incidence of certain birth defects is increased in NBS, with about half of patients having malformed fingers or extra skin between the fingers (called syndactyly). A few patients have been reported to have anal malformations, lack of development of the ovaries and consequent infertility, hip abnormalities, and bone, kidney, and brain abnormalities. Notably lacking is the ataxia, which is progressive loss of coordination, seen in a disorder called ataxia-telangiectasia (A-T), which is otherwise very similar to NBS but is caused by a mutation in a different gene.

People with NBS are at increased risk for infections, most commonly affecting the respiratory tract and urinary tract. Infections of the gastrointestinal tract have also been reported. They are also at increased risk for cancer, mostly B cell lymphoma. Leukemia and other cancers have also been reported.

Diagnosis

A diagnosis of NBS is suspected in children with small head size, slow growth at birth, characteristic facial features including a receding chin and prominent nose, recurrent infections, cancer (particularly B cell lymphoma), and borderline to moderate mental retardation. Prior to the discovery of the nibrin gene, diagnosis could only be confirmed by studying the levels of immune sys-

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tem proteins called immunoglobulins, looking for particular chromosomal changes involving chromosomes 7 and 14, and assessing radiation sensitivity in cells from patients.

Since the gene for NBS was discovered in 1998, it is now possible to look for a mutation in a patient’s nibrin gene. As of 2001, all patients of Slavic origin and approximately 70% of the small number of patients in North America have had two copies of the common five DNA base mutation in the nibrin gene. Other North American patients have had at least one copy of another mutation unique to their family. If a mutation other than the common one is found, it is important to do further investigation to determine whether or not it causes disease, as non-disease causing changes have been reported in the nibrin gene.

Adults who are at risk for having children with NBS, such as siblings of patients, can have carrier testing to determine if they have one altered nibrin gene and are carriers for NBS. During pregnancy, the DNA of a fetus can be tested using cells obtained using the procedures called chorionic villi sampling (CVS), in which cells from the placenta are studied, or amniocentesis, in which skin cells from the amniotic fluid surrounding the baby are tested.

Treatment and management

As of 2001, there is no specific treatment for NBS, although folic acid (a vitamin B derivative) is recommended for prevention of chromosome breaks, since repair of these breaks is compromised in NBS. Similarly, vitamin E is recommended for prevention of further cell damage. For treatment of cancer, high doses of radiation must be avoided, since the damage inflicted on the cells could be fatal.

Prognosis

Patients with NBS have a decreased life span because of the tendency toward infection and cancer. Of the 55 patients in the NBS registry described in 2000, five had died from infections between infancy and eight years of age. Fourteen had died of cancer between the ages of two and 21 years of age. The remaining 36 living patients were between the ages of four and 30.

Resources

BOOKS

Wegner, Rolf-Dieter, et al. “Ataxia-Telangiectasia Variants (Nijmegen Breakage Syndrome).” In Primary Immunodeficiency Diseases: A Molecular and Genetic Approach, edited by Hans D. Ochs, et al. New York: Oxford University Press, 1999, pp. 324-334.

PERIODICALS

The International Nijmegen Breakage Syndrome Study Group.

“Nijmegen Breakage Syndrome.” Archives of Disease in

Childhood 82 (2000): 400-406.

WEBSITES

Concannon, Patrick J., and Richard A. Gatti. “Nijmegen Breakage Syndrome.” GeneClinics. University of Washington, Seattle. http://www.geneclinics.org/profiles/ nijmegen/index.html . (March 31, 2001).

“Nijmegen Breakage Syndrome.” OMIM—Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?251260 . (March 31, 2001).

“Nijmegen Breakage Syndrome.” Virginia Mason Research Center. http://www.vmresearch.org/nbsinfo.htm . (March 31, 2001).

Toni I. Pollin, MS, CGC

Noack syndrome see Pfeiffer syndrome

Non-polyposis colon cancer see Muir-Torre syndrome

I Noonan syndrome

Definition

Noonan syndrome is a condition usually involving a heart problem found at birth, short stature, a broad or webbed neck, pectus excavatum and pectus carinatum (chest deformities), as well as a range of developmental delays. Occasionally, café-au-lait spots (a skin finding) and other features of neurofibromatosis may be present.

Description

First described by the pediatrician and heart specialist Jacqueline Noonan in 1963, Noonan syndrome includes numerous specific features. However, no two affected individuals typically have the exact same combination of these characteristics. As of 2001, there still is no defined list of criteria to diagnose the condition, and no molecular genetic testing exists to confirm a diagnosis. Therefore, attributing an individual’s features to Noonan syndrome is based upon a careful review of medical and family history, a detailed physical examination, and study of other possible diagnoses.

There are three major groups of Noonan syndrome. The classical type is Noonan syndrome, Type 1 (NS1). This is also known as Noonan syndrome, Male Turner syndrome, Female pseudo-Turner syndrome, Turner phenotype with normal karyotype, and Pterygium colli syn-

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