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Sanfilippo syndrome

Sanfillipo syndrome is a lysosomal storage disorder resulting from a deficiency in the lysosomal enzyme heparan-N-sulfatase. more...

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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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Mucopolysaccharidoses
From Gale Encyclopedia of Medicine, 4/6/01 by G. Victor Leipzig

Definition

Mucopolysaccharidosis (MPS) is a general term for a number of inherited diseases in which the accumulation of mucopolysaccharide leads to developmental abnormalities. Other names for the MPS diseases include Hunter, Hurler, Scheie, Morquio, Sanfilippo, Sly, and Maroteaux-Lamy syndromes.

Description

In all forms of MPS, the symptoms include a variety of developmental abnormalities, both physical and mental. The range of severity of symptoms is wide, from very mild to deadly. Most forms of MPS are caused by the absence of a specific enzyme that is necessary for the normal processing of a particular mucopolysaccharide. When an enzyme is missing its "target," mucopolysaccharide accumulates in the body. At least 10 different enzymes are associated with these diseases.

Causes & symptoms

Each type of MPS is an inherited deficiency of an enzyme involved in the metabolism of molecules known as mucopolysaccharides or glycosaminoglycans (GAGs). Each enzyme is necessary for the normal processing of a specific GAG. In the absence of the enzyme, the GAG is not processed normally and therefore accumulates. The excess GAG may be partially excreted in the urine, but still builds up to damaging levels in tissues throughout the body.

Accumulation within the brain is responsible for mental retardation. Accumulation in numerous other tissues accounts for the wide array of symptoms. The accumulating material is stored in cellular structures called lysosomes, and these disorders are therefore also known as lysosomal storage diseases.

All types of MPS (except Hunter syndrome) are autosomal recessive genetic disorders. This means that the defective gene causing the disorder is located on one of the 22 non-sex chromosomes and that a person must receive a copy of this gene from each parent in order to have the syndrome. Hunter syndrome is an X-linked recessive genetic disorder. This means that the defective gene is carried on the X chromosome, one of the two human sex chromosomes. Since a male has only one X chromosome, he will have the disease if the X chromosome inherited from his mother carries the defective gene.

Hurler syndrome (MPS type I H)

Hurler syndrome is caused by a deficiency of the enzyme iduronidase. Patients have a characteristic pattern of facial features described as gargoylism. Skeletal abnormalities include dwarfism, kyphosis, and a broad hand with short fingers. Movement at the joints can be limited. Airway obstruction and respiratory infections are common. Other common symptoms include structural abnormalities of the heart, enlarged spleen and liver, and clouding of the cornea. Mental development is usually normal in the first few years of childhood, but by later childhood severe learning disorders are seen in many patients. Death due to heart or lung failure usually occurs by age 10.

Scheie syndrome (MPS type I S)

This syndrome, also caused by a deficiency of the enzyme iduronidase, can be considered a mild formof Hurler syndrome. At one time, it was designatedMPS type V. Patients often survive through adulthood. Common problems include heart abnormalities and orthopedic difficulties of the hand and back. Conditions of intermediate severity are now referred to as Hurler/Scheie or MPS I H/S.

Hunter syndrome (MPS type II)

Hunter syndrome is caused by a deficiency of the enzyme iduronate sulphate sulphatase. Most patients are severely affected with airway problems similar to those of MPS I. Although dwarfism and kyphosis are common, skeletal abnormalities are generally not as severe as in Hurler syndrome. Neurological degeneration causes death by the mid-teens. These patients are all male, because the responsible gene is X-linked.

Sanfilippo syndrome (MPS type III)

This is the most common form of MPS and it is highly variable. Mental retardation is often severe and associated with behavioral disorders. The four subtypes, A through D, are caused by four different enzyme deficiencies, but lead to similar symptoms.

Morquio syndrome (MPS type IV)

Morquio syndrome, caused by a deficiency of the enzymes galactosamine-6-sulphatase and beta-galactosidase, is one of the less common types of MPS. It is also highly variable in severity. Intelligence is often completely normal. In severe cases, skeletal abnormalities can be extreme and include dwarfism, kyphosis, enlarged sternum, and knock-knees. The earliest symptom of this condition is often an abnormal gait noticed as the child learns to walk. In mild cases, limb stiffness and joint pain are the primary symptoms.

Maroteaux-Lamy syndrome (MPS type VI)

This syndrome, another uncommon type of MPS, is caused by a deficiency of the enzyme N-acetylglucosamine-4-sulphatase. No impact on the nervous system or intelligence is seen. Airway obstruction, however, can be a serious problem.

Sly syndrome (MPS type VII)

This extremely rare syndrome is cause by a deficiency of the enzyme beta-glucuronidase. It is also highly variable, but symptoms are generally similar to those of Hurler syndrome.

Many MPS patients have a problem with constriction of the airway. This constriction may be so serious as to create significant difficulties in administering general anesthesia. Therefore, it is recommended that surgical procedures be performed under local anesthesia whenever possible.

Diagnosis

Diagnosis for each type of MPS is often made on the basis of visible symptoms described above. Biochemical testing can confirm the specific enzyme deficiency and therefore the specific disease type. Detailed DNA analysis can be performed to pinpoint exactly the mutation responsible for a given genetic defect.

Treatment

No true cure is available for inherited diseases like MPS. Treatment for the relief of symptoms is available in some cases. For MPS, as for many other genetic diseases, research is underway that may someday allow gene replacement therapy (the insertion of normal copies of a gene into the cells of patients whose gene copies are defective).

Prevention

No specific preventative measures are available for genetic diseases of this type. For some of the MPS diseases, biochemical tests are available that will identify healthy individuals who are carriers of the defective gene, allowing them to make informed reproductive decisions. In some cases, testing also allows detection of affected fetuses.

Key Terms

Autosomal gene
In humans, a gene found on one of the 22 pairs of non-sex chromosomes.
Enzyme
A protein that catalyzes chemical reactions in the body.
Kyphosis
A hunchback condition caused by flexure of the spine.
Lysosome
A cellular structure involved in the process of localized, intracellular digestion.
Mucopolysaccharides
A group of carbohydrates.
Recessive gene
A gene that must be present in both copies of the gene pair to control expression of a trait.
X-linked gene
A gene carried on the X chromosome, one of the two sex chromosomes in humans. The other sex chromosome is the Y chromosome.

Further Reading

For Your Information

    Periodicals

  • Wraith, J.E. "The Mucopolysaccharidoses: A Clinical Review and Guide to Management."Archives of Disease in Childhood 72(1995): 263-267.

    Organizations

  • National MPS Society. 4441 New York Ave., Island Park, NY 11558. (516) 432-1797. http://members.AOL.com/mpssociety.

Gale Encyclopedia of Medicine. Gale Research, 1999.

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