TAY-SACHS DISEASE

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</script> </td></tr></table><!POP YES 1 0catch 1257897080-0 visited=11%2F10%2F2009; visited=11%2F10%2F2009; visited=11%2F10%2F2009; visited=11%2F10%2F2009; visited=11%2F10%2F2009; visited=11%2F10%2F2009><table cellpadding=0 cellspacing=0 border=0><tr> <td valign="top" colspan=2 height=125 BGCOLOR="#996699" TEXT="#080000" bgproperties="fixed" background="040467d1erlcll.gif"> <div> <FONT SIZE="5" COLOR="#FFFFFF" FACE="Arial" ><B>paediatry part 2</B></FONT><B>     </B><B>|     </B><A HREF="index.htm" TARGET="_top" TITLE="paediatry part 2"><U><B>home</B></U></A></div> <div> <A HREF="id18.htm" TARGET="_top" TITLE="PEARLS 1"><U>PEARLS 1</U></A>   |   <A HREF="id27.htm" TARGET="_top" TITLE="pearls2"><U>pearls2</U></A>   |   <A HREF="id30.htm" TARGET="_top" TITLE="Phenylketonuria (PKU)"><U>Phenylketonuria (PKU)</U></A>   |   <A HREF="id31.htm" TARGET="_top" TITLE="food poisoning"><U>food poisoning</U></A>   |   <A HREF="id32.htm" TARGET="_top" TITLE="acute otitis"><U>acute otitis</U></A>   | 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syndrome"><U>angelman syndrome</U></A>   |   <B>TAY-SACHS DISEASE</B>   |   <A HREF="id24.htm" TARGET="_top" TITLE="krabbes disease"><U>krabbe's disease</U></A>   |   <A HREF="id25.htm" TARGET="_top" TITLE="Refsums Disease"><U>Refsum's Disease</U></A>   |   <A HREF="id29.htm" TARGET="_top" TITLE="meningitis"><U>meningitis</U></A>   |   <A HREF="id17.htm" TARGET="_top" TITLE="Contact Me"><U>Contact Me</U></A></div> <div> </div> </td> </tr><tr> <td valign="top" width=190 BGCOLOR="#FFFFFF" TEXT="#080000"> <div> TAY-SACHS DISEASE</div> <div> <A HREF="id18.htm" TARGET="_top" TITLE="PEARLS 1"><U>PEARLS 1</U></A></div> <div> <A HREF="id27.htm" TARGET="_top" TITLE="pearls2"><U>pearls2</U></A></div> <div> <A HREF="id30.htm" TARGET="_top" TITLE="Phenylketonuria (PKU)"><U>Phenylketonuria (PKU)</U></A></div> <div> <A HREF="id31.htm" TARGET="_top" TITLE="food poisoning"><U>food poisoning</U></A></div> <div> <A HREF="id32.htm" TARGET="_top" TITLE="acute otitis"><U>acute otitis</U></A></div> <div> <A HREF="id33.htm" TARGET="_top" TITLE="immunization"><U>immunization</U></A></div> <div> <A HREF="id34.htm" TARGET="_top" TITLE="craniofacial anomaly"><U>craniofacial anomaly</U></A></div> <div> <A HREF="id35.htm" TARGET="_top" TITLE="chiari malformation"><U>chiari malformation</U></A></div> <div> <A HREF="id36.htm" TARGET="_top" TITLE="PEDIATRIC RESPIRATORY DISORDERS"><U>PEDIATRIC RESPIRATORY DISORDERS</U></A></div> <div> <A HREF="id37.htm" TARGET="_top" TITLE="Cephalhematoma "><U>Cephalhematoma </U></A></div> <div> <A HREF="id38.htm" TARGET="_top" TITLE="Subgaleal Hematoma"><U>Subgaleal Hematoma</U></A></div> <div> <A HREF="id39.htm" TARGET="_top" TITLE="BIRTH INJURY "><U>BIRTH INJURY </U></A></div> <div> <A HREF="id40.htm" TARGET="_top" TITLE="infectious in a new born"><U>infectious in a new born</U></A></div> <div> <A HREF="id41.htm" TARGET="_top" TITLE="jaundice"><U>jaundice</U></A></div> <div> <A HREF="id42.htm" TARGET="_top" TITLE="INFANT OF DIABETIC MOTHER (IDM) "><U>INFANT OF DIABETIC MOTHER (IDM) </U></A></div> <div> <A HREF="id43.htm" TARGET="_top" TITLE="FETAL GROWTH "><U>FETAL GROWTH </U></A></div> <div> <A HREF="id44.htm" TARGET="_top" TITLE="Moebius Syndrome"><U>Moebius Syndrome</U></A></div> <div> <A HREF="id45.htm" TARGET="_top" TITLE="SHORT STATURE"><U>SHORT STATURE</U></A></div> <div> <A HREF="id46.htm" TARGET="_top" TITLE="MICROCEPHALIA"><U>MICROCEPHALIA</U></A></div> <div> <A HREF="id47.htm" TARGET="_top" TITLE="PIERRE ROBIN SYNDROME "><U>PIERRE ROBIN SYNDROME </U></A></div> <div> <A HREF="id19.htm" TARGET="_top" TITLE="Prenatal Diagnosis"><U>Prenatal Diagnosis</U></A></div> <div> <A HREF="id28.htm" TARGET="_top" TITLE="Febrile Seizures "><U>Febrile Seizures </U></A></div> <div> <A HREF="id20.htm" TARGET="_top" TITLE="dvlp bis"><U>dvlp bis</U></A></div> <div> <A HREF="id21.htm" TARGET="_top" TITLE="DEVELOPMENTAL NEUROLOGIC DISEASES"><U>DEVELOPMENTAL NEUROLOGIC DISEASES</U></A></div> <div> <A HREF="id22.htm" TARGET="_top" TITLE="GENETIC DISEASES "><U>GENETIC DISEASES </U></A></div> <div> <A HREF="id26.htm" TARGET="_top" TITLE="angelman syndrome"><U>angelman syndrome</U></A></div> <div> TAY-SACHS DISEASE</div> <div> <A HREF="id24.htm" TARGET="_top" TITLE="krabbes disease"><U>krabbe's disease</U></A></div> <div> <A HREF="id25.htm" TARGET="_top" TITLE="Refsums Disease"><U>Refsum's Disease</U></A></div> <div> <A HREF="id29.htm" TARGET="_top" TITLE="meningitis"><U>meningitis</U></A></div> <div> <A HREF="id17.htm" TARGET="_top" TITLE="Contact Me"><U>Contact Me</U></A></div> </td> <td valign="top" height=355 BGCOLOR="#FFFFFF" TEXT="#080000" background="06515b93.jpg"> <div> TAY-SACHS DISEASE</div> <div> <B>(GM2 Gangliosidosis)</B></div> <div> <B>Common Synonyms:</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b70140ffff0000.gif" HEIGHT="21" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Adult GM2 Gangliosidosis </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b70140ffff0000.gif" HEIGHT="21" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Chronic GM2 Gangliosidosis </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b70140ffff0000.gif" HEIGHT="21" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Adult-Onset Tay-Sachs </B></div> <div> <B>Enzyme Deficiency: beta-hexosaminidase A (Hex A)</B></div> <bR> <bR> <div> <B><U>A. Introduction</U></B><B><U> </U></B></div> <bR> <div> <B>1. Lysosomal sphingolipid storage disroder</B></div> <div> <B>2. Autosomal recessive inheritance</B></div> <div> <B>3. Usually infants of central or eastern European Jews (Ashkenazi)</B></div> <bR> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">fatal genetic disorder in which harmful quantities of a fatty substance called ganglioside GM2 </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">accumulate in the nerve cells in the brain.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Infants with </B><B>Tay-Sachs</B><B> </B><B>disease</B><B> appear to develop normally for the first few months of life.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Then, as nerve cells become distended with fatty material, a relentless deterioration of mental and physical abilities occurs.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The child becomes </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">blind,</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> deaf,</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> and unable to swallow.[dysphagia] </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Muscles begin to atrophy and paralysis sets in. A much rarer form of the disorder which occurs in patients in their twenties and early thirties is characterized by unsteadiness of gait and progressive neurological deterioration.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Patients with </B><B>Tay-Sachs</B><B> have a</B><FONT SIZE="5" COLOR="#FFFF00" FACE="Arial" ><B> </B><B><U>"cherry-red" spot in the back of their eyes</U></B><B>. </B></FONT></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The condition is caused by insufficient activity of an </B><FONT SIZE="4" COLOR="#FFFF00" FACE="Arial" ><B><U>enzyme called hexosaminidase</U></B></FONT><B> </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">A that catalyzes the biodegradation of acidic fatty materials known as gangliosides. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Gangliosides are made and biodegraded rapidly in early life as the brain develops. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Patients and carriers of </B><B>Tay-Sachs</B><B> </B><B>disease</B><B> can be identified by a simple blood test that measures hexosaminidase A activity.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Both parents must be carriers in order to have an affected child. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">When both parents are found to carry a genetic mutation in hexosaminidase A, there is a 25 percent chance with each pregnancy that the child will be affected with </B><B>Tay-Sachs</B><B> </B><B>disease</B><B>.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Prenatal monitoring of pregnancies is available if desired.</B></div> <bR> <div> <B><U>B. Biochemstry and Pathology</U></B></div> <bR> <div> <B>1. Accumulation of GM2 Ganglioside</B></div> <div> <B>a. Due to profound deficiency of lysosomal hydrolase ß-hexosaminidase A</B></div> <div> <B>b. Catalyzes cleavage of terminal ß-linked N-acetylgalactosamine from GM2 Ganglioside</B></div> <div> <B>2. Neuronal Changes</B></div> <div> <B>a. Accumulation of GM2 Ganglioside in neuronal lysosomes</B></div> <div> <B>b. Ballooning of neurons</B></div> <div> <B>c. Lipophilic membranous bodies (composed of GM2 Ganglioside)</B></div> <bR> <bR> <div> <B>C. Symptoms</B></div> <bR> <div> <B>1. Hypotonia</B></div> <div> <B>2. Blindness</B></div> <div> <B>3. Dementia</B></div> <div> <B>4. Seizures</B></div> <div> <B>5. Death occurs age 3-5 years</B></div> <bR> <div> <B><U>Genotype-Phenotype Correlations </U></B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">HEX A enzymatic activity. </B><B>The level of the residual activity of the HEX A enzyme correlates inversely with the severity of the disease; i.e., the lower the level of the enzymatic activity, the more severe the phenotype is likely to be. Individuals with the acute infantile form (TSD) have two null alleles with no HEX A enzymatic activity. Individuals with juvenile or chronic and adult-onset forms of hexosaminidase A deficiency are usually compound heterozygotes for a null allele and an allele that results in residual but low activity of the HEX A enzyme toward GM2 ganglioside.</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">HEXA</B><B> mutations associated with acute infantile GM2 gangliosidosis (TSD). </B><B>Of the more than 70 specific mutations in the alpha subunit of the </B><B>HEXA</B><B> gene that have been described, the great majority (more than 60) are associated with the acute infantile form [</B><B>Gravel et al 1997</B><B>].</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">B1 variant associated with juvenile and chronic GM2 gangliosidosis (HEX A-deficient). </B><B>The B1 variant is a defective HEX A enzyme that has some activity toward GM2 ganglioside. The cause of the most common B1 variant is the mutation Arg178His, which is predominantly found in persons of Portuguese background. An individual who is a compound heterozygote for a non-expressing (null) allele and an allele causing a B1 variant has the juvenile phenotype. An individual who is homozygous for a mutation causing a B1 variant has twice the enzymatic activity as a compound heterozygote and has the milder chronic phenotype.</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">HEXA</B><B> mutations associated with adult-onset GM2 gangliosidosis (HEX A-deficient). </B><B>Only two </B><B>HEXA</B><B> mutations responsible for adult-onset GM2 gangliosidosis (HEX A-deficient) have been identified. The Gly269Ser mutation occurs with significant frequency in the Ashkenazi Jewish population and results in an unstable alpha subunit precursor, which fails to associate with the beta subunit. The other mutation, Gly250Asp, occurs in exon seven of the alpha subunit. Typically, either of these two mutations in combination with a null allele, or when homozygous, results in the adult-onset phenotype.</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">HEXA</B><B> pseudodeficiency alleles. </B><B>Individuals heterozygous for a pseudodeficiency allele have an apparent deficiency of HEX A enzymatic activity like that of a heterozygote for TSD. Individuals with two altered </B><B>HEXA</B><B> alleles, one a pseudodeficiency allele and the second a disease-related mutation, have extremely low or absent HEX A enzymatic activity with synthetic substrates, but have no evidence of neurologic abnormality even into the seventh decade of life (which is the longest that any of these individuals has been followed). Such individuals have been called "pseudodeficient" or "HEX A minus, normal". Most individuals with pseudodeficiency are identified through carrier screening programs when a healthy individual appears to have HEX A enzymatic activity levels similar to those of a child with Tay-Sachs disease.</B></div> <bR> <div> <B>D. Prevention</B></div> <div> <B>1. No treatment currently available</B></div> <div> <B>2. Carrier screening is highly effective method for prevention</B></div> <div> <B>3. Screening error rates <2% (extremely rare after 1988)</B></div> <div> <B>4. Amniocentesis or chorionic villus sampling can also be done</B></div> <bR> <bR> <div> <B>How is Tay-Sachs disease diagnosed?</B><FONT SIZE="3" COLOR="#00FF00" FACE="Arial" ><B> </B></FONT></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ff0000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">An individual with </B><B>Tay-Sachs</B><B> </B><B>disease</B><B> has very low levels of hex A in their blood.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ff0000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> For individuals suspected of having </B><B>Tay-Sachs</B><B> </B><B>disease</B><B>, a simple blood sample can determine the level of this enzyme. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ff0000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Prenatal diagnosis for </B><B>Tay-Sachs</B><B> </B><B>disease</B><B> is available using samples collected with procedures called chorionic villus sampling (CVS) or amniocentesis, which are performed early in pregnancy</B></div> <bR> <div> <B> <TABLE BORDER="2" CELLPADDING="2" CELLSPACING="1" WIDTH="921" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="BOX" RULES="ALL" ALIGN="BOTTOM" HSPACE="0" VSPACE="0" BGCOLOR=#000066 > <tR> <tD VALIGN=TOP HEIGHT= 2113 WIDTH="909"><div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Tay-Sachs</B><B> </B><B>Disease</B><B> is caused by the absence of a vital enzyme called Hexosamindase A (Hex-A).</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">A person's chances of being a TSD Carrier are significantly higher if he or she is of Eastern European (Ashkenazi) Jewish descent</B></div> <bR> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Absence of the Hex A enzyme activity leads to an accumulation of the fat (lipid) GM2 ganglioside in nerve cells;</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> the Hex A activity is needed to break down this lipid.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> When Hex A activity is significantly deficient, the resulting accumulation of GM2 ganglioside in the nerve cells (neurons) affects the functioning of the nervous system.</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">measuring the Hex A enzyme activity in serum, leukocytes (white blood cells), or skin fibroblasts.</B></div> <bR> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">baby with </B><B>Tay-Sachs</B><B> </B><B>disease</B><B> appears healthy at birth, and seems to be developing normally for a few months. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Symptoms generally appear by six months of age.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> While symptoms vary from one child to the next, there is always a slowing down of development.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Gradually, </B><B>Tay-Sachs</B><B> children lose motor skills and mental functions. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Over time, the child becomes blind, deaf, mentally retarded, paralyzed and non responsive to the environment. </B><B>Tay-Sachs</B><B> children usually die by age five.</B></div> <div> <FONT SIZE="3" COLOR="#FFFF00" FACE="Arial" ><B><IMG SRC="06732bb0.gif" border=0 width="306" height="187" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></FONT><FONT SIZE="3" COLOR="#000000" FACE="Arial" >I</FONT><B>f two carriers for </B><B>Tay-Sachs</B><B> </B><B>disease</B><B> have a child together, each child has a: </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ccff3300.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">1-in-4 (25%) chance of having </B><B>Tay-Sachs</B><B> </B><B>disease</B><B>, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ccff3300.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">2-in-4 (50%) chance of being a carrier, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ccff3300.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">1-in-4 (25%) chance of neither having </B><B>Tay-Sachs</B><B> </B><B>disease</B><B> nor being a carrier. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ccff3300.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Unaffected siblings of individuals with </B><B>Tay-Sachs</B><B> </B><B>disease</B><B> have a 2/3 (66%) chance of being carriers. </B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">There is a one-in-four chance that any child they have will inherit a </B><B>Tay-Sachs</B><B> gene from each parent and have the </B><B>disease</B><B>. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">There is a one-in-four chance that the child will inherit the normal gene from each parent and be completely free of the </B><B>disease</B><B> and the </B><B>Tay-Sachs</B><B> gene. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">There is a two-in-four chance that the child will inherit one of each kind of gene and be a carrier like the parents and free of </B><B>disease</B><B>. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">If only one parent is a carrier, none of their children can have the </B><B>disease</B><B>, but each child has a 50-50 chance of inheriting the </B><B>Tay-Sachs</B><B> gene and being a carrier. </B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The normal function of Hex A is to break down GM2 ganglioside, which is a normal component of cell membranes, and is particularly abundant in nerve tissue.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> This lipid is created normally in the body, and is not connected with fat in the diet. In the normal process of metabolism, cells age and die, and must be disposed of.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The cell membranes are degraded and the component molecules are recycled.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> When there is only partial Hex A activity present, there is not complete break-down of GM2 ganglioside from the membranes, and there is some accumulation in nerve cells.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The accumulation interferes with the activity of the cells, and there is a slow deterioration of the nervous system.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Hex A is made up of two separate parts called subunits, each of which is a unique protein whose synthesis is controlled by different gene. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">There is an alpha-subunit and a beta-subunit that make up the Hex A enzyme. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">There is also a third protein, called an activator protein, that is required for Hex A to be active in cells. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The active enzyme therefore, is a very large molecule made up of these three distinct parts, each of which is synthesized separately and then assembled to form the active molecule.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Both the infantile and late onset forms of Tay-Sachs are the result of deleterious mutations in the gene on chromosome 15 that codes for the alpha-subunit of Hex A</B></div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The phenotypes of hexosaminidase A deficiency include the following: </div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Acute infantile (Tay-Sachs disease)</B> with rapid progression and death before age four years </div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Juvenile (subacute)</B> with later onset and survival into late childhood or adolescence </div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Chronic and adult-onset</B> with long-term survival. Patients have several different phenotypes, including progressive dystonia, spinocerebellar degeneration, motor neuron disease with muscle weakness and fasciculations, and/or psychosis. </div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Acute infantile GM2 gangliosidosis (HEX A-deficient) [Tay-Sachs disease (TSD)]. </B>Affected infants generally appear to be completely normal at birth. Mild motor weakness begins at three to six months of age, along with myoclonic jerks and an exaggerated startle reaction to sharp noise.</div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">By six to ten months of age, the infant fails to achieve new motor skills or even loses previously demonstrated skills. Decreasing visual attentiveness and unusual eye movements are associated with pallor of the perifoveal macula of the retina with prominence of the fovea centralis, the so-called cherry-red spot, which is seen in virtually all patients.</div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">After eight to ten months of age, progression of the disease is rapid. Spontaneous or purposeful voluntary movements diminish and the infant becomes progressively less responsive. Vision deteriorates rapidly. Seizures are common by 12 months of age. Subtle partial complex seizures or absence attacks typically become more frequent and more severe.</div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Progressive enlargement of the head typically begins by 18 months of age; it results from reactive cerebral gliosis, not hydrocephalus.</div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Further deterioration in the second year of life results in decerebrate posturing, difficulties in swallowing, worsening seizures, and finally an unresponsive, vegetative state. Death usually occurs between two and four years of age from bronchopneumonia.</div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Juvenile (subacute) GM2 gangliosidosis (HEX A-deficient). </B>Juvenile GM2 gangliosidosis (HEX A-deficient) often begins with ataxia and incoordination between two and ten years of age. Speech, life skills, and cognition decline. Spasticity and seizures are present by the end of the first decade of life. Loss of vision occurs much later than in the acute infantile form of the disease, and a cherry-red spot is not consistently observed. Instead, optic atrophy and retinitis pigmentosa may be seen late in the course. A vegetative state with decerebrate rigidity develops by 10 to 15 years of age, followed within a few years by death, usually due to infection. In some cases, the disease pursues a particularly aggressive course, culminating in death in two to four years.</div> <bR> <bR> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Chronic and adult-onset GM2 gangliosidoses (HEX A-deficient). </B>These conditions represent a spectrum of later-onset, more slowly progressive neurodegenerative disorders, associated with low levels of residual HEX A enzyme activity. Early symptoms may range from muscle weakness to extrapyramidal findings to altered cerebellar manifestations.</div> <bR> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffff0000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Patients with </B><B>adult-onset disease</B><B> tend to show progressive muscle wasting, weakness, fasciculations, and dysarthria, indistinguishable from progressive adolescent-onset </B><B>spinal muscular atrophy</B><B> (Kugelberg-Welander disease) or early onset </B><B>ALS</B><B>.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffff0000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Upper motor neuron signs may be present. As many as 40% of patients have psychiatric manifestations (without dementia) including recurrent psychotic depression, bipolar symptoms, and acute hebephrenic schizophrenia with disorganization of thought, agitation, delusions, hallucinations, and paranoia </B></div> <bR> <bR> </tD> </tR> </TABLE></B></div> <DIV ALIGN="LEFT"></DIV> <div> <B><IMG SRC="069926d0.gif" border=0 width="402" height="365" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></div> <div> <B> <TABLE BORDER="2" CELLPADDING="2" CELLSPACING="1" WIDTH="1001" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="BOX" RULES="ALL" ALIGN="BOTTOM" HSPACE="0" VSPACE="0" BGCOLOR=#000033 > <tR> <tD VALIGN=TOP HEIGHT= 738 WIDTH="71"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="738" ALIGN="bottom" WIDTH="71" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=TOP WIDTH="911"><div> Hexosaminidase A Deficiency</div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Gene: </B><I><U>HEXA</U></I><I> </I>(hexosaminidase A) </div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Pathologic allelic variants: </B>Of the more than 70 <I>HEXA</I> mutations identified to date, the vast majority (>60) are associated with the acute infantile phenotype (Tay-Sachs disease). All the small insertions or deletions producing frameshifts and the nucleotide substitutions producing stop codons result in this clinical phenotype. In general, these mutations are immunologically CRM-negative. Most splice mutations fall into this category, but there are important exceptions (see following section). Among Ashkenazi Jewish people in North America and Israel, the two mutations associated with the acute infantile form account for 90 to 95% of all alleles; the mutation Gly269Ser associated with the chronic form accounts for 3%, and the two pseudodeficiency alleles (Arg247Trp) account for 2%. In the non-Jewish general population, about 35% of alleles are accounted for by two mutations associated with the acute infantile phenotype, and about 5% are accounted for by mutations associated with the juvenile, chronic, and adult-onset types. Of particular importance is that ~35% of enzymatically defined, non-Jewish heterozygotes are carriers for one of the two pseudodeficiency alleles (Arg247Trp or Arg249Trp).</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The mutations that account for most of the TSD occurring in Ashkenazi Jews are null alleles, because they result in no protein product, although the gene is transcriptionally active in both cases. The most frequent allele is a 4-bp insertion in exon 11, +TATC1278, which creates a frameshift and downstream stop codon in the coding sequence. Although the <I>HEXA</I> gene is transcribed normally, the mRNA is undetectable by Northern blotting. The second major allele is a donor splice-junction mutation in intron 12, +1 IVS- 12G>C, which results in the production of several aberrantly spliced mRNAs. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Several mutations have been described that affect subunit assembly or processing of the newly synthesized alpha precursor polypeptide. Most have been detected at the 3' end of the protein, although there is no direct evidence for a sequence or structure near the C-terminus specifically involved in subcellular transport. </div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Abnormal product:</B> The mutations result in a variety of effects, ranging from defective processing or subunit assembly to defective catalytic activity. </div> <div> Gene Involved:  <A NAME="hexa"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A><I>HEXA</I> </div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Locus: </B>15q23-q24 </div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Normal allelic variants: </B>The <I>HEXA</I> gene spans approximately 35,000 base pairs, contains 14 exons, and has both 5' regulatory elements (TATA) and 3' untranslated regions. </div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Normal product:</B> Beta-hexosaminidase alpha chain. The <I>HEXA</I> gene encodes the alpha chain of the heterodimeric protein, beta-hexosaminidase A (HEX A), which is also called GM2 gangliosidase. The HEX A protein is comprised of a single alpha chain and a single beta chain, which is encoded by the gene <I>HEXB</I> (chromosomal locus 5q13). This isoenzyme cleaves the terminal beta-linked N-acetylgalactosamine from GM2 ganglioside. </div> <bR> <bR> <bR> </tD> </tR> </TABLE></B></div> <bR> </td> </tr></table></body>