Brief Description of the Disease

The mucopolysaccharidoses (MPSs) are a family of metabolic disorders caused by the deficiency of lysosomal enzymes needed to degrade glycosaminoglycan (GAG).[1] GAG is an important constituent of the extracellular matrix, joint fluid, and connective tissue throughout the body. Progressive accumulation of GAG within the cells of various organs ultimately compromises their function. The major sites of disease differ depending on the specific enzyme deficiency; therefore, clinical presentation and approaches to therapy are different for the various disease types.

Defect

Metabolism

Specific Type

MPS type I

Forms or Kinds

HURLER SYNDROME do not make a substance called lysosomal alpha-L-iduronidase.  Without the enzyme, glycosaminoglycans build up and damage organs, including the heart. Symptoms can range from mild to severe.

HURLER SCHEIE SYNDROME is caused by mutations in the IDUA gene (4p16.3) leading to partial deficiency in the alpha-L-iduronidase enzyme and lysosomal accumulation of dermatan sulfate and heparan sulfate.

SCHEIE SYNDROME  is the mildest form of mucopolysaccharidosis type 1. 

Manifestation 

Clinical manifestation show a chronic multisystemic and progressive course.[3] The disease is highly heterogeneous, spanning a spectrum of severity. Children with Hurler syndrome appear normal at birth and develop the characteristic appearance over the first years of life. Symptoms across the types include facial dysmorphism, corneal clouding, hepatomegaly, valvular heart disease, obstructive airway disease, developmental delay, hearing loss, skeletal deformities,[4] and joint stiffness. For patients with the more severe form of the disease, the most typical symptoms occur early in life. These patients typically have numerous progressively debilitating symptoms, including mental retardation.

Incidence

Precise figures for mucopolysaccharidosis type I (MPS I) incidence are lacking, but estimated incidence is approximately 1 case per 100,000 births.

Inheritance

Inherited in an autosomal recessive manner and affects both sexes.

Diagnosis 

CLINICAL DIAGNOSIS/EVALUATION (i.e physical manifestation of characteristics), BIOCHEMICAL TESTING (GAG, Alpha-L-iduronidase), MOLECULAR GENETIC TESTING 

Prognosis

LIFESPAN  ranges from death in early childhood in the most severe form to adulthood in the least severe variant. Lifespan is less than 10 years for severe cases.

Treatment

Hematopoietic stem cell transplantation (HSCT) in selected children with severe MPS I before age two years can increase survival, reduce facial coarseness and hepatosplenomegaly, improve hearing, and maintain normal heart function. HSCT does not significantly improve skeletal manifestations or corneal clouding. HSCT may slow the course of cognitive decline in children with mild, but not significant, cognitive impairment at the time of transplantation. Due to the morbidity and mortality associated with HSCT, it is currently recommended primarily for children with severe MPS I who may experience some reduction in CNS manifestations.

Enzyme replacement therapy (ERT) with laronidase (Aldurazyme®), licensed for treatment of the non-CNS manifestations of MPS I, improves liver size, linear growth, joint mobility, breathing, and sleep apnea in persons with attenuated disease.

Management

Multidisciplinary and encompasses both the curative and palliative elements.[7] Regular evaluation at a major center with special interest and expertise in the management of the disease is important.

References 

MPS  TYPE II

HUNTER SYNDROME – caused by a reduced or absent activity of the enzyme iduronate 2-sulfatase. The clinical features and severity of symptoms of MPS II are widely variable ranging from severe disease to an attenuated form, which generally presents at a later onset with a milder clinical presentation 

Forms or Kinds

Type A MPS II is the more severe form and has clinical features very similar to those observed with Hurler syndrome, except that corneal clouding is not seen and clinical features do not progress as quickly as they do in Hurler syndrome. Development is delayed.  Type B MPS II resemble children with Hurler/Scheie (MPS IH/S) or Scheie syndromes (MPS IS). These children usually have normal intelligence but may have airway obstruction secondary to accumulation of mucopolysaccharide in the trachea and bronchi.

Manifestation

In general, symptoms may include coarse faces, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, and profound neurologic involvement leading to developmental delays and regression. The clinical presentation of MPS II is similar to that of MPS I with the notable difference of the lack of corneal clouding in MPS II.

Incidence

1 in 170,000 male births.

Inheritance

The inheritance pattern is X-linked and as such MPS II is observed almost exclusively in males.

Diagnosis

Diagnostic Test which includes both the quantitative analysis of total GAGs and thin layer chromatography (TLC). 

Prognosis

Type A MPS II children frequently are deaf and may survive into the second and third decades of life. Type B MPS II survive well into adulthood and may live into the seventh decade of life. Most of these patients develop cardiac valvular disease.

Treatment 

BMT -Bone Marrow Transplantation ; ERT (Enzyme Replacement Therapy) Idursulfase, Elaprase (Shire Human Genetics Therapies, Inc).

Management

Multidisciplinary approach and includes pediatricians, neurologists, orthopedists, otolaryngologists, ophthalmologists, and occupational and physical therapists, as well as geneticists and counselors.  Annual follow-up includes the following:

Echocardiography and ECG

References

MPS TYPE III

SANFILIPPO  is caused by a reduced or absent activity of 1 of 4 enzymes, resulting in a defect of heparan sulfate degradation. Patients with MPS III uniformly excrete heparan sulfate resulting in similar clinical phenotypes, and are further classified as type A, B, C, or D based upon the specific enzyme deficiency. Sanfilippo syndrome is characterized by severe central nervous system (CNS) degeneration, but only mild physical disease. Such disproportionate involvement of the CNS is unique among the MPSs.  The occurrence of MPS III varies by subtype with types A and B being the most common and types C and D being very rare.

Forms or Kinds

  • Type A lack the enzyme heparan sulfate sulfatase (most severe form)
  • Type B lack the enzyme N -acetyl-alpha-D-glucosaminidase (NAG).[6]
  • Type C lack acetyl-CoA:alpha-glucosaminide acetyltransferase.
  • Type D lack the enzyme N- acetylglucosamine-6-sulfatase.

Manifestations

Sanfilippo syndrome is characterized by severe central nervous system (CNS) degeneration, but only mild physical disease. Such disproportionate involvement of the CNS is unique among the MPSs. Onset of clinical features, most commonly behavioral problems and delayed development, usually occurs between 2 and 6 years in a child who previously appeared normal. Severe neurologic degeneration occurs in most patients by 6 to 10 years of age, accompanied by a rapid deterioration of social and adaptive skills.

Incidence

The incidence of MPS III (for all four types combined) is about one in 70,000 births.

Inheritance

Autosomal recessive Mendelian pattern. The gene mutations are located in the autosomes and not in the sex chromosomes;[10] therefore, Sanfilippo syndrome affects males and females equally.

Diagnosis

Laboratory Test in which diagnosis is confirmed by specific enzymatic assay.  Neuroimaging Test (i.e. MRI) to look for changes in brain structure,CT Scan, Radiographic Skeletal survey. Othe test includes EEG, Polysomnography, Echocardiography.

Prognosis

Has a progressive process with a devastating prognosis. Over time, patients develop CNS degeneration and progress to a vegetative state. Death usually occurs before age 20 years, primarily from cardiopulmonary arrest due to airway obstruction and/or pulmonary infection. Type IIIA is the most severe form; most patients with this form die during their teenage years.

Treatment

No treatment for the underlying cause is available. Medical treatment is supportive and is directed toward improving the patient’s quality of life. BMT and ERT is not an option.

Management

A multidisciplinary approach is indicated.  The treatment of individual patients requires consultation and ongoing care with pediatric neurologists, ophthalmologists, audiologists, cardiologists, gastroenterologists, and orthopedists.

References

MPS TYPE  IV

MORQUIO Syndrome Progressive disorder with multiple organ and tissue involvement. Wide spectrum of involvement between the two types. Onset is variable but usually obvious between 1 and 3 years of age. Short-trunk dwarfism; progressive and severe skeletal dysplasia with subsequent effects on the central nervous system. Survival beyond the 3rd decade not common in more severe cases.

Forms or Kinds

  • MPS IV A (Morquio A syndrome) is caused by a reduced or absent N-acetylgalactosamine-6-sulfate sulfatase.
  • MPS IVB (Morquio B syndrome) is caused by a reduced or absent beta-galactosidase activity which gives rise to the physical manifestations of the disease.

Manifestation

MPS IV A Clinical features and severity of symptoms of MPS IVA are widely variable, but insufficiency, and cardiac disease. Intelligence is usually normalmay include skeletal dysplasia, short stature,dental anomalies, corneal clouding, respiratory.

MPS IV B  Clinical features and severity of symptoms of MPS IVB are widely variable ranging from severe disease to an attenuated form, which generally presents at a later onset with a milder clinical presentation.  In general, symptoms may include coarse facies, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, but no neurological involvement.

Incidence

MPS IVA syndrome range from 1 in 200,000 to 1 in 300,000 live births.   The incidence of MPS IVB is estimated to be about 1 in 250,000 live births.  No racial predilection is noted.

Inheritance

autosomal recessive

Diagnosis

enzyme assay

Prognosis

Patients with mild manifestations of Morquio syndrome (mucopolysaccharidosis type IV), regardless of type, have been reported to survive into the seventh decade of life. Patients with severe.  manifestations, primarily related to cervical instability, do not survive this long.

Treatment

No disease-specific treatment available.  ERT is currently under development.

Management

Symptom management. Medications for supportive care, such as nonsteroidal anti-inflammatory drugs (NSAIDs) for joint pain, antibiotics for pulmonary infections, and oxygen for pulmonary compromise and obstructive sleep apnea, can be used to treat the manifestations of this disorder.

References

MPS TYPE VI

Maroteaux-Lamy SyndromeAn inherited disorder that typically manifests in early childhood with retarded growth, dysostosis multiplex, inguinal or umbilical hernias, recurrent respiratory illness, hepatosplenomegaly, and coarse facial features.

Manifestation

Clinical features and severity of symptoms are widely variable, but typically include short stature, dysostosis multiplex, facial dysmorphism, stiff joints, claw-hand deformities, carpal tunnel syndrome, hepatosplenomegaly, corneal clouding, and cardiac defects. Intelligence is usually normal.

Incidence

Estimates of the incidence of MPS VI range from 1 in 200,000 to 1 in 300,000. 

Inheritance

MPS VI is panethnic, although increased birth frequency has been reported in certain populations (Turkish population living in Germany).[2  MPS VI is inherited as an autosomal recessive trait and appears equally in males and females.

Prognosis

Death in 2nd to 3rd decade in severe cases, usually due to heart failure.

Treatment

ERT – GALSULFASE  (Naglazyme) BIOMARIN Pharma

Management

Require ongoing medical care from numerous subspecialists. In addition, patients should receive routine pediatric care, including immunizations. 

References  

MPS TYPE VII  

Sly Syndrome – caused by a deficiency of the enzyme beta-glucuronidase. The phenotype varies significantly from mild to severe presentations and may include macrocephaly, short stature, dysostosis multiplex, hepatomegaly, coarse facies, and impairment of cognitive function.

Manifestation

Characterized by the same feauture as MPS IH and MPS II

Incidence

MPS VII is extremely rare, affecting approximately 1 in 1,500,000 individuals.

Inheritance

Transmission is autosomal recessive. Males and females are affected in equal numbers.

Diagnosis

enzyme assay

Prognosis

 Most often leading to death in utero. Neonatal and childhood forms have a very limited life expectancy, whereas milder forms have a prolonged survival.

Treatment

Medication is not currently a component of care

Management

Bone marrow transplantation in some cases.  The symptomatic intervention for includes, but is not limited to, management of respiratory and cardiovascular complications, skeletal manifestations, arthropathy, loss of hearing and vision, GI symptoms, and communicating hydrocephalus.

References