Mucopolysaccharidoses are hereditary lysosomal storage disorders caused by deficiencies in enzymes that break down glycosaminoglycans. This results in glycosaminoglycan accumulation in tissues and organs, leading to symptoms like facial abnormalities, short stature, corneal clouding, developmental delays, bone deformities, organ enlargement, and neurological issues. Diagnosis involves testing urine for glycosaminoglycan levels and measuring enzyme activity levels. Treatment focuses on managing symptoms through supportive care, physical therapy, surgeries, and enzyme replacement therapy or hematopoietic stem cell transplantation to reduce clinical effects.

1. MUCOPOLYSACHRIDOSIS

2. Contents
 Introduction
 Clinical presentation
 Types
 Management

3. Introduction

4. Introduction
 Mucopolysaccharidoses are hereditary, progressive diseases caused
by mutations of genes coding for lysosomal enzymes leading to
defects in stepwise breakdown of
glycosaminoglycans (GAGs).
 Glycosaminoglycans _formally named mucopolysaccharides_
are large, complex polymers of linear repeating sulfated acidic and
amino sugar disaccharide units widely distributed in most
of the tissues.
Neufeld E, Muenzer J. The mucopolysaccharidoses.The Metabolic and Molecular Basis of Inherited Disease. 8 ed. New York. NY: McGraw-Hill;
2001:3421-52

5. Introduction
 For examples; they are components of the ground substance of bone
and cartilage, lubricant in joint fluid, and the surface
coating that initially binds growth factors to cells.
 The metabolic recycling of GAGs requires the stepwise degradation
of the terminal sulfate, acidic, and amino sugar residues by a series
of lysosomal enzymes.
 The deficiency of one of these enzymes blocks degradation of the
substrate and results in a specific disorder.

6. Mode of Inheritance
 All types of MPS are autosomal recessive
disorders except type II (Hunter syndrome)
which is X-linked recessive.
 The estimated total incidence
of all types of MPS of approximately
1 in 20,000 live births.
 The most common subtype is MPS-III
followed by MPS-I and MPS-II
Neufeld E, Muenzer J. The mucopolysaccharidoses.The Metabolic and Molecular Basis of Inherited Disease. 8 ed. New York. NY: McGraw-Hill;
2001:3421-52

7. Classification

8. Classification contd…
 According to their dominant clinical features MPSs can be
grouped into four broad categories:
 Soft tissue storage and skeletal disease with or without brain disease
(MPS I, II, VII).
 Soft tissue and skeletal disease (MPS VI)
 Primarily skeletal disorders (MPS IVA, IVB)
 Primarily central nervous system disorders (MPS III A-D)
Neufeld E, Muenzer J. The mucopolysaccharidoses.The Metabolic and Molecular Basis of Inherited Disease. 8 ed. New York. NY: McGraw-Hill;

9. Clinical presentation

10. Clinical Presentation
 The mucopolysaccharidoses share many clinical features but
have varying degrees of severity depending on the
mucopolysaccharidosis subtype.
 These features may not be apparent at birth but progress as
storage of glycosaminoglycans increases with time affecting
bone, skeletal structure, connective tissues, and brain and
internal organs.

11. Common Presentations
 Mental retardation
 Developmental delay
 Severe behavioral problems
 Corneal clouding
 Coarse facial features
 Short stature ,short trunk
 Skeletal irregularities
Neufeld E, Muenzer J. The mucopolysaccharidoses.The Metabolic and Molecular Basis of Inherited Disease. 8 ed. New York. NY: McGraw-Hill;
2001:3421-52

12. Contd..
 Hepatosplenomegaly
 Hernias
 Joint stiffness
 Hydrocephalus
 Dysostosis multiplex
 Cardiac disease
 Retinal degeneration
 Hair loss or Hirsutism

15. Cardiac manifestation
 IH (Hurler)
 Most severe - heart muscle thick/weak
 Heart vessels thickened - heart attack/angina
 Thickened/nodular leaky valves - mitral valve/aortic valve
 IS (Scheie)
 Involve heart valves - aortic/mitral
 II (Hunter)
 Heart Vessels - Heart attack
 Thickened valves - mitral/aortic leak
Gatzoulis M A , et al: Cardiac involvement in mucopolysaccharidoses: effects of allogeneic bone marrow transplantation. Arch Dis Child. 1995
September; 73(3): 259–260.

16.  IIIA (Sanfilippo)
 Aortic valve leak, mitral valve leak
 IVA (Morquio)
 Heart wall, thickened/leaky valves - aortic/mitral
 VI (Maroteaux-Lamy)
 Heart wall thickened/stiff, weak
 Thickened/narrow/leaky valves - mitral/aortic valves
 VII (Sly)
 Leaky valve aortic
Gatzoulis M A , et al: Cardiac involvement in mucopolysaccharidoses: effects of allogeneic bone marrow transplantation. Arch Dis Child. 1995
September; 73(3): 259–260.

17. Clinical presentation
Coarse facial features
(flat nasal bridge, thick lips and
large tongue, Prominent forehead)
Moderate corneal opacifation
Gatzoulis M A , et al: Cardiac involvement in mucopolysaccharidoses: effects of allogeneic bone marrow transplantation. Arch Dis Child. 1995
September; 73(3): 259–260.

18. Clinical Presentation
Sever kyphoscliosis in patient with
Morquio disease (MPS IV)
Gatzoulis M A , et al: Cardiac involvement in mucopolysaccharidoses: effects of allogeneic bone marrow transplantation. Arch Dis Child. 1995

19. Dysostosis multiplex In patient with MPS type VI:
A, B) hands of patients at the age of 7 and 16 years : deformity and shortening
of metacarpal bones.
C, D) the spine of patient at the age of 11 and 16 years : scoliosis, abnormal shape
of the vertebral bodies.
E, F) the pelvis of patients at the age of 11 and 16 years : irregular shape of the
pelvis, hypoplastic hip acetabulum, lopsided head of hip bones.Gatzoulis M A , et al: Cardiac involvement in mucopolysaccharidoses: effects of allogeneic bone marrow transplantation. Arch Dis Child. 1995

20. Types

21. MPS I (Hurler)
 Deficiency of α-L-iduronidase
 Divided into three subtypes:
1) Hurler disease:
 Is a severe, progressive disorder with multiple organ and
tissue involvement that results in premature death,
usually
by 10 years of age.
Clinical features: •Corneal clouding
•Dysostosis multiplex
•Hepatosplenomegal
y
• Mental retardation
•Cardiomyopathy
• Coarse facial
features
Clinical features and diagnosis of the mucopolysaccharidoses, Uptodate, http://www.uptodate.com/contents/clinical-features-and-diagnosis-of-the-mucopolysaccharidoses

22. MPS I (Hurler)
2) Hurler-Scheie Disease
 Progresses less rapidly than Hurler syndrome.
 The onset of symptoms is usually observed between
3 and 8 yr of age.
 Patients typically die in their twenties of cardiac
disease or respiratory failure
Clinical features:
 Joint stiffness is the most presenting features
 Usually have normal intelligence
 Cardiac disease
 Dysostosis multiplex.
Clinical features and diagnosis of the mucopolysaccharidoses, Uptodate, http://www.uptodate.com/contents/clinical-features-and-diagnosis-of-the-mucopolysaccharidoses

23. 3) Scheie syndrome
 least severe form of MPS I, Most die in their middle
decades with cardiac disease
 Late diagnosis (teenage years)
Clinical features:
 Most presenting features are joint stiffness and
corneal clouding
 Hydrocephalus, optical nerve compression
 Aortic valve disease
MPS I (Hurler)
Clinical features and diagnosis of the mucopolysaccharidoses, Uptodate, http://www.uptodate.com/contents/clinical-features-and-diagnosis-of-the-mucopolysaccharidoses

24. MPS II (Hunter)
 Deficiency of iduronate-2-sulfatase.
 Is an X-linked disorder
 Manifests almost exclusively in males (except in case of skewed
inactivation of the X chromosome carrying the normal gene).
Clinical features and diagnosis of the mucopolysaccharidoses, Uptodate, http://www.uptodate.com/contents/clinical-features-and-diagnosis-of-the-mucopolysaccharidoses

25.  Clinical features:
 The severe form shares features with Hurler syndrome
except of slow progression and absence of corneal
clouding.
 Patients with the mild form have minimal CNS involvement,
slow progression of somatic deterioration and preservation
of intelligence in adult life.
 In mild form, survival to ages 65 and 87 yr has been
reported in mild form.

26. MPS III (Sanfilippo syndrome)
 Most common type of all MPS
 Divided into four subtypes (A-D).Each type is caused by a different enzyme
deficiency involved in the degradation of heparan sulfate
 Clinical features:
 Progressive dementia
 Aggressive behavior
 Hyperactivity, Sleep disorders
Clinical features and diagnosis of the mucopolysaccharidoses, Uptodate, http://www.uptodate.com/contents/clinical-features-and-diagnosis-of-the-mucopolysaccharidoses

27.  Communicating hydrocephalus
 Spasticity , Seizures
 Deafness and loss of vision
 Mild somatic involvement ( splenomegaly, skeletal deformities)

28. MPS IV (Morquio disease)
 Subtyped into two categories:
1) MPS IV-A: N-acetylgalactosamine-6-sulfatase deficiency.
2) MPS IV-B: β-galactosidase deficiency.
 Both result in the defective degradation of keratan sulfate
Clinical features and diagnosis of the mucopolysaccharidoses, Uptodate, http://www.uptodate.com/contents/clinical-features-and-diagnosis-of-the-mucopolysaccharidoses

29.  Clinical features:
 Severe skeletal dysplasia (Dysostosis multiplex occurs early).
 Cervical cord compression may occur after minor falls.
 Short-trunk dwarfism (<125 cm).
 Preservation of intelligence.
 Mild somatic involvement.

30. MPS VI (Maroteaux-Lamy )
 Arylsulfatase B deficiency and subsequent deposition of
dermatan sulfate, and chondroitin 4-sulfate
 Occurs in mild, intermediate, and severe forms
 Clinical features:
 Similar to hurler in somatic manifestations.
 Normal intelligence.
 Marked corneal clouding.
 valvular disorders
Clinical features and diagnosis of the mucopolysaccharidoses, Uptodate, http://www.uptodate.com/contents/clinical-features-and-diagnosis-of-the-mucopolysaccharidoses

31. MPS VII (Sly syndrome)
 Deficiency of β-glucuronidase
 Hydrops fetalis is a common presentation in sever form
 Clinical features:
 Similar to MPS I with significant soft tissue and skeletal
abnormalities
 Dysostosis multiplex
 Corneal clouding

32. Management

33. Diagnosis
 Clinical feature: MPS disorder should be suspected in a
child with coarse facial features, bone disease,
developmental delay, short stature,
hepatosplenomegaly, hernia, corneal clouding.
 Skeletal radiographs: Dysostosis multiplex
 GAG concentration: Measurement of urinary GAG
concentration, electrophoresis.
Seyrantepe V, Tihy F, Pshezhetsky AV. The microcellmediated transfer of human chromosome 8 restores the deficient Nacetylytransferase
activity in skin fibroblasts of Mucopolysaccharidosis type IIIC patients. Hum Genet. Sep 2006;120(2):2936.

34. Diagnosis contd..
 Enzyme activity assay: The definitive diagnosis of MPS
requires of, usually in peripheral blood leukocytes
 Prenatal diagnosis: Offered for selected family
Seyrantepe V, Tihy F, Pshezhetsky AV. The microcellmediated transfer of human chromosome 8 restores the deficient Nacetylytransferase
activity in skin fibroblasts of Mucopolysaccharidosis type IIIC patients. Hum Genet. Sep 2006;120(2):2936.

35. Management
 Evaluations Following Initial Diagnosis:
 Thorough Developmental assessment.
 Skeletal survey: to determine the involvement of the spine
and degree and extent of joint involvement.
 Cardiac evaluation with echocardiography.

36.  Brain MRI, including assessment of possible
hydrocephalus.
 Hearing assessment
 Ophthalmologic examination
 Assessment of spinal cord and peripheral nerveSeyrantepe V, Tihy F, Pshezhetsky AV. The microcellmediated transfer of human chromosome 8 restores the deficient Nacetylytransferase
activity in skin fibroblasts of Mucopolysaccharidosis type IIIC patients. Hum Genet. Sep 2006;120(2):2936.

37. Management
 Treatment of Manifestations:
 Supportive management can improve the quality of life
for affected individuals and their families.
 Skeletal manifestation : Physical therapy is a critical aspect
of MPS therapy, range of motion exercises appear to offer
some benefits in preserving joint function.
 Valvular disease: Cardiac valve replacement should be
considered

38.  Hydrocephaly: Ventriculoperitoneal shunting improve the
quality of life .
 spinal cord compression: Early surgical intervention
prevent severe complications
 Corneal clouding : Corneal transplantation is successful
for individuals with attenuated disease, although donor
grafts eventually become cloudy
Seyrantepe V, Tihy F, Pshezhetsky AV. The microcellmediated transfer of human chromosome 8 restores the deficient Nacetylytransferase
activity in skin fibroblasts of Mucopolysaccharidosis type IIIC patients. Hum Genet. Sep 2006;120(2):2936.

39.  Enzyme-replacement therapy (ERT):
 Currently (ERT) available for MPS type I ,II and VI.
 (ERT) Has proven useful in reducing somatic symptoms
and pain but show no improvement in neurological
involvement as enzymes can not cross the blood
brain barrier.
Management

40. Management
Hematopoietic Stem Cell Transplantation (HSCT)
 (HSCT) procedure carries a high risk of morbidity and mortality
Pulmonary and cardiac complications post-HSCT appear to be significant
 Despite the high risk of procedure, HSCT has been successful in reducing
the progression of some findings in children with severe MPSI
 Successful HSCT reduces facial coarseness, and hepatosplenomegaly,
improves hearing, airway obstruction and maintains normal heart function
Ross CJ, Bastedo L, Maier SA, Sands MS, Chang PL. Treatment of a lysosomal storage disease, mucopolysaccharidosis VII, with microencapsulated
recombinant cells. Hum Gene Ther. Oct 10 2000;11(15):211727

41. Management
 The skeletal manifestations and corneal clouding
continue to progress at the same rate in children
treated with HSCT and in untreated children
 Children showing significant cognitive impairment
prior to undergoing HSCT and ERT do not show
correction of existing impairment.
 Survival is increased roughly 67% compared to
those not receiving HSCT
Ross CJ, Bastedo L, Maier SA, Sands MS, Chang PL. Treatment of a lysosomal storage disease, mucopolysaccharidosis VII, with microencapsulated
recombinant cells. Hum Gene Ther. Oct 10 2000;11(15):211727

42. Summary
 Mucopolysaccharidoses (MPS) are lysosomal storage
disorders
caused by the deficiency of enzymes required for
breakdown of glycosaminoglycans (GAGs).
 GAGs accumulate in the lysosomes, resulting in cellular
dysfunction and clinical abnormalities.
 An MPS disorder should be suspected in a child with
coarse facial features, short stature, corneal clouding,
developmental delay, bone disease (dysostosis multiplex),

43.  Biochemical evaluation includes measurement of
urinary GAG concentration
 Definitive diagnosis requires assay of enzyme activity,
usually in peripheral blood leukocytes
 Supportive management can improve the quality of
life for affected individuals and their families
 ERT,HSCT reduce the progression of somatic
involvement but not neurological involvement.
Summary
Ross CJ, Bastedo L, Maier SA, Sands MS, Chang PL. Treatment of a lysosomal storage disease, mucopolysaccharidosis VII, with microencapsulated
recombinant cells. Hum Gene Ther. Oct 10 2000;11(15):211727