Sanfillipo syndrome is a lysosomal storage disorder resulting from a deficiency in the lysosomal enzyme heparan-N-sulfatase. 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. The lysosomal storage diseases are a group of over thirty disorders that result from defects in lysosomal function. ... Lysosomes are organelles that contain digestive enzymes (acid hydrolases) to digest macromolecules. ... Glycosaminoglycans (GAGs) are long unbranched polysaccharides, made up of repeating disaccharides that may be sulphated (e. ...

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. The incidence of disease is defined as the number of new cases of disease occurring in a population during a defined time interval. ... Ashkenazi Jews, also known as Ashkenazic Jews or Ashkenazim (אַשְׁכֲּנָזִי אַשְׁכֲּנָזִים Standard Hebrew, Aškanazi,Aškanazim, Tiberian Hebrew, ʾAškănāzî, ʾAškănāzîm, pronounced sing. ... A rare disease has such a low prevalence in a population that a doctor in a busy general practice would not expect to see more than one case a year. ...

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. Pica is an abnormal appetite for soil, flour, chalk, starch or other non-foods. ...

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. The blood-brain barrier is a physical barrier between the blood vessels in the central nervous system, and most parts of the central nervous system itself. ...

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. Gene therapy using an Adenovirus vector. ... The blood-brain barrier is a physical barrier between the blood vessels in the central nervous system, and most parts of the central nervous system itself. ... Mouse embryonic stem cells. ...

External links

• OMIM number 252900
• The National MPS Society page on MPS-III