Sanfilippo syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Sanfilippo Syndrome
ICD-10 E76.2
ICD-9 277.5
OMIM 252900 252920 252940 252930
DiseasesDB 29177
MedlinePlus 001210
eMedicine ped/2040 
MeSH D009084

Overview

Sanfilippo syndrome, or Mucopolysaccharidosis III (MPS-III) is a rare genetic disease. This lysosomal storage disorders is due to deficiency in one of the enzymes needed to breakdown 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 has an incidence of approximately 1.89 per 100 000 live births. Higher rates are found in certain populations such as the Ashkenazi Jews. It is a rare disease.

Historical Perspective

Classification

Pathophysiology

The four types of MPS-III are due to specific enzyme deficiencies affecting the breakdown of heparan sulfate, which then builds up in various organs. All four types have autosomal recessive inheritance.

Genetics of MPS-III
MPS-III type enzyme gene location
MPS-III A heparan N-sulfatase 17q25.3
MPS-III B N-acetyl-alpha-D-glucosaminidase 17q21
MPS-III C acetyl-CoA:alpha-glucosaminide acetyltransferase 8p11-q13
MPS-III D N-acetylglucosamine-G-sulfate sulfatase 12q14

Causes

Differentiating Sanfilippo syndrome from Other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications, and Prognosis

Natural History

Complications

Prognosis

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 care providers. 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 diarrhea, 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.

Diagnostic Criteria

History and Symptoms

Physical Examination

Laboratory Findings

Imaging Findings

Other Diagnostic Studies

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.

Medical Therapy

Surgery

Prevention

See also

External links

References



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