Mucopolysaccharidoses ppt

1. Mucopolysaccharidosis Prepared by: Dr. YaserAlharthi alharthiy@yahoo.com Pediatric Resident

2. Outline • INTRODUCTION • CLASSIFICATION • CLINICAL FEATURES • DIAGNOSIS • MANAGEMENT • SUMMARY

3. Introduction • Mucopolysaccharidoses are hereditary, progressive diseases caused by mutations of genes coding for lysosomal enzymes leading to defects in stepwise breakdown ofglycosaminoglycans (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. • 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.

4. Introduction • 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.

5. 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.(uptodate) • The most common subtype is MPS-III followed by MPS-I and MPS-II

6. Classification

7. Classification 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)

8. 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.

9. Common Presentations -Mental retardation -Developmental delay -Severe behavioral problems -Corneal clouding - Coarse facial features - Short stature ,short trunk - Skeletal irregularities • -Hepatosplenomegaly • - Hernias • - Joint stiffness • - Hydrocephalus • -Dysostosis multiplex • - Cardiac disease • - Retinal degeneration • - Hair loss or Hirsutism

11. Clinical Presentation

12. Clinical Presentation Coarse facial features (flat nasal bridge, thick lips and largetongue, Prominent forehead) Moderate cornealopacifation

13. Clinical Presentation Sever kyphoscliosis in patient withMorquio disease (MPS IV)

14. 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.

15. Clinical Presentation • A retrospective cohort study(2000-2010) done in India aimed to recognize the most presenting features in patients with MPS. • They include all patients who have these criteria : 1) Clinical features: Coarse face, developmental delay/mental retardation, corneal clouding, hepatosplenomegaly, joint contractures, bone/spine deformities 2) Radiography: Dysostosis multiplex 3) Positive urine test (Total GAG excretion and MPS electrophoresis)

16. Clinical Presentation • Results : - 55 Patients (0.9%) out of 6110 referrals was having MPS. - Median age at presentation: 36 months - M:F ratio 2:1 (37 males, 18 females) - Family history: 27% MamtaMuranjan et al ,Mucopolysaccharidosis:A Diagnostic Journey in a Cohort of Indian Patients

17. Clinical Presentation Most presenting features in previous study summarized in this table:

18. MPS I (Hurler) • Deficiency of α-L-iduronidase • Divided into three subtypes: • 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 -Hepatosplenomegaly - Retinal degeneration - Mental retardation -Cardiomyopathy - Coarse facial features -Valvular heart disease

19. 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.

20. MPS I (Hurler) 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

21. 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: • 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.

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

23. 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: • 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.

24. 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

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

26. 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. • Enzyme activity assay: The definitive diagnosis of MPS requires of, usually in peripheral blood leukocytes • Prenatal diagnosis: Offered for selected family

27. 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. • Brain MRI, including assessment of possible hydrocephalus. • Hearing assessment • Ophthalmologic examination • Assessment of spinal cord and peripheral nerve involvement .

28. 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 . • 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

29. Management 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.

30. 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 (Neufeld & Muenzer 2001). • Despite the high risk of procedure, HSCT has been successful in reducing the progression of some findings in children with severe MPSI(Neufeld & Muenzer 2001), (Souillet et al 2003,). • Successful HSCT reduces facial coarseness, and hepatosplenomegaly, improves hearing, airway obstruction and maintains normal heart function(Munoz-Rojas et al 2008)

31. Management • In one study, Echo was performed in 16 patients with MPS (seven patients (44%) with cardiac involvement) undergoing bone marrow transplantation (BMT) • One year after BMT, left ventricular restriction resolved in 2/3 of patients, at mean follow up of 2.5 years, no progression of preexisting or development of new cardiac involvement was noted. M A Gatzoulis, et al: Cardiac involvement in mucopolysaccharidoses: effects of allogeneic bone marrow transplantation. Arch Dis Child. 1995 September; 73(3): 259–260.

32. Management • The skeletal manifestations and corneal clouding continue to progress at the same rate in children treated with HSCT and in untreated children (Taylor et al 2008). • 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 (Moore et al 2008)

33. 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), hepatosplenomegaly, joint stiffness.

34. Summary • 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.

35. References • Clinical features and diagnosis of the mucopolysaccharidoses, Uptodate, http://www.uptodate.com/contents/clinical-features-and-diagnosis-of-the-mucopolysaccharidoseslast update Oct 2012. • Gatzoulis M A , et al: Cardiac involvement in mucopolysaccharidoses: effects of allogeneic bone marrow transplantation. Arch Dis Child. 1995 September; 73(3): 259–260. • Moore D, et al. The prevalence of and survival in Mucopolysaccharidosis I: Hurler, Hurler-Scheie and Scheie syndromes in the UK. Orphanet J Rare Dis. 2008;3:24 • Munoz-Rojas MV, et al. Intrathecal enzyme replacement therapy in a patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J Med Genet A. 2008;146A:2538–44. • Neufeld E, Muenzer J. The mucopolysaccharidoses.The Metabolic and Molecular Basis of Inherited Disease. 8 ed. New York. NY: McGraw-Hill; 2001:3421-52 • Nelson textbook of pediatrics, 19th edition. • Souillet G, Guffonet al. Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources. Bone Marrow Transplant. 2003;31:1105–17.

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