A baby boy or girl born with Tay-Sachs disease looks and actsnormal for the first few months of life. In most of its 39 weeks inutero, its fetal brain cells have been steadily piling up lipid, and thisfatty accumulation of gangliosides continues after birth.It continues until death, which usually occurs between two and fiveyears of age. There is no known treatment for the inherited malady,which begins to show itself when the infant starts to crawl and situp.Soon, the child loses these motor skills. Its characteristically doll-like face -- typically, with translucent skin, long eyelashes and pinkskin -- goes blank. Muscles weaken and eyes become sightless.Hearing, on the other hand, seems sharpened, as a Tay-Sachsdisease child's joints knee-jerk straight in response to any suddensound. This startle syndrome is symptomatic of the disease in itsfirst year.Later, mental and motor deterioration progress rapidly; deafnessjoins the earlier blindness; seizures and general paralysis set in. Thestricken child cannot communicate with the outside world, anddeath (usually from bronchial pneumonia) seems merciful when itcomes.This horrendous childhood affliction results from a mutation in theHexa gene, which encodes the enzyme responsible for preventinglipids from ballooning out the lysosomes of the brain's neurons.That waste-disposing enzyme, missing in Tay-Sachs disease, iscalled b-hexosaminidase A. In humans, the Hexa gene resides onchromosome 15.First Jewish, Now GeneralTay-Sachs, like a number of other lysosomal storage diseases, isrelatively rare. Traditionally, it affected almost exclusively childrenborn into families of Ashkenazi Jews. The aberrant gene is thoughtto have arisen perhaps centuries ago in the Jewish settlements ofEastern Europe.Tay-Sachs is a rare autosomal recessive disease. The U.S. census of1970 estimated 200 Tay-Sachs infants among total Jewish births of1,182,000. In contrast, it listed only 33 among 17,960,000 non-Jewish births.Since that year, prenatal screening of Jewish parents for the mutantHexa gene has drastically lowered the incidence of Tay-Sachs inthis ethnic gene pool. On the other hand, said molecular biologistRichard Proia, "Non-Jews aren't screened, so it turns out that moreTay-Sachs infants are born to them these days than to Jews." Headds that the current incidence is high among Louisiana Cajuns .Proia, who heads the genetics and biochemistry section at theNational Institute of Diabetes and Digestive and Kidney Diseases atthe National Institutes of Health (NIH), will present a poster nextweek in Toronto at the 1994 annual meeting of the AmericanSociety of Human Genetics. It is titled: "Targeted disruption of theHexa gene results in mice with biochemical and pathologicalfeatures of Tay-Sachs disease."His full paper appears in the current (Oct. 11) Proceedings of theNational Academy of Sciences (PNAS).Proia and his co-workers at several NIH institutes crippled themurine Hexa gene in mouse embryonic stem cells, and raised ageneration of rodents to serve as biochemical and pathologicalmodels for human Tay-Sachs."As far as I know," Proia told BioWorld Today, "these mice are thefirst animal models for the study of Tay-Sachs."First Tay-Sachs Models Pass Behavior TestsSure enough, for lack of the enzyme that rids the brain of lipidbuild-up, cerebral lysosomes in the knockout mice dulyaccumulated the fatty substance. However, unlike the humancondition in which virtually every neuronal cell in the brain andcentral nervous system pile up the excess gangliosides, in the mice,only certain brain regions did so.Nor did they display any untoward symptoms; instead, they areliving out their normal life spans in apparent health, vigor andfertility. All passed cum laude their behavioral lab tests for motorcoordination, balance, memory and spontaneous exploratorylocomotion.To explain this anomaly, Proia and his team theorize that micegestate their fetuses for only three weeks, as opposed to 39 inhumans, so that the fewer neurons affected in the animals don'thave enough time to turn on the sensory and motor deficits of Tay-Sachs."As a result," the PNAS paper surmises, "the Hexa _/_ mice maymirror a very early stage of the human disease."But at the biochemical level, the mice are prized for their ability tomimic the underlying neuropathology of the disease. "Putting it alltogether," he said, "it's a very useful tool for looking at Tay-Sachs,and the whole group of lysosomal storage diseases."Proia will be sharing his mouse colony with "certain peopleinterested in the biochemistry of gangliosides, and those studyingnew therapeutic approaches to treatment."At the NIH, he and his co-authors "are looking at therapeutic waysto reverse the kinds of neuropathology that we have in the mice.We'll be trying gene therapy technologies, and transplantation ofneuronal cells, to see if that might help out what we see in thebrains of these mice."Their first effort will go toward trying to prevent the storage fromoccurring. "If that works, then it would be interesting to see if wecould reverse storage that has already taken place."The team is also approaching the problem from the opposite end, todetermine what those gangliosides are doing in the gray matter inthe first place. "We're using this knockout technique," Proia said,"to knock out the enzymes involved in the synthesis, rather than thedegradation, of these gangliosides, to see what their function mightbe." n

-- David N. Leff Science Editor

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