What is Sanfillippo Syndrome A Sanfillippo Syndrome A?
Sanfilippo syndrome A, or mucopolysaccharidosis III (MPS-III) A is a rare autosomal recessive lysosomal storage disease. It is caused by a deficiency of the enzymes heparan N-sulfatase needed to break down 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. The condition is named for Sylvester Sanfilippo, the pediatrician who first described the disease
Sign and symptoms?
Symptoms often appear after the first year of life. A decline in learning ability typically occurs between ages 2 and 6. The child may have normal growth during the first few years, but final height is below average. Delayed development is followed by worsening mental status. Other symptoms include:
What genes are related to sanfillippo syndrome ASanfillippo syndrome A is caused by themutation in SGHS gene , was found to be located to the long arm of chromosome 17q25.3, thegene encoding the enzyme heparan N-sulfatase affecting the breakdown of heparan sulfate,which then builds up in various organs. Since MPSIII A is an autosomal recessive disorder, the child needs to receive the abnormal gene from both parents in order to show any clinical symptoms. Mutations in these genes reduce or eliminate enzyme function. A lack of any one of these enzymes disrupts the breakdown of heparan sulfate. As a result, partially broken down heparan sulfate accumulates within cells, specifically inside the lysosomes. Lysosomes are compartments in the cell that digest and recycle different types of molecules. Conditions such as MPS III that cause molecules to build up inside the lysosomes are called lysosomal storage disorders. Researchers believe that the accumulation of GAGs interferes with the functions of other proteins inside the lysosomes and disrupts the normal functions of cells. It is unknown why the buildup of heparan sulfate mostly affects the central nervous system in MPS III.
How the people inherit sanfillippo syndrome AThis condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. There is a 25% chance that a child will be completely normal The risk is the same for males and females. The risk to have a child who is a carrier like the parents is 50% with each pregnancy The risk for both carrier parents to pass the defective gene and have an affected child is 25% with each pregnancy . If an individual receives one normal gene and another gene for the disease, the person will only be a carrier for the disease.
DiagnosisUrine tests will be done. People with Sanfilippo syndrome have large amounts of a mucopolysaccharide called heparan sulfate in the urine.The diagnosis can be made by an enzyme study from leucocytes by heparan N-sulfatase and molecular diagnosis can be made by SGHS gene study. Prenatal diagnosis can be carried out at 11 weeks of pregnancy by direct chorionic villi study or at 16 weeks by amniotic fluid cultured cells for the enzyme or molecular study in case of known identified mutation in the gene.
Treatment remains largely supportive. The behavioral disturbances of MPS-III respond poorly to medication. If an early diagnosis 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.
When to contact a Medical Professional?
When a diagnosis of Sanfilippo syndrome A is made.When pregnancy is planned in a family with history of Sanfilippo syndrome A.
Who to contact for more information?
The Department of Health Research and Indian Council of Medical Research have constituted a National Task Force to perform a multicentric collaborative study at different research institutes across the country. Further information can be found at http://www.icmrmetbionetindia.org/taskforce- sdisoredrs.php Lysosomal Storage Society of India - LSDSS http://www.lsdss.org
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Dr Madhulika Kabra
All India Institute of Medical Sciences,New Delh