The enzyme performs a crucial step in the breakdown of the glycosaminoglycan heparan sulfate which is found in the extra-cellular matrix and on cell surface glycoproteins. Although undegraded heparan sulfate is the primary stored substrate, glycolipids such as gangliosides are also stored despite no genetic defect in the enzymes associated with their breakdown.

MPS-III A has an incidence of approximately 1 in 115 000 live births. Higher rates are found in certain populations such as the Ashkenazi jews. It is a rare disease.

Natural History and Diagnosis

It should be noted that MPS-III A, B, C and D are considered to be clinically indistinguishable, although mutations in different genes are responsible for each disease. The following discussion is therefore applicable to all four conditions.

The disease manifests in young children. Affected infants are apparently normal, although some mild facial dysmorphism may be noticeable. The stiff joints, hirsuitism and coarse hair typical of other mucopolysaccharidoses are usually not present until late in the disease. The child often develops normally initially. Acquisition of speech is often slow and incomplete. The disease then progresses to increasing behavioural disturbance including temper tantrums, hyperactivity, destructiveness, aggressive behaviour, pica and sleep disturbance. As affected children have normal muscle strength and mobility, the behavioural disturbances are very difficult to manage. The disordered sleep in particular presents a significant problem to carers. In the final phase of the illness, children become increasingly immobile and unresponsive, often require wheelchairs, and develop swallowing difficulties and seizures. Death eventually results from inanition. The life-span of an affected child does not usually extend beyond late teens to early twenties.

Although the clinical features of the disease are mainly neurological, patients may also develop diarrhoea, carious teeth, and an enlarged liver and spleen. There is a broad range of clinical severity. The disease may very rarely present later in life as a psychotic episode.

The diagnosis may be confirmed by assay of enzyme levels in tissue samples and gene sequencing. Prenatal diagnosis is possible.

Treatment

Treatment remains largely supportive. The behavioural disturbances of MPS-III respond poorly to medication. If an early diagnsosis is made, bone marrow replacement may be beneficial. Although the missing enzyme can be manufactured and given intravenously, it cannot penetrate the blood-brain barrier and therefore cannot treat the neurological manifestations of the disease.

Along with many other lysosomal storage diseases, MPS-III exists as a model of a monogenetic disease involving the central nervous system. Several promising therapies are in development. Gene therapy is under investigation for MPS-III in animal models. Other potential therapies include chemical modification of deficient enzymes to allow them to penetrate the brain blood-brain barrier, stabilisation of abnormal but active enzyme to prevent its degradation, and implantation of stem cells strongly expressing the missing enzyme. For any future treatment to be successful, it must be administered as early as possible. Currently MPS-III is mainly diagnosed clinically, by which stage it is probably too late for any treatment to be very effective. Neonatal screening programs would provide the earliest possible diagnosis.

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There's hope for optimism - Brief Article
From Christian Century, 11/4/98 by Martin E. Marty

Optimism is hard to come by this autumn. Don't confuse it with hope, in any case. In the best of circumstances I agree with Elbert Hubbard: optimism is "fatty degeneration of intelligence." In any circumstances I remain with Oscar Wilde: "The basis of optimism is sheer terror." In the present circumstances the terror is sufficiently palpable to remove occasions for that fatty degeneration.

How do I sustain a light heart this autumn? By 5:58 A.M. I daily dash back into the bedroom to turn off the alarm before my spouse's radio invades with news of the Asian economy, the Washington scene, Laramie, Bosnia, the NBA strike, etc. I scan the newspapers.

For a moment things looked up when I saw in a headline the word "optimists"--"Key finds bolster optimists." The story talked about the possibility of life existing on other planets. "There has been a revival in the serious search for life," says Stanford University scientist Chris Chyba. Where? In inert churches? Among lifeless believers going through the motions of believing? Among those long benumbed by the New Age meditators? Finding life in those places would cheer us.

No, it is the belief that conditions may be right for life forms to survive in more remote stretches of the universe. Of course, there is a qualification: "Yet even with the new optimism that life is out there, many scientists believe the evolution of intelligent life remains highly uncertain."

I am faithfully (with the emphasis on faith) committed to rejoicing in scientific discovery. But this kind, for all its appeal to curiosity and intelligence, inspires little optimism or hope. The center of our Milky Way is 30,000 light-years away and the Andromeda galaxy 2.5 million light-years away. So communication between us and the microbes out there is not likely. One has to look elsewhere for signs of hope.

I found signs in some other stories in the newspaper that day. One teeny story far from the front page was: "U.S. Teenage Pregnancies at 20-Year Low." The article also reported that the abortion rate dropped during the first half of this decade. That is very good news.

When I got to the local sections of the paper, which means when I got closer to real people, intelligent life close up, things brightened more. The city honored a policeman killed in the line of duty by naming a street after him. A photo shows his mother carrying the street sign, "Michael Ceriale Street." She is smiling. Another picture, "Girl's Parents Raise Funds--and Hope," shows a mother holding her daughter, who is afflicted with Sanfilippo's syndrome. The family is raising money for research of the disease. "Work is a Test of Faith for Muslims" features the picture of an executive who finds it inconvenient but necessary to pray five times a day. And so he prays.

From the obituary page a familiar face smiles at me. I knew Margaret Pfrommer, who contracted polio in 1956 and became paraplegic. This woman of faith turned into a "fiesty and revered advocate for the disabled for 25 years." It took hours for her even to get to work, but she chose to live alone with the help of drop-in aides. Margaret used a "sip and puff" straw to answer phones, operate a computer, take communion and more. She combined creative anger and angrily creative faith. A Loyola professor: "She is one of the most remarkable human beings I've ever met. She had a desire to serve others beyond any person I've ever met." You don't need optimism when people like Margaret breathe hope, even if through that sip-and-puff straw.

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