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Wood, Heather. “Gene therapy for mucopolysaccharidosis shows promise.” (2017): 512-512. Access from

What is Mucopolysaccharidosis?

Mucopolysaccharidosis (MPS) is caused by a defect in one of the lysosomal enzymes leading to improper breakdown of mucopolysaccharides (long chains of sugar molecules found in the body). Due to this improper breakdown, these sugars buildup in cells, blood, skeleton, arteries connective tissue. Sugar buildup is also found in vital organs like the liver, spleen, respiratory system, central nervous system and bone marrow. This accumulation causes damage to cells, tissues and organs subsequently affecting organ and system functions.

Across the globe, MPS affects 1 in every 25,000 persons. MPS occurs equally among males and females.

There are different types of MPS based on the type of mucopolysaccharides affected:
  • MPS 1 H – is the severest type of mucopolysaccharidosis. It is caused by a deficiency of the enzyme alpha-L-iduronidase. This causes an excess accumulation of dermatan and heparan sulfates. This disorder presents itself in the first six months of life. Babies experience developmental delays, recurrent respiratory and urinary infections, noisy breathing, clouding cornea in the eye, spine deformities and other joint issues. Mental regression usually occurs after the age of two.
    Scheie syndrome (mucopolysaccharidosis type I-S; MPS 1-S) is the mildest type of mucopolysaccharidosis. People with Scheie syndrome lack an enzyme known as alpha-L-iduronidase. Affected people usually have normal height, development, intelligence and life expectancy.
  • MPS I H/S (Hurler-Scheie syndrome) – is extremely rare and affected individuals have a less severe form of Hurler syndrome, but a more severe form of Scheie syndrome. Affected individuals are usually diagnosed between the ages three to six years. They may present with enlargement of the spleen and liver, coarse facial features, short stature, joint stiffness, other skeletal issues, clouding corneas and mild developmental delays.
  • MPS II-(Hunter syndrome) – this is the only type of MPS which is X-linked and inherited from the mother. Symptoms appear around the age of two and children present with short stature, joint stiffness, skeletal issues, coarse facial features, macrocephaly (large head), short neck and broad chest, hearing loss, liver and spleen enlargement. In the milder type of MPS IIB, individual intelligence may be slightly affected but in the severe type of MPS IIA intellectual disability may be severe.
  • MPS III A, B, C, and D (Sanfillipo syndrome) – has four subtypes which are A, B, C and D caused by different enzyme deficiencies. Early signs include developmental delays like crawling, sitting up or walking, sleeplessness and hyperactivity. All types of Sanfillipo syndrome present with different degrees of intellectual delays, loss of skills like language and fine motor skills and hearing loss. Eventually some individuals lose the ability to walk and perform daily activities.
  • MPS IV A and B (Morquio syndrome) has two subtypes Morquio syndrome A and B. Morquio is due to a deficiency of the enzyme N-acetyl-galactosamine-6-sulfatase and beta-galactosidase, leading to an accumulation of keratan and chondroitin sulfate in type A and keratan sulfate in type B. Most affected people have normal intelligence. The subtype MPS IV B is milder than MPS IV A. Common symptoms include short neck, stunted growth and short stature, knock knees, curvature of the spine and broad chest. In most cases of MPS IV A, people experience difficulties with mobility and daily activities.
  • MPS VI (Maroteaux-Lamy syndrome) – is due to a deficiency in the enzyme N-acetylgalactosamine-4-sulfatase leading to an accumulation of dermatan sulfate. The severity varies among affected individuals with some presenting with a mild form while others may be more severe. Common signs include coarse facial features, prominent chest, clouding corneas, umbilical hernia, enlargement of liver and spleen, skeletal issues and cardiac abnormalities. In most cases, intelligence is unaffected.
  • MPS VII (Sly syndrome) – is due to a deficiency in the enzyme beta-glucuronidase leading to an accumulation of three glycosaminoglycans: dermatan sulfate, heparan sulfate and chondroitin sulfate. Again symptoms vary among individuals. Some may present with intellectual disability while others are unaffected. Common signs include coarse facial features, prominent chest, clouding corneas, umbilical hernia, enlargement of liver and spleen, skeletal issues and cardiac abnormalities. In rare cases, infants present with accumulation of fluid in various tissues of the body (hydrops fetalis).
  • MPS IX (hyaluronidase deficiency) – is a very rare type of MPS due to a deficiency in the enzyme hyaluronidase needed to breakdown the mucopolysaccharides – hyaluronan (hyaluronic acid). Symptoms include short stature, frequent ear infections and abnormal soft tissue masses.
All types of MPS is inherited in an autosomal recessive pattern (two copies of the mutated gene from the parents) except Hunter Syndrome which is X-linked.

Symptoms usually appear in infancy or early childhood. Signs and symptoms of MPS can be grouped into the following categories. These include:

  • Musculoskeletal abnormalities – short stature, stiff joints
  • Facial features – coarse features, flat nose, thick lips
  • Respiratory issues – frequent bronchial infections, sleep apnea, obstructed airways
  • Cardiovascular issues – valve dysfunction, hypertension, congestive heart disease
  • Ophthalmologic issues – corneal clouding, glaucoma, retinal degeneration
  • Hearing – progressive deafness
  • Neurological – hydrocephalus, spinal issues
If the pediatrician suspects any form of MPS, he/she will usually take a family history and history of the child’s symptoms along with a detailed clinical examination of the child. Some of the tests that are used to diagnose MPS include:
  • biochemical tests – serum assays for lysosomal enzymes
  • urinalysis – to test for abnormal excretion of glycosaminoglycans
  • molecular test – DNA tests like Next Generation Sequencing (NGS) to locate the exact mutation causing the form of MPS.
Currently, no permanent cure is available for MPS. Treatment is aimed at preventing complications and enabling independent living. An interdisciplinary team of doctors including pediatricians, neurologists, orthopedicians, pulmonologist, cardiologist and physiotherapists will be required to take care of the clinical needs of the child/adult. In the early stages when just diagnosed, it is important to immediately start ERT treatment to prevent further deterioration and prevent organ damage. ERT involves an intravenous (IV) infusion every 2 weeks which can even be taken at home. ERT helps in reducing symptoms like liver and spleen enlargement, joint stiffness and cardiac issues. The US Food and Drug Administration (US FDA) has approved the following enzymes for different types of MPS:
  • laronidase (Aldurazyme) for MPS I. This is approved for Hurler and Hurler-Scheie types of MPS I. The drug is manufactured by BioMarin and distributed by Sanofi Genzyme
  • idursulfase (Elaprase) for MPS II. The drug is manufactured by Shire
  • elosufase alfa (Vimizin) for MPS IVA. The drug is a product of BioMarin
  • galsulfase (Naglazyme) for MPS VI – Maroteaux-Lamy syndrome. The drug is a product of BioMarin
Supportive treatment may include respiratory support like bipap or ventilators if needed. Physiotherapy is highly recommended to preserve muscle strength. Wheelchairs may be required in some cases. Investigational therapies like gene therapy and gene editing are in the clinical research stage and proving to be exciting. Abeona therapeutics is working on a next generation adeno-associated viral (AAV)-based gene therapies for MPS III (Sanfilippo syndrome). This therapy will deliver a normal copy of the gene and promises to be a one-time cure. Esteve is working on a gene therapy platform for Sanfillipo B and Hunter syndromes. Orchard therapeutics is working with lentiviral vectors to develop a gene therapy for Sanfillipo B. Lysogene is working on gene therapy for MPS IIIA. MeuSix has a gene therapy candidate for MPS VI. Regenxbio is looking at gene therapy for MPS I. Sangamo is developing gene editing candidates for MPS I and II.
Children and adults with MPS must be encouraged to participate in all life activities and must be encouraged to go to regular schools, colleges and participate in social activities. Genetic counselling and psychosocial counselling must be made available whenever required with other supportive measures.

If there is a known case of MPS in the family, it is absolutely essential for closest female relatives like siblings, uncles, aunts and cousins to test for carrier status.

If a woman with a carrier status is pregnant, prenatal test is essential to determine if the fetus has the disease mutation.

Mucopolysaccharidosis Overview