Mucopolysaccharidoses (MPSs) are a group of genetic lysosomal disorders in which persons have low levels of specific enzymes that leads to an abnormal accumulation of complex carbohydrates (mucopolysaccharides or glycosaminoglycans).

There are numerous types of MPSs based on the enzyme deficiencyand the specific complex carbohydrate accumulating. Most children born with an MPS appear normal at birth, but the progressive nature of these conditions means it is imperative that clinicians recognize early symptoms of these different MPSs as soon as possible so that these persons, usually young children, can get proper treatment or enter a clinical trial as quickly as possible.

 For more information about some of the clinical trials currently underway for the various MPSs, visit clinicaltrials.gov or the National MPS Society.

 

Overview of Mucopolysaccharidosis

 

Types of MPS

MPS I (Hurler, Hurler-Scheie, and Scheie)

Children with MPS I (Hurler-Scheie syndrome) have insufficient levels of alpha-L-iduronidase which is essential in breaking down the mucopolysaccharides dermatan sulfate and heparan sulfate. Babies with MPS I appear normal but as more cells become damaged due to the accumulation of those mucopolysaccharides, symptoms start to appear. In children with the most severe form (often referred to as Hurler syndrome), early symptoms usually appear within the first year of life and the most prominent feature usually being course facial bone structure as well as numerous other physical and intellectual disabilities. Others may have a less severe, also referred to an attenuated MPS I.

 

Incidence. Severe MPS I occurs in approximately 1 in 100,000 newborns while attenuated MPS I occurs in about 1 in 500,000 newborns.

Symptoms/Diagnosis. In the more severe type of the disease, symptoms can include course facial features, developmental delay, recurrent urine and upper respiratory infections, noisy breathing and a persistent nasal discharge. Hydrocephalus may also occur in these young children. Other symptoms may include clouding of the cornea, large tongue, misaligned teeth, curved back and severe joint stiffness. Children with the severe form also show progressive mental retardation that often begins after the age of 2 years. Without treatment, these children do not live past the age of 10 years.

Milder forms of MPS 1 are more difficult to diagnose and symptoms may not appear until the person is a much older (5 years to 20 years of age). These children tend to have normal intelligence, stature and life expectancy. However, common symptoms can include stiff joints, clouding of the cornea, and cardiac abnormalities.

Management. Managing persons with MPS I is largely symptomatic and can involve multiple specialties.

There is no curative treatment for MPS I but treatments are available to attenuate the progressive of the disease, including bone marrow transplantation and/or Aldurazyme (laronidase), an FDA-approved enzyme replacement therapy (ERT). For more information, visit the treatment website at https://www.aldurazyme.com.

Clinical trials. Numerous clinical trials are recruiting patients with MPS I, including several gene therapy and stem cell transplantation studies. Due to the progressive nature of the condition, persons diagnosed with MPS I should seek treatment or possibly enrol in a clinical trial as soon as possible. To learn more, visit clinicaltrials.gov/

MPS II (Hunter syndrome)

 MPS II (Hunter syndrome) is an X-linked recessive genetic condition. As such, it mostly  affects boys. Their inherited genetic abnormality leads to insufficient levels of iduronate-2-sulfatase, an enzyme involved in the metabolism of glycosaminoglycans(GAGs). Babies with MPS II appear normal but as more cells become damaged due to accumulating toxic levels of GAGs(most notably dermatan and heparan sulfates) in cells, tissues, and organs,symptoms start to appear – usually at about the age of 2 to 4 years.

 

 

Like many MPSs, the most prominent feature is usually course facial features, but they will have numerous other physical and intellectual disabilities that will progress as the child ages. Without treatment these boys gradually lose the ability to talk, walk and eat. Most will not live past their teens without proper treatment.

Incidence. Hunter Syndrome (Mucopolysaccharidosis/MPS II) occurs in 1 in 100,000 to 150,000 male births.

Symptoms/Diagnosis. Symptoms that often lead to a diagnosis are the physical appearance of the child and their cognitive problems. These boys and course facial features (large round cheeks, broad nose, thick lips, large head) as well as less noticeable symptoms such as joint stiffness, , developmental delays, recurrent respiratory infections, bone thickening, enlarged liver and spleen, muscle weakness, cardiovascular problems, vision and hearing problems. After the age of about 5 years, growth will slow, and they will generally have a shorter stature compared to their peers. Approximately 75 – 80% of the boys will also begin to show cognitive and behavioural symptoms at the age of 2 -4 years (poor concentration, decline in learning, hyperactive, aggressive). All of these symptoms will progress if not treated properly.

As with many MPS conditions, there are more severe and milder forms of MPS II. Those with the more severe form will continue to regress and seldom live past their teens. Those with milder forms of the condition may live into adulthood and typically do not have cognitive disabilities.

Management. Managing persons is largely symptomatic and can involve multiple specialties. There is no curative treatment for MPS II but Elaprase (idursulfase), an FDA-approved enzyme replacement therapy (ERT) is available and can delay progression of the disease. The ERT cannot cross the blood brain barrier so the treat will not delay the cognitive impairment common in most boys with MPS II. For more information, visit the treatment website at http://www.elaprase.com/.

Clinical trials. Numerous clinical trials are recruiting patients with MPS II, including several gene therapy and other ERT studies. Due to the progressive nature of the condition, persons diagnosed with MPS II should seek treatment or possibly enrol in a clinical trial as soon as possible. To learn more, visit clinicaltrials.gov/

MPS III (Sanfilippo syndrome)

MPS III (Sanfilippo syndrome) is inherited in an autosomal recessive manner, which means a child must  inherits 2 copies of the altered gene, 1 from each carrier parent in order to show symptoms.

 

All 4 types of MPS III are caused by mutations in 4 different genes that regulate 4 different enzymes that metabolize heparan sulfate.

TypeGene mutationEnzyme affected
MPS IIIASGSHheparan N-sulfatase
MPS IIIBNAGLUalpha-N-acetylglucosaminidase
MPS IIICHGSNATheparan-alpha-glucosaminide N-Acetyltransferase
MPS IIIDGNSN-acetylglucosamine 6-sulfatase

Children with MPS III usually appear normal at birth and generally meet developmental milestones in the first couple of years of life. However, intelligent and behavioural problems often appear when the child reaches the age of 2-5 years and those problems are extremely difficult to manage. It is a progressive disease and the majority of children with MPS III will not live past their teens.

Incidence. MPS IIIA and MPS IIIB are the 2 more common forms of this rare disease with incidence rates of  1 in 100,000 and 1 in 200,000 births, respectively. MPS IIIC and IIID extremely rare with incidence rates of 1 in 1.5 million and 1 in 1 million births, respectively.

Symptoms/Diagnosis. There are several intellectual and behaviour symptoms that begin to appear between the ages of 2 to 5 years of age in children with MPSIII. The disease can take some time to be properly diagnosed since early symptoms (speech delay, insomnia, hyperactivity, recurrent ear/sinus infections, etc.) can mimic more common conditions like attention deficit hyperactivity disorder, autism, and/or intellectual disability.  Physically, many children with MPS III show coarse facial features, rough hair, skeletal pathologies, hepatosplenomegaly, and hearing loss.

 The MPS IIIs are diagnosed by understanding the pattern of symptoms and confirmed but an enzyme assay. As the disease progresses, intellectual disability will progress and the child may develop seizures, dystonia, and loss of various motor functions (walking, eating). One studyfound the average age of death for children with MPS IIIA is approximately 15 years, 19 years for MPS IIIB and 23.5 years for MPS IIIC but there is a lot of variance in the population. The most common causes of death were listed as pneumonia or cardiorespiratory failure.

Management. Managing persons is largely symptomatic and can involve multiple specialties. There is no curative treatment for MPS III but numerous treatments are in development.

Clinical trials. Numerous clinical trials are recruiting patients with MPS III, including gene therapy and enzyme replacement therapy studies. Due to the progressive nature of the condition, persons diagnosed with MPS III should seek treatment or possibly enrol in a clinical trial as soon as possible. To learn more, visit clinicaltrials.gov/

Transpher A Study.  An open-label, dose-escalation clinical trial assessing the safety of one-time gene therapy ABO-102 for patients with MPS IIIA. To learn more, visit here.

MPS IV (Morquio syndrome)

MPS IV, or Morquio syndrome can be divided into 2 subtypes, MPS IVA (Morquio A syndrome) and MPS IVB (Morquio B syndrome). The more common form is MPS IVA which accounts for 95% of MPS IV cases. MPS IVA is due to a mutation in the GALNSgene that leads to a deficiency in the GALNS enzyme while MPS IVB  is due to a mutation GLB1 gene that leads to a deficiency in the beta-galactosidase enzyme. In both types of the disease, the net result is an accumulation of keratan sulfate in cells and tissue that leads to a plethora of problems, most notably skeletal deformities.

Incidence. The incidence of MPS IV is estimated to be 1 in 200,000 – 300,000 persons.

Symptoms/Diagnosis. Like many MPS individuals, babies with MPS IV appear healthy at birth but as they get to about the age of 2 or 3 years, characteristic symptoms will be begin to appear, most notably the course facial features (enlarged head, broad mouth, prominent cheekbones, small nose, widely spaced teeth, and widely separated eyes). As they grow, skeletal problems will become very apparent. They tend to have a shortened torso relative to their limbs. Scoliosis of the spine is fairly common while their joints tend to be hypermobile. Unlike most other MPSs, individuals with MPS IV do not show a decline in intelligence as the disease progresses.

Due to the striking physical features found in MPS IV, its diagnosis will be suspected by a team of specialists but will be confirmed by enzyme or genetic testing.

Management. Managing persons is largely symptomatic and can involve multiple specialties, especially to accommodate the skeletal problems. There is no curative treatment for MPS IV but Vimizin (elosulfase alfa), an FDA-approved ERT is available and can delay progression of the disease. For more information, visit the treatment website at https://www.vimizim.com

Clinical trials. Numerous clinical trials are recruiting patients with MPS IV to better understand its natural history as well as to assess newer treatment options. To learn more, visit clinicaltrials.gov/

MPS VI (Maroteaux-Lamy syndrome)

MPS VI, or Maroteaux-Lamy syndrome, is somewhat different from the other MPSs in its large variance in disease severity and symptoms. It is an autosomal recessive disorder in which mutations in the ARSBgene lead to a disruption in the enzyme arylsulfatase B (also referred to as N-acetylgalactosamine-4-sulfatase). The end result in an accumulation of glycosaminoglycans (GAGs). Those with the more severe form of the disease will begin to show symptoms around the age of 2 or 3 years while those with less progressive forms of the disease may go years or decades before being diagnosed.

Incidence. Since many people may have mild versions of this MPS VI and have not been diagnosed, its incidence is not well established.

Symptoms/Diagnosis. In persons with the more rapid onset MPS IV, symptoms will begin to appear by about the age 2 or 3 years. As with many MPSs, the course facial features are the most dominate symptom. These individuals may also experience numerous skeletal, sensory, and cardiovascular problems that will require specialized care. Persons with MPS IV tend to be of short stature with degenerative joint disease and numerous skeletal abnormalities, (e.g., short hands, thick clavicle, curvature of spine, prominent breastbone, severe hip abnormalities, etc.,) that can lead to a variety of complications.

Clouding of the eyes and hearing loss are also common. The accumulation of  GAGs in the heart and lungs can lead to an overabundance of cardiovascular and pulmonary problems as well. Most children with the rapid onset form of MPS VI will have a lifetime of therapy and pain while those with slow onset form may not be that limited by the disease.

A diagnosis of MPS VI is established in individuals suspected of having MPS VI via urine samples to test for dermatan sulfate and a blood sample to measure arylsulfatase B activity.

Management. Managing persons is largely symptomatic and can involve multiple specialties, especially to accommodate the skeletal, dental, pulmonary, and cardiovascular problems. There is no curative treatment for MPS VI but Naglazyme (galsulfase), an FDA-approved ERT is available and can delay progression of the disease. For more information, visit the treatment website at https://www.naglazyme.com/

Clinical trials. Numerous clinical trials are recruiting patients with MPS VI with a wide variety of treatment options being investigated. To learn more, visit clinicaltrials.gov/

MPS VII (Sly syndrome)

MPS VII (Sly syndrome) is an autosomal recessive condition in which mutations of the GUSBgene lead to a deficiency of β-glucuronidase (GUS) activity. The end result is an accumulation of chondroitin sulfate, dermatan sulfate and heparan sulfate.

Persons with MPS VIII show a large variance of disease onset, severity, and symptoms. In the more severe forms, skeletal and neurological symptoms will usually present in the first 4 years of life whereas those with mild forms of MPS VII may go years or decades without being diagnosed.

Incidence. The incidence of MPS VI is estimated to be 1 in 250,000 births but our understanding of this disease, and its variability, likely means this estimate is inaccurate.

Symptoms/Diagnosis. Symptoms vary greatly in this populations but some common features present in most MPSs are also present in MPS VII (course facial features, cloudy cornea, skeletal abnormalities, intellectual disabilities, etc.). Key symptoms that lead to a diagnosis will often be the dysmorphic features (macrocephaly, coarse facial features, frontal prominence, premature closure of sagittal lambdoid sutures, and a shortened neck). Short stature and joint deformities (contractures) that affect mobility. Individuals with this condition may also have dysostosis multiplex, auditory impairment, gastrointestinal problems, enlarged liver and spleen, cardiovascular abnormalities, and hearing and visual impairments. Also, children with MPS IV can have cognitive impairment.

Due to the high variance in this population, it is difficult to properly describe which symptoms will dominate a person with MPS VII.

Diagnosis of MPS VII is usually suggested following a clinical examination and urine tests for excess glycosaminoglycan (GAG) excretion.  Enzyme activity assay (for beta-glucoronidase) is considered the gold standard for a definitive diagnosis of MPS VII.

Management. Managing persons is largely symptomatic and can involve multiple specialties, especially to accommodate the neurological, pulmonary, sensory, and cardiovascular problems. There is no curative treatment for MPS VII but Mepsevii (vestronidase alfa-vjbk), an FDA-approved ERT is available and can delay progression of the disease. For more information, visit the treatment website at http://www.mepsevii.com/hcp/

Clinical trials. A few clinical trials are recruiting patients with MPS VII are being investigated. To learn more, visit clinicaltrials.gov/

 

Resources

Advocacy Groups and Nonprofit Organizations

National MPS Society is an umbrella patient organization that supports families affected by all MPSs. It all funds research and educational/awareness programs.

Project Alive is a non-profit corporation focussed on finding a cure for MPS II. To date, they have raised over $2 million towards funding a gene therapy for MPS II.

Johan’s Just Begun is a not-for profit organization that funds research directed towards treatment options for patients with MPS IIIC.

Cure Sanfilippo Foundation is a not-for profit organization that fund research directed towards a cure and treatment options for patients with Sanfilippo Syndrome.

Team Sanfilippo Foundation is a non-profit medical research foundation founded by parents of children with Sanfilippo Syndrome. Their mission is to fund potential therapies that can be in clinical trials in the near future.

MPS SuperHero Foundation is a South Florida parent-led nonprofit organization established in 2016 by Monica and Avram, after their son Kalel was diagnosed with MPS II (Hunter Syndrome).

Hunter Syndrome Foundation aims to fund and find a cure for Hunter Syndrome or Mucopolysaccharidosis Type II (MPS II).

Sock-it-2-Hunters Syndrome is dedicated to fundraising for research and development towards finding a cure for MPSII.

Rare Disease Organizations

EURORDIS
A non-governmental patient-driven alliance of patient organizations representing 724 rare disease patient organizations in 64 countries.

National Organization for Rare Disorders
Provides a unified voice for the 30 million people who wake up every day to fight the battle with a rare disease, including parents and caregivers.

Rare Disease Legislative Advocates
A program of the EveryLife Foundation for Rare Diseases designed to support the advocacy of all rare disease patients and organizations.

Genetic Alliance
A nonprofit health advocacy organization that engages individuals, families, and communities to transform health. They create ways to make it easier to find or build solutions in health services and research.

Global Genes
A rare disease patient advocacy organization that aims to build awareness, educate the global community and provide critical connections and resources that equip advocates to become activists for their disease.

Clinical Trials

ClinicalTrials.gov
An online database of publicly and privately supported clinical studies conducted around the world. ClinicalTrials.gov currently lists thousands of studies with locations in all 50 states and in 191 countries.

Transpher A Study
An open-label, dose-escalation clinical trial assessing the safety of one-time gene therapy ABO-102 for patients with MPS IIIA.

Gene Therapy in Patients with MPS II (Hunter Syndrome)  

A Phase I/II multicenter, open-label study to evaluate the safety, tolerability, and pharmacodynamics of RGX-121 in pediatric patients with MPS II (Hunter syndrome)

Gene Therapy in Patients with MPS I

A Phase I multicenter, open-label study to evaluate the safety, tolerability, and pharmacodynamics of RGX-111 in patients with MPS I

Genetic Testing

Genetics Home Reference
An online resource from the National Institutes of Health. The website provides easy-to-understand information about genetic conditions and a range of topics. You’ll find basic explanations of how genes work and how mutations cause disorders. It also includes current information about genetic testing, gene therapy, and the Human Genome Project.

National Society of Genetic Counselors
Provides a helpful, easy-to-use online directory to help connect physicians, patients, and other genetic counselors. Search by state, city, counselor’s name, institution, work setting, type of specialty, or zip code.

General Health Resources

Agency for Healthcare & Research Quality (AHRQ)
Aims to provide evidence to make health care safer, higher quality, more accessible, equitable and affordable, and to work with the US Department of Health and Human Services and with other partners to ensure that the evidence is used and understood.

Health Hotlines (National Library of Medicine)
A community service to help the public locate health-related information.

Social Security Administration Compassionate Allowances Program
Provides a way of quickly identifying diseases and other medical conditions that may qualify for financial assistance.

Center on Technology & Disability
Designed to increase the capacity of families and providers to advocate for, acquire, and implement effective assistive and instructional technology practices, devices, and services for those who suffer from disabilities.

National Human Genome Research Institute
Developed with the goal of mapping the human genome, the group provides a list of resources for financial assistance with genetic testing.

National Library of Medicine
Provides guidance on how to find reliable information online regarding human genetics.

Patient Advocate Foundation
Provides professional case management services to individuals facing barriers to healthcare access for chronic and disabling disease, medical debt crisis, and employment-related issues at no cost.

Physician Materials

Sanfilippo Syndrome (MPS III) Fact Sheet and Screening Guide for Physicians  Provided by Cure Sanfilippo Foundation.

What is Sanfilippo Syndrome and What Causes It?  Provided by Cure Sanfilippo Foundation.

 

Patient Support Groups

National MPS Society is an umbrella patient organization that supports families affected by all MPSs. It all funds research and educational/awareness programs.

Project Alive is a non-profit corporation focussed on finding a cure for MPS II. To date, they have raised over $2 million towards funding a gene therapy for MPS II.

Johan’s Just Begun is a not-for profit organization that funds research directed towards treatment options for patients with MPS IIIC. http://jonahsjustbegun.org/

Cure Sanfilippo Foundation is a not-for profit organization that fund research directed towards a cure and treatment options for patients with Sanfilippo Syndrome. 

Team Sanfilippo Foundation is a non-profit medical research foundation founded by parents of children with Sanfilippo Syndrome. Their mission is to fund potential therapies that can be in clinical trials in the near future.

MPS SuperHero Foundation is a South Florida parent-led nonprofit organization established in 2016 by Monica and Avram, after their son Kalel was diagnosed with MPS II (Hunter Syndrome).

Hunter Syndrome Foundation aims to fund and find a cure for Hunter Syndrome or Mucopolysaccharidosis Type II (MPS II).

Sock-it-2-Hunters Syndrome is dedicated to fundraising for research and development towards finding a cure for MPSII.

Patient Support Materials

MPS Awareness Calendar from the National MPS Society PDF  

MPS Day Tri-fold from the National MPS Society PDF

MPS Q and A Cards from the National MPS Society PDF

MPS Brochure PDF

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