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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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include IUGR and polyhydramnios. Both findings often lead to an obvious difference in the size of a pregnant woman’s uterus and her estimated weeks of pregnancy. A woman whose fetus has severe IUGR and normal amniotic fluid, often appears less pregnant than she actually is. In contrast, a woman with polyhydramnios often appears more pregnant, or larger. A detailed prenatal ultrasound test may be used to obtain pictures of abnormalities of the fetus as well as possible abnormalities of the placenta whenever there is an apparent discrepancy in a woman’s size and her dates.

Two groups have separately reported diagnosis of NLS using ultrasound. However, in both cases, the diagnosis was formally established only after delivery. A number of the physical findings associated with NLS, particularly those involving the face, limbs, and brain, may be apparent following a detailed ultrasound later in pregnancy. In experienced hands and with the knowledge of a previous affected infant, some of these findings may be observed earlier.

In one of the published cases, a diagnosis of NLS was helped by the physical findings of an ultrasound exam at 32 weeks of pregnancy. The fetus was found to have many of the abnormalities associated with NLS. In the second report, ultrasound was used to assess fetal movement patterns at 34 weeks of pregnancy. Abnormal fetal movement is indicative of abnormal brain development. The authors were able to document a lack of normal fetal activity, such as breathing movements, sucking, swallowing, hiccups, and movements of the arms and legs in a fetus diagnosed with NLS after birth.

Accurate diagnosis of this condition is difficult before birth for those couples in which no NLS gene has been identified and no family history of NLS is known. While the combination of abnormal physical development and possibly abnormal fetal activity is highly indicative of a severe genetic condition, both would not be specific enough to pinpoint Neu-Laxova syndrome as the cause in all cases. Other genetic syndromes would be under consideration, pending a clinical examination after delivery.

For this reason, a careful physical evaluation after birth is critical in establishing a diagnosis of NLS. For those infants who are stillborn and for those who die after delivery, an autopsy is also helpful in documenting all of the associated internal abnormalities. A precise diagnosis facilitates accurate genetic counseling, including prognosis for an affected child and the risk of recurrence for future pregnancies.

Treatment and management

For those couples who have had a previous child with Neu-Laxova syndrome, serial prenatal ultrasound

evaluations should be offered to monitor fetal growth, screen for physical abnormalities, and, assess fetal wellbeing later in pregnancy given the increased risk for stillbirth. Ultrasound diagnosis of any of the structural birth defects associated with NLS in these families should be considered evidence of the disorder. Since some of these findings may not become evident until later in pregnancy, termination of the pregnancy may not be an option for some couples. Plans for the remainder of the pregnancy as well as delivery can, however, be discussed. Given the serious prognosis associated with NLS, some parents may find a non-interventionist approach during labor and delivery, such as no fetal monitoring or Cesarean section delivery, acceptable. A clinical examination after birth is recommended.

Most infants with NLS have either been stillborn or died very shortly after delivery. However, there is one reported case of an affected Japanese infant who lived for 134 days. Humane medical care is therefore appropriate in survivors although the prognosis would still be extremely poor.

An autopsy is recommended on all affected infants after death to document and confirm all of the associated physical abnormalities. While this acts as a way to confirm the diagnosis, it is also a useful way to continue to add to the knowledge about the syndrome and its physical effects.

Prognosis

The number of infants described with Neu-Laxova syndrome is small. However, with the exception of the reported infant who lived 134 days, all affected children have either died before delivery or shortly thereafter. Neu-Laxova syndrome is a serious genetic condition whose anomalies prevent long-term survival.

Resources

BOOKS

Jones, K. L., ed. “Neu-Laxova syndrome.” In Smith’s

Recognizable Pattern of Human Malformations. W. B. Saunders Company, Philadelphia, 1997.

PERIODICALS

Kainer, F., et al. “Qualitative analysis of fetal movement patterns in the Neu-Laxova syndrome.” Prenatal Diagnosis 16, no. 7 (July 1996): 667-669.

Shapiro, I., et al. “Neu-Laxova syndrome: Prenatal ultrasonographic diagnosis, clinical and pathological studies, and new manifestations.” American Journal of Medical Genetics 43, no. 3 (June 1992): 602-605.

ORGANIZATIONS

Genetic Alliance. 4301 Connecticut Ave. NW, #404, Washington, DC 20008-2304. (800) 336-GENE (Helpline) or (202)

syndrome Laxova-Neu

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966-5557. Fax: (888) 394-3937 info@geneticalliance.http://www.geneticalliance.org .

Lissencephaly Network, Inc. 716 Autumn Ridge Lane, Fort Wayne, IN 46804-6402. (219) 432-4310. Fax: (219) 432-4310. lissennet@lissencephaly.org. http://www

.lissencephaly.org .

WEBSITES

TheFetus.net,

http://www.thefetus.net/sections/articles/Syndromes/

Neu_Laxova.html.

“OMIM—Online Mendelian Inheritance in Man.”

http://www.ncbi.nlm.nih.gov/omim .

Terri A. Knutel, MS, CGC

Neural tube defect see Spina bifida

I Neural tube defects

Definition

Neural tube defects are a group of severe birth defects in which the brain and spinal cord are malformed and lack the protective skeletal and soft tissue encasement.

Description

Incomplete formation and protection of the brain or spinal cord with bony and soft tissue coverings during the fourth week of embryo formation are known collectively as neural tube defects. Lesions may occur anywhere in the midline of the head or spine. These defects are among the most common serious birth defects, but they vary considerably in their severity. In some cases, the brain or spinal cord is completely exposed, in some cases protected by a tough membrane (meninges), and in other cases covered by skin.

Spina bifida accounts for about two-thirds of all neural tube defects. The spine defect may appear anywhere from the neck to the buttocks. In its most severe form, termed “spinal rachischisis,” the entire spinal canal is open exposing the spinal cord and nerves. More commonly, the defect appears as a localized mass on the back that is covered by skin or by the meninges.

Anencephaly, the second most common neural tube defect, accounts for about one-third of cases. Two major subtypes occur. In the most severe form, all of the skull bones are missing and the brain is exposed in its entirety. The second form, in which only a part of the skull is

K E Y T E R M S

Embryo—The earliest stage of development of a human infant, usually used to refer to the first eight weeks of pregnancy. The term fetus is used from roughly the third month of pregnancy until delivery.

Hydrocephalus—The excess accumulation of cerebrospinal fluid around the brain, often causing enlargement of the head.

Meninges—The two-layered membrane that covers the brain and spinal cord.

missing and a portion of the brain exposed, is termed “meroacrania.”

Encephaloceles are the least common form of neural tube defects, comprising less than ten percent of birth defects. With encephaloceles, a portion of the skull bones are missing leaving a bony hole through which the brain and its coverings herniate (protrude). Encephaloceles occur in the midline from the base of the nose, to the junction of the skull and neck. As with spina bifida, the severity varies greatly. In its mildest form, encephaloceles may appear as only a small area of faulty skin development with or without any underlying skull defect. At the severe end of the spectrum, most of the brain may be herniated outside of the skull into a skin-covered sac.

Genetic profile

Most neural tube defects (80-90%) occur as isolated defects. Neural tube defects of this variety are believed to arise through the combined influence of genetic and environmental forces. This multifactorial causation presumes that one or more predisposing genes collaborate with one or more environmental influences to lead to the birth defect. Poor nutrition is believed to be an environmental risk factor and hereditary defects in the absorption and utilization of folic acid are presumptive genetic predisposing factors. After a couple has one infant with a neural tube defect, the recurrence risk is 3-5%. After the birth of two NTD-affected infants, the risk increases to 8-10%.

When neural tube defects occur concurrently with other malformations there is a greater likelihood of an underlying specific genetic or environmental cause. Genetic causes include chromosome aberrations and single gene mutations. Environmental causes include maternal diabetes mellitus, exposure to prolonged hyperthermia, and seizure medications during the early months of pregnancy.

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defects tube Neural

This illustration depicts three common neural tube defects. Spina bifida appears as a localized mass on the back covered by skin or by the meninges, the three-layered membrane that envelops the spinal cord. Anencephaly is a lethal birth defect characterized by absence of all or part of the skull and scalp and malformation of the brain. Encephaloceles are rare and are characterized by protrusion of brain tissue and membranes through the skull. (Greenwood Genetic Center)

Demographics

Neural tube defects occur worldwide. It appears that the highest prevalence (about one in 100 pregnancies) exists in certain northern provinces in China; an intermediate prevalence (about one in 300-500 pregnancies) has been found in Ireland and in Central and South America; and the lowest prevalence (less than one in 2,000 pregnancies) has been found in the Scandinavian countries. In the United States, the highest prevalence has occurred in the Southeast. Worldwide there has been a steady downward trend in prevalence rates over the past 50-70 years.

Signs and symptoms

Because of the faulty development of the spinal cord and nerves, a number of consequences are commonly seen in spina bifida. As a rule, the nerves below the level of the defect develop in a faulty manner and fail to function, resulting in paralysis and loss of sensation below the level of the spinal lesion. Since most defects occur in the lumbar region, the lower limbs are usually paralyzed and lack normal sensation. Furthermore, the bowel and blad-

der have inadequate nerve connections, causing inability to control bladder and bowel function. Sexual function is likewise impaired. Hydrocephaly develops in most infants either before or after surgical repair of the spine defect.

In anencephaly, the brain is destroyed by exposure during intrauterine life. Most infants with anencephaly are stillborn, or die within the initial days or weeks after birth.

Infants with encephaloceles have variable neurologic impairments depending on the extent of brain involvement. When only the brain covering is involved, the individual may escape any adverse effect. However, when the brain is involved in the defect, impairments of the special senses such as sight, hearing, and cognitive thinking commonly result.

Diagnosis

At birth, the diagnosis is usually obvious based on external findings. Prenatal diagnosis may be made with ultrasound examination after 12-14 weeks of pregnancy.

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Screening of pregnancies can be carried out at 16 weeks by testing the mother’s blood for the level of alpha-feto- protein. Open neural tube defects leak this fetal chemical into the surrounding amniotic fluid, a small portion of which is absorbed into the mother’s blood.

Treatment and management

No treatment is available for anencephaly. Aggressive surgical and medical management has improved survival and function of infants with spina bifida. Surgery closes the defect, providing protection against injury and infection. A common complication that may occur before or after surgical correction is the accumulation of excessive cerebral spinal fluid (hydrocephaly) in the major cavities (ventricles) within the brain. Hydrocephaly is usually treated with the placement of a mechanical shunt, which allows the cerebral spinal fluid from the ventricles to drain into the circulation or another body cavity. A number of medical and surgical procedures have been used to protect the urinary system as well. Walking may be achieved with orthopedic devices. Encephaloceles are usually repaired by surgery soon after birth. The success of surgery often depends on the amount of brain tissue involved in the encephalocele.

It has been found that 400 micrograms of folic acid taken during the periconceptional period (two to three months prior to conception, and two to three months following conceptions) protects against most neural tube defects. While there are a number of foods (green leafy vegetables, legumes, liver, and orange juice) that are good sources of natural folic acid, synthetic folic acid is available in over-the-counter multivitamins and a number of fully-fortified breakfast cereals.

Additionally, a population-wide increase in folic acid intake has been achieved through the fortification of enriched cereal grain flours since January 1998, a measure authorized by the United States Food and Drug Administration. The increased blood folic acid levels achieved in recent years has likely resulted from the synergy of dietary, supplementation, and fortification sources of folic acid.

Prognosis

Infants with anencephaly are usually stillborn or die within the initial days of life. Eighty to ninety percent of infants with spina bifida survive with surgery. Paralysis below the level of the defect, including an inability to control bowel and bladder function, and hydrocephaly are complications experienced by most survivors. Intellectual function is normal in most cases.

The prognosis for infants with encephaloceles varies considerably. Small encephaloceles may cause no disability whether surgical correction is performed or not. Infants with larger encephaloceles may have residual impairment of vision, hearing, nerve function, and intellectual capacity.

Resources

PERIODICALS

Sells, C. J., and J. G. Hall, Guest Editors. “Neural Tube Defects.” Mental Retardation and Developmental Disabilities Research Reviews 4, no. 4 (1998) Wiley-Liss.

ORGANIZATIONS

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

.org .

National Birth Defects Prevention Network. Atlanta, GA (770) 488-3550. http://www.nbdpn.org .

Shriners Hospitals for Children. International Shrine Headquarters, 2900 Rocky Point Dr., Tampa, FL 336071460. (813) 281-0300.

Spina Bifida Association of America. 4590 MacArthur Blvd. NW, Suite 250, Washington, DC 20007-4226. (800) 6213141 or (202) 944-3285. Fax: (202) 944-3295.

Roger E. Stevenson, MD

I Neuraminidase deficiency

Definition

Neuraminidase deficiency, or sialidosis, is a rare inherited metabolic disorder with multiple symptoms that can include skeletal abnormalities and progressive neurological degeneration.

Description

Nomenclature

Neuraminidase deficiency is caused by a mutation, or change, in the NEU1 gene that codes for the lysosomal enzyme alpha-N-acetylneuraminidase, or neuraminidase for short. This enzyme sometimes is referred to as sialidase. It is also sometimes called N-acetyl-neu- raminic acid hydrolase. The disorder is manifested in one of two forms, known as sialidosis types I and II. Sialidosis type I is the milder form of the disorder, with symptoms typically appearing during adolescence. It is known as the non-dysmorphic or normophormic form of sialidosis. Sialidosis type II is the more severe form of

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neuraminidase deficiency, with symptoms developing in the fetus, at birth, or during infancy or early childhood. It is known as the dysmorphic form of sialidosis.

Over the years, this disorder has been called by a number of different names, in addition to neuraminidase deficiency, alpha-neuraminidase deficiency, sialidase deficiency, and sialidosis. It sometimes is known as cherry-red spot and myoclonus syndrome, cherry-red spot myoclonus epilepsy syndrome, or myoclonus and cherry-red spot syndrome, in reference to characteristic symptoms of the disorder. Other names include glycoprotein neuraminidase deficiency, NEUG deficiency, NEU or NEU1 deficiency, and neuraminidase 1 deficiency. Sialidosis type I sometimes is referred to as juvenile sialidosis and type II as infantile sialidosis, in reference to the age of onset.

Lysosomal storage diseases

Lysosomes are membrane-bound spherical compartments or vesicles within the cytosol, the semi-fluid areas of cells. Lysosomes contain more than 50 different enzymes that are responsible for digesting, or hydrolyzing, large molecules and cellular components. These include proteins, polysaccharides, which are long, linear or branched chains of sugars, and lipids, which are large insoluble biomolecules that are usually built from fatty acids. The smaller breakdown products from the lysosomes are recycled to the cytosol.

Neuraminidase deficiency is one of at least 41 genet- ically-distinct lysosomal storage diseases. These disorders result from mutations in the genes encoding the hydrolytic enzymes of the lysosome. In these disorders, some of the macromolecules in the lysosomes cannot be degraded and they, or their partial-breakdown products, accumulate there. The lysosomes swell to the point where cellular function is disrupted.

Neuraminidase deficiency, particularly sialidosis type II, commonly has been classified as the lysosomal storage disease called mucolipidosis type I (ML I), formerly lipomucopolysaccharidosis. This is because the symptoms of neuraminidase deficiency are similar to various mucolipidosis disorders. However mucolipidoses are characterized by the accumulation of large and complex lipid-polysaccharides. In contrast, neuraminidase deficiency leads to the accumulation of specific types of short chains of sugar called oligosaccharides and of certain proteins with oligosaccharides attached to them, called glycoproteins. Thus, it may be more appropriate to classify neuraminidase deficiency as an oligosaccharide storage disease, since it leads to the accumulation of excess oligosaccharides in various tissues throughout the body and the excretion of oligosaccharides.

Neuraminidase

Neuraminidase, or sialidase, is a type of enzyme known as an exoglycosidase because it cleaves terminal sugar units, or residues, off oligosaccharides. Specifically, neuraminidase cleaves, or hydrolyzes, terminal sialic acid residues. Sialic acid, also known as N-acetyl- neuraminic acid, is a type of sugar molecule that often is at an end of an oligosaccharide. The oligosaccharides with sialic acid residues may be attached to proteins (glycoproteins). Therefore, neuraminidase deficiency prevents the proper breakdown of oligosaccharides and glycoproteins that contain sialic acid and the disorder is characterized by the accumulation and excretion of these substances.

In addition to interfering with the lysosomal breakdown of sialic acid compounds, neuraminidase deficiency can lead to abnormal proteins. Following protein synthesis, some lysosomal enzymes reach the lysosome in an inactive form and require further processing for activation. One such processing step is the neuramini- dase-catalyzed removal of sialic acid residues from oligosaccharides on the enzymes. Lysosomal hydrolases that require further processing by neuraminidase include acid phosphatase, alpha-mannosidase, arylsulfatase B, and alpha-glucosidase.

Under conditions of neuraminidase deficiency, sialyloligosaccharides accumulate in various cells, including lymphocytes (white blood cells that produce antibodies), fibroblasts (connective tissue cells), bone marrow cells, Kupffer cells of the liver, and Schwann cells, which form the myelin sheaths of nerve fibers. Furthermore, proteins with sialic acid attachments accumulate and can be detected in fibroblasts and in the urine.

Neuraminidase exists in the lysosome in a high- molecular-weight complex with three other proteins: the enzyme beta-galactosidase, the enzyme N-acetylgalac- tosamine-6-sulfate sulfatase (GALNS), and a multi-func- tional enzyme called protective protein/cathepsin A (PPCA). Neuraminidase must be associated with PPCA in order for the neuraminidase to reach the lysosome. Once inside the lysosome, PPCA mediates the association of as many as 24 neuraminidase molecules to form active neuraminidase. The active enzyme remains associated with PPCA and beta-galactosidase, which appear to be necessary for protecting and stabilizing the neuraminidase activity. A distinct lysosomal storage disease, neuraminidase deficiency with beta-galactosidase deficiency, or galactosialidosis, results from mutations in the gene encoding PPCA. In this disorder, both neuraminidase and beta-galactosidase are deficient.

deficiency Neuraminidase

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Genetic profile

Inheritance of neuraminidase deficiency

Neuraminidase deficiency is an autosomal recessive disorder that can be caused by any one of a number of different mutations in the NEU1 gene encoding the lysosomal neuraminidase. The disorder is autosomal because the NEU1 gene is located on chromosome 6, rather than on the X or Y sex chromosomes. The disorder is recessive because it only develops when both genes encoding neuraminidase, one inherited from each parent, are defective; however, the two defective NEU1 genes do not need to carry the same mutations. If the two mutations are identical, the individual is a homozygote. If the two mutations are different, the affected individual is called a compound heterozygote. Individuals with one defective gene and one normal gene encoding neuraminidase may have reduced levels of the active enzyme, but they do not have symptoms of neuraminidase deficiency.

All of the offspring of two parents with neuraminidase deficiency will inherit the disorder. All of the offspring of one parent with neuraminidase deficiency and one parent with a single defective NEU1 gene will inherit at least one defective NEU1 gene. They will have a 50% chance of inheriting two defective genes and, therefore, developing neuraminidase deficiency. The offspring of one parent with neuraminidase deficiency and one parent with normal NEU1 genes will inherit a defective gene from the affected parent, but will not develop neuraminidase deficiency. The offspring of parents who both carry one defective NEU1 gene have a 50% chance of inheriting one defective NEU1 gene and a 25% chance of inheriting two genes and developing neuraminidase deficiency. Finally, the children of one parent with a single defective NEU1 gene and one parent with normal NEU1 genes will have a 50% chance of inheriting the defective gene, but will not develop neuraminidase deficiency.

Mutations in the NEU1 gene

A number of different mutations that can cause neuraminidase deficiency have been identified in the NEU1 gene. The type of neuraminidase deficiency, sialidoses types I or II, as well as the severity of the symptoms, depends on the specific mutation(s) that are present. Some mutations change one amino acid out of the 415 amino acids that compose a single neuraminidase molecule. Other identified mutations result in a shortened enzyme. Many of the identified mutations are clustered in one region on the surface of the protein. These mutations result in a sharp reduction in the activity of the enzyme

and lead to the rapid degradation of neuraminidase inside the lysosome.

Some mutations in the NEU1 gene lead to a complete absence of neuraminidase activity, with little or no neuraminidase enzyme present in the lysosomes. These mutations usually result in the severe, infantile-onset, type II sialidosis. Other mutations result in an inactive protein that is present in the lysosome. These mutations generally result in juvenile-onset, type II sialidosis, with symptoms of intermediate severity. Some mutations significantly reduce, but do not obliterate, neuraminidase activity in the lysosome. Individuals with at least one mutated gene of this type are not completely neu- raminidase-deficient and have mild, type I sialidosis. Occasionally, individuals have multiple mutations in the NEU1 gene, leading to more severe forms of neuraminidase deficiency.

Demographics

Neuraminidase deficiency is an extremely rare disorder. Because of its similarities to many other disorders, it has been difficult to determine its frequency. In the United States, it is estimated to occur in one out of every 250,000 live births. In Australia, the estimate is one out of 4.2 million. Since neuraminidase deficiency is an autosomal rather than a sex-linked disorder, it occurs equally in males and females.

As an autosomal recessive disorder, neuraminidase deficiency requires two copies of the defective gene, one inherited from each parent. Thus, neuraminidase deficiency is much more common in the offspring of couples who are related to each other (consanguineous marriages), such as first or second cousins.

Sialidosis type I appears to be more common among Italians. Type 2 sialidosis seems to occur more frequently among Japanese.

Signs and symptoms

The clinical symptoms of neuraminidase deficiency are similar to the symptoms of the mucolipidoses, including I-cell disease (mucolipidosis II) and pseudoHurler polydystrophy (mucolipidosis III). Furthermore, the clinical distinctions between sialidoses types I and II may not be clearly defined.

Sialidosis type I

The symptoms of sialidosis type I do not appear until the second decade of life. Infants and children with this form of neuraminidase deficiency may have a normal

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appearance and grow normally until adolescence. At that time, the appearance of red spots in both eyes, known as cherry-red macules or cherry-red macular spots, may be one of the first symptoms of neuraminidase deficiency. Eventually, color and/or night blindness may develop. Cataracts may occur and vision may deteriorate gradually into blindness.

Other symptoms of sialidosis type I include myoclonus. These are sudden involuntary muscle contractions, which may eventually develop into myoclonic seizures. The myoclonus may become debilitating, even in sialidosis type I. Individuals with this form of neuraminidase deficiency may have increased deep tendon reflexes and may develop tremors and various other neurological conditions. There may be a progressive loss of muscle coordination, called ataxia, and walking and standing may become increasingly difficult. Speech problems, such as slurring, may develop.

The above symptoms also may occur in sialidosis type II. However, in addition to the age of onset, type I can be distinguished from type II by the absence of skeletal and facial abnormalities. Furthermore, individuals with this form of neuraminidase deficiency have normal intelligence.

Sialidosis type II

Sialidosis type II has three forms: congenital or neonatal, with symptoms present at or before birth; infantile, with symptoms developing at birth or during the first year of life; and juvenile, with symptoms developing between the ages of two and twenty.

Symptoms of sialidosis type II vary from mild to severe, but are always more severe than in type I sialidosis. With neonatal onset, infants may be born with ascites (accumulation of fluid in the abdominal cavity), swollen liver and spleen (hepatosplenomegaly), hernia of the umbilicus or the groin, and other abnormalities. With severe forms of the disorder, children may die in infancy. With milder forms, they may show no symptoms for the first ten years of life. Thus, ascites, hepatosplenomegaly, and hernias may develop later. Children with neuraminidase deficiency may grow abnormally fast. Cherry-red macules, myoclonus, and other neurological abnormalities, including tremors, may be present. The myoclonus may progress into a form of epilepsy. These children may have mild to severe mental retardation.

Sialidosis type II is characterized by a variety of skeletal malformations (dysostosis multiplex). Obvious symptoms may include distinctive, coarse facial features

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.

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.

Lipid—Large, complex biomolecule, such as a fatty acid, that will not dissolve in water. A major constituent of membranes.

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.

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

(called coarse facies), a short trunk with relatively long legs and arms, and a prominent breast bone (pectus carinatum). In addition, there may be a lack of muscle tone and strength (hypotonia) and the progressive wasting of muscular tissue.

The hearing may be affected in sialidosis type II. Individuals may have difficulty breathing (dyspnea). Cardiac problems may develop and severe congenital sialidosis type II apparently can result in severely-dilated coronary arteries. Loose bowel movements are common with this form of neuraminidase deficiency.

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Diagnosis

Neuraminidase activity

Typically, neuraminidase deficiency is diagnosed by measuring the activity of the enzyme in cultures of fibroblast cells that have been grown from cells obtained via a skin biopsy. Lysosomal neuraminidase also can be measured in leukocytes (white blood cells). However, human cells have two other types of neuraminidase, encoded by different genes. One of these enzymes is present in the cell membrane and the other is in the cytosol of various cells, including leukocytes. These enzymes are not deficient in sialidosis and their activities can interfere with the measurement of lysosomal neuraminidase.

Neuraminidase activity usually is measured by testing the ability of fibroblast cell preparations to hydrolyze, or cleave, a synthetic compound such as 4-methylumbel- liferyl-D-N-acetylneuraminic acid. Hydrolysis by neuraminidase liberates 4-methylumbelliferone, which is a compound with a fluorescence that can be measured accurately. Neuraminidase is an unstable enzyme and special precautions are needed to test for its activity. The normal range of neuraminidase activity in fibroblasts is 95-653 picomoles per minute per milligram of protein. In leukocytes, the normal range is 6-60 picomoles per minute per milligram of protein. Levels of active neuraminidase are much lower in sialidosis type II as compared with type I.

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, or partiallydegraded proteins with sialyloligosaccharides still attached, also can be detected in the urine under conditions of neuraminidase deficiency.

Histology

Neuraminidase deficiency and other lysosomal storage diseases interfere with the normal lysosomal breakdown of cellular components. As a result, the lysosomes may fill up with large molecules that are only partially digested. In the case of neuraminidase deficiency, the lysosomes fill up with sialyloligosaccharides and sialylglycopeptides. 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, bone marrow cells, epithelial skin cells, and fibroblasts.

Sialidosis type II

Infants with sialidosis type II often have visual symptoms of the disorder at birth, including facial and skeletal abnormalities. Skeletal x rays may be used to diagnose the dysostosis multiplex of this type of neuraminidase deficiency. Magnetic resonance imaging (MRI) may be used to determine brain atrophy.

Prenatal diagnosis

Neuraminidase deficiency may be diagnosed prenatally. In at-risk fetuses, cultured fetal cells from the amniotic fluid, obtained by amniocentesis, or cultured chorionic villi cells, obtained by chorionic villi sampling in the early weeks of pregnancy, may be tested for neuraminidase activity. Since carriers of a single mutated NEU1 gene do not have symptoms of neuraminidase deficiency, it may be difficult to recognize an at-risk fetus unless there is a family history of the disorder.

Treatment and management

At present, there is no treatment for neuraminidase deficiency. Rather, attempts are made to manage individual symptoms. Myoclonic seizures, in particular, are very difficult to control.

Prognosis

Individuals with sialidosis type I may have a nearnormal life expectancy. However, the myoclonus may be progressively debilitating and myoclonic seizures can be fatal. Children with neonatal-onset sialidosis type II usually are stillborn or die at a young age. Those with infan- tile-onset sialidosis type II rarely survive through adolescence.

Resources

BOOKS

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

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

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

PERIODICALS

Bonten, E. J., et al. “Novel Mutations in Lysosomal Neuraminidase Identify Functional Domains and Determine Clinical Severity in Sialidosis.” Human Molecular Genetics 9, 18 (November 1, 2000): 2715-25.

Lukong, K. E., et al. “Characterization of the Sialidase Molecular Defects in Sialidosis Patients Suggests the Structural Organization of the Lysosomal Multienzyme Complex.” Human Molecular Genetics 9, 7 (April 12, 2000): 1075-85.

ORGANIZATIONS

Canadian Society for Mucopolysaccharide and Related Diseases. PO Box 64714, Unionville, ONT L3R OM9. Canada (905) 479-8701 or (800) 667-1846. http://www

.mpssociety.ca .

International Society for Mannosidosis and Related Diseases. 3210 Batavia Ave., Baltimore, MD 21214. (410) 2544903. info@mannosidosis.org. http://www.mannosidosis

.org .

National MPS Society. 102 Aspen Dr., Downingtown, PA 19335. (610) 942-0100. Fax: (610) 942-7188. info @mpssociety.org. http://www.mpssociety.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 Neuraminidase deficiency with beta-galactosidase deficiency

Definition

Neuraminidase deficiency with beta-galactosidase deficiency, commonly-known as galactosialidosis, is a rare inherited metabolic disorder with multiple symptoms that can include skeletal abnormalities, mental retardation, and progressive neurological degeneration.

Description

Neuraminidase deficiency with beta-galactosidase deficiency, or galactosialidosis, is a very rare genetic disorder with progressive signs and symptoms that are almost identical to those of neuraminidase deficiency alone, a disorder that is often called sialidosis. These

symptoms can include skeletal and facial abnormalities, seizures, vision and hearing loss, cardiac and kidney problems, and mental retardation. However, as with sialidosis, the severity of the symptoms of galactosialidosis vary greatly.

Galactosialidosis is also known as Goldberg syndrome, after M. F. Goldberg and colleagues who first described the disorder in 1971. The disorder is also sometimes called protective protein/cathepsin A (or PPCA) deficiency, deficiency of lysosomal protective protein, or deficiency of cathepsin A.

Galactosialidosis is caused by a mutation, or change, in the gene encoding an enzyme called protective protein/cathepsin A (PPCA). PPCA forms a very large multienzyme complex with three other enzymes: beta-galactosidase, N-acetylgalactosamine-6-sulfate sulfatase (GALNS), and alpha-N-acetylneuraminidase. The latter enzyme is commonly referred to as neuraminidase or sialidase. Whereas sialidosis is caused by a mutation in the gene encoding neuraminidase, a mutation in the gene encoding PPCA can affect the activities of all of the enzymes in the complex. However neuraminidase is the enzyme that is most dependent on PPCA. Without functional PPCA, there is little or no neuraminidase activity. Although beta-galactosidase activity is reduced, a significant amount of active enzyme remains. Therefore, the symptoms of neuraminidase deficiency with beta-galac- tosidase deficiency are more similar to those of sialidosis than to those of beta-galactosidase deficiency. Mutations in the gene encoding beta-galactosidase can result in the disorders known as GM1 gangliosidosis (beta-galactosi- dosis) or Morquio B disease.

Galactosialidosis is subdivided into three types, depending on the age of onset: severe, neonatal or earlyinfantile; milder, late-infantile; and juvenile/adult. The juvenile/adult form is the most common. There also is an atypical form of galactosialidosis. The type and severity of the disorder depends on the specific mutation(s) present in the genes encoding PPCA.

Lysosomal storage diseases

Neuraminidase, beta-galactosidase, PPCA, and GALNS are all enzymes that function inside lysosomes. Lysosomes are membrane-bound spherical compartments or vesicles within the cytosol (fluid part) of cells. Lysosomes contain more than 50 different enzymes that are responsible for digesting, or hydrolyzing, large molecules and cellular components. These include proteins, polysaccharides (long, linear or branched chains of sugars), and lipids, which are large, insoluble biomolecules that are usually built from fatty acids. The smaller breakdown products from the lysosome are recycled back to the cytosol.

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Galactosialidosis is one of at least 41 genetically distinct lysosomal storage diseases. In these disorders, some of the macromolecules in the lysosome cannot be degraded. Instead, these large molecules, or their partialbreakdown products, accumulate, and the lysosomes swell to the point that cellular function is disrupted.

Neuraminidase deficiency

Neuraminidase removes sialic acid from the ends of oligosaccharides, which are relatively short chains of sugars. Sialic acid, also known as N-acetylneuraminic acid, is a type of sugar molecule that often is at an end of an oligosaccharide. These oligosaccharides with terminal sialic acid residues may be attached to proteins, called glycoproteins.

Neuraminidase deficiency prevents the breakdown of oligosaccharides and glycoproteins that contain sialic acid and leads to the accumulation and excretion of these substances. It also can lead to the production of abnormal proteins. Following protein synthesis, some lysosomal enzymes reach the lysosome in an inactive form and require further processing for activation. One such processing step is the neuraminidase-catalyzed removal of sialic acid residues from oligosaccharides on enzymes. Thus, under conditions of neuraminidase deficiency, other lysosomal enzymes may not behave properly.

Protective protein/cathepsin A

PPCA is required for the transport of neuraminidase to the lysosome. Once inside the lysosome, the enzymatic activity of PPCA may be involved in the activation of neuraminidase. Furthermore, PPCA mediates the association of multiple molecules of neuraminidase and betagalactosidase, as well as GALNS. In the absence of PPCA, all three enzymes are rapidly degraded in the lysosome. Thus, PPCA protects and stabilizes these enzyme activities. In the absence of PPCA, substrates for these enzymes may accumulate to dangerous levels.

Gangliosides are very complex components of cell membranes. They are made up of a long-chain amino alcohol called sphingosine, a long-chain fatty acid, and a very complex oligosaccharide that contains sialic acid. The lysosomal beta-galactosidase is responsible for hydrolyzing gangliosides.

GALNS catalyzes the first step in the lysosomal breakdown of a special type of sugar called keratan sulfate. Both gangliosides and keratan sulfate may accumulate in galactosialidosis.

In addition to its protective functions, PPCA has at least three enzymatic activities of its own, including the ability to cleave (break apart), or hydrolyze, other proteins. Some of the neurological abnormalities that

develop with galactosialidosis may be due to the loss of this activity, particularly PPCAs ability to cleave endothe- lin-1. This peptide is overabundant and abnormally distributed in the neurons and glial cells of the brain and spinal cord of individuals with galactosialidosis.

Genetic profile

Galactosialidosis is an autosomal recessive disorder that can be caused by any one of a number of different mutations in the gene encoding PPCA. This gene is known as PPGB, for beta-galactosidase protective protein. The disorder is autosomal since the PPGB gene is located on chromosome 20, rather than on the X or Y sex chromosomes. The disorder is recessive because it only develops when both genes encoding PPCA, one inherited from each parent, are abnormal. However, the two defective genes do not need to carry the same mutations. If the two mutations are identical, the individual is a homozygote. If the two mutations are different, the affected individual is called a compound heterozygote.

PPCA mutations

The type of galactosialidosis and the severity of the symptoms depend on the specific mutations that are present. In general, the higher the level of PPCA activity in the lysosomes, the milder the characteristics of galactosialidosis, and the later the onset of disease.

With some mutations of the PPGB gene, very little of the precursor protein to PPCA is produced and there is no mature PPCA in the lysosome. With other mutations, the precursor protein may not be correctly processed into mature protein. Some individuals with severe earlyinfantile galactosialidosis carry mutations that prevent precursor PPCA from being targeted to the lysosome. The lysosomes of these individuals have no PPCA.

In contrast, individuals with the late-infantile form of galactosialidosis carry at least one mutant PPGB gene whose product can reach the lysosome. However, there may be only a small amount of PPCA in the lysosome; the PPCA may lack enzymatic activity; the PPCA chains may be unable to combine to form the normal twochained form; or the PPCA may be degraded rapidly. Nevertheless, with these mutations, the symptoms of galactosialidosis are mild and progress very slowly with no mental retardation.

Other identified mutations prevent the PPCA molecules from folding properly or shorten the PPCA protein so that it cannot form a complex with the other enzymes.

Compound heterozygotes, with different mutations in their PPGB genes, usually have symptoms that are intermediate in severity between those of homozygotes for each of the two mutations. Occasionally, the symp-

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