About mucopolysaccharidosis type iii

What is mucopolysaccharidosis type iii?

The Mucopolysaccharidoses (MPS Disorders) are a group of rare genetic disorders caused by the deficiency of one of the lysosomal enzymes, resulting in an inability to metabolize complex carbohydrates (mucopolysaccharides) into simpler molecules. High concentrations of mucopolysaccharides in the cells of the central nervous system, including the brain, cause the neurological and developmental deficits that accompany these disorders.

Mucopolysaccharides are rather thick jelly-like ("muco") compounds made of long chains ("poly") of sugar-like (saccharides) molecules used to make connective tissues in the body.

Lysosomal enzymes are found in the lysosome, a very small membrane-contained body (organelle) found in the cytoplasm of most cells. The lysosome is often called the "waste disposal plant" of the cell. The accumulation of these large, undegraded mucopolysaccharides in the cells of the body is the cause of a number of physical symptoms and abnormalities.

MPS-III (Sanfilippo Syndrome) is one of seven MPS Disorders. It is an inborn error of metabolism that is transmitted as an autosomal recessive genetic disorder. MPS-lll has been subdivided into four types: MPS-III Type A, MPS-III Type B, MPS-III Type C, and MPS-III Type D. All types are associated with some degree of mental deterioration, but the severity depends on the particular type of MPS-lll. Several physical defects may be present, and the severity of these defects varies with the type of MPS-III. In the case of each type of MPS-III, abnormal amounts of a specific, chemically complex molecule is excreted in the urine. The excreted chemical is the same for each of the four types of MPS-III, since the defective gene involves a different step, and thus a different enzyme, in the deconstruction of the same mucopolysaccharide. By testing for one or another of these enzymes, the variant type may be readily identified.

What are the symptoms for mucopolysaccharidosis type iii?

Sanfilippo syndrome often goes unnoticed during the first months — or even years — of a child's life. Even though there may be some signs at an early age, doctors usually confuse them for other conditions.

Most of the Sanfilippo syndrome symptoms start at the age between 1 and 6 years — they include developmental delay, trouble sleeping, and frequent infections.

Common symptoms seen at the first Sanfilippo syndrome stage include:

  • Behavioral issues
  • Speech and development delays
  • Persistent diarrhea
  • Frequent infections, especially in the ear and throat
  • Trouble sleeping

As the disorder progresses, a child with Sanfilippo syndrome will start displaying even more severe symptoms. Often, kids at this stage need to use a feeding tube because they lose their motor skills by then. During this stage, sleep and behavioral issues become more pronounced.

The second stage of Sanfilippo syndrome is marked by these symptoms:

  • Extreme restlessness
  • Gradual loss of language
  • Hyperactivity
  • Hearing loss
  • Seizures
  • Progressive intellectual disability

In the final stage, an affected child will lose their motor skills, which will slow them down considerably. Movement disorders and loss of walking ability are common, and at this stage, most children aren’t able to speak or eat anything. Children at this stage will usually show:

  • Movement disorders
  • Contractures of hands and fingers
  • Frequent falling
  • Arthritis
  • Visual impairment

What are the causes for mucopolysaccharidosis type iii?

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.

What are the treatments for mucopolysaccharidosis type iii?

There's no cure for Sanfilippo syndrome. But several symptom-specific treatments can be prescribed to elevate the affected child’s quality of life. 

There are a few possible therapeutic avenues under research that may help treat Sanfilippo syndrome in the future. One such avenue is enzyme-replacement therapy, where the child is injected with an infusion of the enzyme they can’t produce — which allows them to metabolize heparan sulfate until the next injection.

What are the risk factors for mucopolysaccharidosis type iii?

Mucopolysaccharidosis type III, also known as Sanfilippo syndrome, is an inborn error in the metabolism of mucopolysaccharides. It reflects in deficiency or little activity of enzymes required for the catabolism of mucopolysaccharides leading to its accumulation. The disease presents with neurological manifestations such as autism, intellectual disability, behavioral problems, sleep disturbances, developmental regression, and seizures. The disease progression may be either rapid or slow; the disease course begins in middle-late adulthood. The treatments are available to improve symptoms and support psychomotor abilities.
Risk factors
1. The disease is caused by genetic mutations in one or more of the genes GNS, HGSNAT, NAGLU, and SGSH that code for the synthesis of enzymes involved in the metabolism of mucopolysaccharides.
2. Therefore, the primary risk factor is a genetic predisposition, that is, a family history of the disease. The mutations are inherited in autosomal recessive mode.
3. A sibling born to an affected child has a 25 percent chance of suffering from the disease with early onset and a 50 percent chance of being a carrier without symptoms.
4. When a patient suffers pulmonary involvement, the procedure requiring anesthesia in centers without sophisticated equipment and inexperienced care providers poses a risk of complex airway issues.
5. Hip surgeries pose the risk of developing osteonecrosis of the femoral head.
6. Environments not adapted to handle unpredictable behaviors pose a threat of secondary injuries.

Symptoms
Neurological manifestations: autism, intellectual disability, behavioral problems, sleep disturbances, developmental regression, seizures (in later stages),Systemic manifestations: joint stiffness, contractures, scoliosis, hip dysplasia, respiratory tract and sinopulmonary infections, cardiac disease, hearing loss,In children: loss of motor and cognitive skills, verbal skills (between 10 and 15 years), Coarse and thick hair, Dysmorphisms (alae nasi, lips, and ear helices or lobules and macroglossia),Hyperactivity and aggressive behavior (decreases with age),Gastrointestinal problems: episodic diarrhea, problems with chewing and swallowing food, increasing risks for aspiration pneumonia and weight loss, Inguinal and umbilical hernias,Atrophy of the optic nerve and retinal degeneration at later stages
Conditions
Autism spectrum disorder,Klüver-Bucy syndrome,Carpal tunnel syndrome
Drugs
Melatonin and melatonin agonists (sleep disturbances), risperidone(for psychiatric disorder),Anti-epileptic medicines such as carbamazepine, clobazam, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, sodium valproate, topiramate, lacosamide, and zonisamide

Is there a cure/medications for mucopolysaccharidosis type iii?

Mucopolysaccharidosis type III, also known as Sanfilippo syndrome, is a multisystem lysosomal storage disorder. Mutations in the genes GNG, HGSNAT, NAGLU, and SGSH encode the synthesis of enzymes involved in the catabolism of mucopolysaccharides (a large sugar molecule). The deficiency of the enzymes leads to the accumulation of the substrate. It primarily affects the central nervous system causing neurological problems, including autism, intellectual disability, behavioral problems, sleep disturbances, developmental regression, and seizures. The disease usually decreases the lifespan of the patient to two or three decades.
Treatment
Since the disease is genetic in origin, there is no complete cure yet. Symptomatic and supportive treatment helps improve the quality of life. They are as follows:
1. Seizures: Anti-epileptic medicines such as carbamazepine, clobazam, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, sodium valproate, topiramate, lacosamide, and zonisamide.
2. Neurodevelopmental delays: Supportive therapies include speech therapy, physiotherapy, and occupational therapy.
3. Psychiatric or behavioral problems: Risperidone is a preferable drug to treat hyperactivity.
Antipsychotic drugs may also help.
A physically safe environment at home for children prevents secondary injuries due to aggressive and hyperactive behavior.
4. Sleep disorder: Melatonin or Melatonin agonist (ramelteon) can treat sleep disturbances. Other medicines such as benzodiazepine and z-drugs can help insomnia with sleep onset issues.
Pulmonologist involvement is necessary for sleep apnea.
5. Skeleto-muscular problems: Physical therapy and hydrotherapy for joint stiffness. Vitamin D therapy for low bone mineral density.
6. Hearing loss: Ear tube insertion and hearing aid use are viable options for patients with hearing loss.

Symptoms
Neurological manifestations: autism, intellectual disability, behavioral problems, sleep disturbances, developmental regression, seizures (in later stages),Systemic manifestations: joint stiffness, contractures, scoliosis, hip dysplasia, respiratory tract and sinopulmonary infections, cardiac disease, hearing loss,In children: loss of motor and cognitive skills, verbal skills (between 10 and 15 years), Coarse and thick hair, Dysmorphisms (alae nasi, lips, and ear helices or lobules and macroglossia),Hyperactivity and aggressive behavior (decreases with age),Gastrointestinal problems: episodic diarrhea, problems with chewing and swallowing food, increasing risks for aspiration pneumonia and weight loss, Inguinal and umbilical hernias,Atrophy of the optic nerve and retinal degeneration at later stages
Conditions
Autism spectrum disorder,Klüver-Bucy syndrome,Carpal tunnel syndrome
Drugs
Melatonin and melatonin agonists (sleep disturbances), risperidone(for psychiatric disorder),Anti-epileptic medicines such as carbamazepine, clobazam, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, sodium valproate, topiramate, lacosamide, and zonisamide

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