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Sanfilippo Syndrome

Mucopolysaccharidosis type 3, Mucopoly-saccharidosis type 3, MPSIII, Sanfilippo disease, Mucopolysaccharidosis type III, MPS IIIA, MPS 3A

Overview

Mucopolysaccharidosis type III is a progressive disorder that mainly affects the brain and spinal cord (central nervous system).

People with MPS III generally do not display any features of the condition at birth, but they begin to show signs and symptoms of the disorder during early childhood. Affected children often initially have delayed speech and behavior problems. They may become restless, destructive, anxious, or aggressive. Sleep disturbances are also very common in children with MPS III. This condition causes progressive intellectual disability and the loss of previously acquired skills (developmental regression). In later stages of the disorder, people with MPS III may develop seizures and movement disorders.

The physical features of MPS III are less pronounced than those of other types of mucopolysaccharidosis. Individuals with MPS III typically have mildly "coarse" facial features, a large head (macrocephaly), a slightly enlarged liver (mild hepatomegaly), and a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia). Some people with MPS III have short stature, joint stiffness, or mild dysostosis multiplex, which refers to multiple skeletal abnormalities seen on x-ray. Affected individuals often develop chronic diarrhea and recurrent upper respiratory and ear infections. People with MPS III may also experience hearing loss and vision problems.

MPS III is divided into types IIIA, IIIB, IIIC, and IIID, which are distinguished by their genetic cause. The different types of MPS III have similar signs and symptoms, although the features of MPS IIIA typically appear earlier in life and progress more rapidly. People with MPS III usually live into adolescence or early adulthood.

Symptoms - Sanfilippo Syndrome

  • Symptoms typically appear between ages 2 and 6
  • Extreme activity, restlessness, sleepnessness, and difficult behavior
  • Language and understanding will gradually be lost
  • Some children will never become toilet trained
  • Unsteadiness on feet
  • Tendancy to fall frequently
  • Losing the ability to walk
  • Muscle spasms
  • Dystonia (sustained muscle contractions)
  • Continuous jerking movements
  • Seizures
  • Sleep disorders
  • Rreduced endurance over time 
  • Abnormal metabolism of medications
  • Increased pain tolerance
  • Mildest physical abnormalities of MPS diseases
  • Fairly normal height
  • Abnormal facial features such as thick lips with upper lip upturned, fleshy nose tip, eyes that stick out slightly, flat face
  • Llarge heads for children (but not in older patients)
  • Thick hair and more hair than usual on the body
  • Dark bushy eyebrows that may meet in the middle 
  • May have enlarged tongue
  • Gum ridges that may be broad
  • Abnormal teeth: widely spaced apart and poorly formed, with fragile enamel
  • Vision problems associated with damaged retina that can result in night blindness and loss of peripheral vision 
  • Hearing loss
  • Frequent ear infections
  • Frequent sinus infections
  • Enlarged tonsils and adenoids that partly block the airway
  • Nnarrowed, floopy, or softer than usual wind-pipe
  • Lung problems and reduced lung function
  • Ssleep apnea (rare) 
  • Frequent coughs and colds
  • Mild heart valve problems 
  • Slightly enlarged liver and spleen (hepatosplenomegaly) 
  • Umbilical and inguinal hernias
  • Minimal problems with bone formation and growth 
  • Joint stiffness
  • Osteoporosis at a young age leading to an increased risk of fractures
  • Hips may become dislocated 
  • Fingers occassionally bent due to joint stiffness
  • Difficulty extending arms fully
  • Tight achilles tendon 
  • Knock-knees
  • Broad feet, toes may be curled under

Causes - Sanfilippo Syndrome

Mutations in the GNS, HGSNAT, NAGLU, and SGSH genes cause MPS III. These genes provide instructions for making enzymes involved in the breakdown of large sugar molecules called glycosaminoglycans (GAGs). GAGs were originally called mucopolysaccharides, which is where this condition gets its name. The GNS, HGSNAT, NAGLU, and SGSH enzymes are involved in the step-wise breakdown of a subset of GAGs called heparan sulfate.

MPS IIIA is caused by mutations in the SGSH gene, and MPS IIIB is caused by NAGLU gene mutations. Mutations in the HGSNAT gene result in MPS IIIC, and GNS gene mutations cause MPS IIID. 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.

Prevention - Sanfilippo Syndrome

Not supplied.

Diagnosis - Sanfilippo Syndrome

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, hirsuteness and coarse hair typical of other mucopolysaccharidoses are usually not present until late in the disease. After an initial symptom-free interval, patients usually present with a slowing of development and/or behavioral problems, followed by progressive intellectual decline resulting in severe dementia and progressive motor disease. Acquisition of speech is often slow and incomplete. The disease 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. 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. 

Of all the MPS diseases, MPS III produces the mildest physical abnormalities. It is important, however, that simple and treatable conditions such as ear infections and toothaches not be overlooked because of behavior problems that make examination difficult. Children with MPS III often have an increased tolerance of pain. Bumps and bruises or ear infections that would be painful for other children often go unnoticed in children with MPS III. Parents may need to search for a doctor with the patience and interest in treating a child with a long-term illness. Some children with MPS III may have a blood-clotting problem during and after surgery. 

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

Prognosis - Sanfilippo Syndrome

Not supplied.

Treatment - Sanfilippo Syndrome

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.

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 in particular is under Phase I/II clinical trial in France since October 2011 under the leadership of Paris-based biotechnology company Lysogene. Other potential therapies include chemical modification of deficient enzymes to allow them to penetrate the 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.

The group of Grzegorz Węgrzyn, from the Department of Molecular Biology at the University of Gdansk, Poland, has found that the flavonoid genistein decreases the pathological accumulation of glycosaminoglycans in Sanfilippo syndrome. In vitro, animal studies and clinical experiments suggest that the symptoms of the disease may be alleviated by an adequate dose of genistein. Despite its reported beneficial properties, Genistein also has toxic side effects.

A couple of US-based groups have recently been organized to speed the development of new treatments for Sanfilippo syndrome.

Resources - Sanfilippo Syndrome

  • NIH
  • Genetics Home Reference
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