Mucopolysaccharidoses

definition ,types,causes,presentations,most common types,diagnosis ,differential diagnosis ,treatment ,prevention

1. Mucopolysaccharidoses Prof. Dr. Saad S Al Ani Senior Pediatric Consultant Head of Pediatric Department Khorfakkan Hospital Sharjah ,UAE [email protected]

2. Mucopolysaccharidoses Hereditary, progressive diseases caused by mutations of genes coding for lysosomal enzymes needed to degrade glycos amino glycans (GAGs) (acid mucopolysaccharides). 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 2

3. Glycos amino glycan ( G A G ) A long-chain complex carbohydrate composed of: Uronic acids Amino sugars Neutral sugars . www.mun.ca 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3

4. Glycos amino glycan s ( G A G s ) The major GAGs are: Chondroitin -4- sulfate Chondroitin - 6- sulfate Heparan sulfate Dermatan sulfate Keratan sulfate Hyaluronan 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 4

5. Glycos amino glycan s ( G A G s ) (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 5 Major constituents of the ground substance of connective tissue , as well as nuclear and cell membranes

6. Proteoglycans degradation 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 6 www.glycoforum.gr.jp Proteoglycans Protein core Proteolytic Stepwise degradation GAG moiety

7. Proteoglycans degradation disturbance 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 7 Absent or grossly reduced activity of mutated lysosomal enzymes Proteoglycans Glycos amino glycan s ( G A G s ) Intralysosomal

8. Proteoglycans degradation disturbance (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 8 printablecolouringpages.co.uk Distended lysosomes cell function Characteristic pattern of clinical, radiologic, and biochemical abnormalities Specific diseases can be recognized that evolve from the intracellular accumulation of different degradation products

9. Rule of fingers 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 9 Heparan sulfate ( impaired degradation ) Mental deficiency Dermatan sulfate, Chondroitin sulfates, Keratan sulfate ( impaired degradation ) Mesenchymal abnormalities

10. Mucopolysaccharidoses Mucopolysaccharidoses are autosomal recessive disorders , with the exception of Hunter disease , which is X- linked recessive . 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 10

11. Mucopolysaccharidoses (cont.) Overall frequency is between 3.5/100,000 and 4.5/100,000 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 11 teamsanfilippo.org http://dxline.info/ Diseases /hurler-syndrome flipper.diff.org The most common subtype is Sanfilippo disease (MPS-III) followed by Hurler disease ( MPS-I ) And Hunter disease (MPS II

12. Sanfilippo Syndrome(MPSIII) A deficiency in one of the enzymes required to break down glycosaminoglycan heparan sulfate ( found on the cell surface glycoproteins and also in extra-cellular matrix) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 12 http:// www.primehealthchannel.com/sanfilippo-syndrome A rare form of lysosomal storage disease Inherited in an autosomal recessive pattern www.primehealthchannel.com

13. Sanfilippo Syndrome (cont.) The incidence vary geographically, One per : - 50000 people in the Netherlands - 66000 people in Australia - 280000 cases in Northern Ireland 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 13 http:// www.primehealthchannel.com/sanfilippo-syndrome www.internationalstudentinsurance.com www.gapyear.com www.carhirecomparison.ie

14. Sanfilippo Syndrome (cont.) Deficiency in one of the four enzymes: 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 14 1. Heparan N- sulfatase (type A)

15. Sanfilippo Syndrome (cont.) 2. Alpha-N- acetylglucosaminidase (type B) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 15

16. Sanfilippo Syndrome (cont.) 3. Acetyl -Co Alpha- glucosaminide acetyltransferase (type C) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 16

17. Sanfilippo Syndrome (cont.) 4. N- acetylglucosamine 6-sulfatase (type D) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 17

18. Sanfilippo Syndrome (cont.) Patients are characterized by slowly progressive , severe CNS involvement with mild somatic disease 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 18 Onset of clinical features usually occurs between 2 and 6 yr in a child who previously appeared normal.

19. Sanfilippo Syndrome (cont.) Presenting features include: Delayed development Hyperactivity with aggressive behavior Coarse hair Hirsutism Sleep disorders Mild hepatosplenomegaly 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 19 articleactive.com

20. Sanfilippo Syndrome (cont.) Severe neurologic deterioration occurs in most patients by 6-10 yr of age , accompanied by rapid deterioration of social and adaptive skills 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 20 ellendelbloggolo.blogspot.com

21. Sanfilippo Syndrome (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 21 ellendelbloggolo.blogspot.com Severe behavior problems such as: - Sleep disturbance - Uncontrolled hyperactivity - Temper tantrums - Destructive behavior - Physical aggression are common

22. Sanfilippo Syndrome (cont .) Delays in diagnosis of MPS III are common due to : - Mild physical features - Hyperactivity - Slowly progressive neurologic disease 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 22 rareshare.org

23. MPS 1 MPS I is caused by mutations of the IUA gene on chromosome 4p16.3 encoding α-L- iduronidase 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 23 www.patienthelp.org

24. MPS1 (cont.) Deficiency of α-L- iduronidase results in a broad clinical spectrum, from severe Hurler disease to mild Scheie diseases 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 24 www.patienthelp.org

25. Hurler Disease (MPS I) This is a severe form of MPS I , and it is progressive disorder with multiple organ and tissue involvement that results in premature death, usually by 10 yr of age 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 25 www.eyecalcs.com

26. Hurler Disease (cont.) An infant with Hurler syndrome appears normal at birth , but inguinal hernias are often present 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 26 www.eyecalcs.com

27. Hurler Disease (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 27 www.eyecalcs.com Most patients have: Recurrent upper respiratory tract and ear infections Noisy breathing Persistent copious nasal discharge

28. Hurler Disease (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 28 www.eyecalcs.com Cardiac involvement include: Valvular heart disease: Mitral and Aortic valves incompetence Coronary artery narrowing Obstructive airway disease , notably during sleep , may necessitate tracheotomy .

29. Hurler Disease (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 29 www.eyecalcs.com Most children with Hurler syndrome acquire social but only limited language skills because of : Developmental delay Combined conductive and neurosensory hearing loss An enlarged tongue

30. Hurler Disease (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 30 www.eyecalcs.com Headache and sleep disturbance due to: Progressive ventricular enlargement with increased intracranial pressure caused by communicating hydrocephalus

31. Hurler Disease (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 31 www.eyecalcs.com Common eye involvement include: Corneal clouding Glaucoma Retinal degeneration

32. Hurler Disease (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 32 www.eyecalcs.com Skeletal abnormalities include: Enlarged , coarsely trabeculated diaphyses of the long bones Irregular metaphyses and epiphyses

33. Hurler Disease (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 33 www.eyecalcs.com Radio-graphs show a characteristic skeletal dysplasia known as dysostosis multiplex The earliest radiographic signs are thick ribs and ovoid vertebral bodies http:// www.keywordpicture.com/keyword/arthrogryposis%20multiplex http:// www.maroteaux-lamy.com/Turkish/HCP/Bones.aspx

34. Hurler Disease (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 34 www.eyecalcs.com With progression of the disease macrocephaly develops, with: Thickened calvarium Premature closure of lambdoid and sagittal sutures Shallow orbits

35. Hurler Disease (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 35 www.eyecalcs.com Cont. Enlarged J-shaped sella Abnormal spacing of teeth with dentigenous cysts

36. Hurler Disease (cont.) Diagnosis Usually made between 6 and 24 mo of age with evidence of: Hepatosplenomegaly Coarse facial features Corneal clouding Large tongue 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 36 www.eyecalcs.com nlm.nih.gov

37. Hurler Disease (cont.) Diagnosis -Prominent forehead Joint stiffness Short stature Skeletal dysplasia 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 37 www.eyecalcs.com http:// www.scripps.org/articles/99-frontal-bossing http:// www.nemours.org/service/medical/skeletal-dysplasia http:// doctorsgates.blogspot.ae http:// emedicine.medscape.com/article/951148-overview

38. Hurler Disease (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 38 www.eyecalcs.com Common causes of death : Obstructive airway disease Respiratory infection Cardiac complications

39. Hunter disease (MPS II) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 39 Is an X-linked disorder caused by the deficiency of iduronate-2-sulfatase (IDS ) flipper.diff.org

40. Hunter disease (MPS II ) (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 40 flipper.diff.org The gene encoding IDS is mapped to Xq28 . Point mutations of the IDS gene have been detected in about 80% of patients with MPS II Hunter disease manifests almost exclusively in males . it has been observed in a few females

41. 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 41 www.treypurcell.com

42. Hunter disease (MPS II ) (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 42 flipper.diff.org Patients with severe MPS II have features similar to those of Hurler disease except for: Lack of corneal clouding Slower progression of: Somatic and Central nervous system (CNS) deterioration

43. Hunter disease (MPS II ) (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 43 flipper.diff.org Clinical manifestations : Coarse facial features Short stature Dysostosis multiplex Joint stiffness Mental retardation manifest between 2 and 4 yr of age .

44. Hunter disease (MPS II ) (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 44 flipper.diff.org The following may present Grouped skin papules Extensive Mongolian spots Chronic diarrhea Communicating hydrocephalus and spastic paraplegia

45. Hunter disease (MPS II ) (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 45 Patients with the mild form have: Prolonged life span Minimal CNS involvement Slow progression of somatic deterioration with preservation of intelligence in adult life flipper.diff.org

46. Hunter disease (MPS II ) (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 46 In severely affected patients: Extensive , slowly progressive neurologic involvement Death , which usually occurs between 10 and 15 yr of age. flipper.diff.org

47. Hunter disease (MPS II ) (cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 47 In both the mild and severe forms : Airway involvement Valvular cardiac disease Hearing impairment Carpal tunnel syndrome Joint stiffness Are common and can result in significant loss of function flipper.diff.org

48. Diagnosis of MPS 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 48 Any individual who is suspected o f an MPS disorder based on: Clinical features Radiographic results Urinary GAG screening tests Should have a definitive diagnosis established by enzyme assay

49. Differential diagnosis 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 49 Mucolipidoses Oligosaccharidoses In these conditions, the urinary excretion of GAGs is not elevated 3. Neurodegenerative and dwarfing conditions Mucopolysaccharidoses can be differentiate from them by the present of: Hurler- like facial features Joint contractures Dysostosis multiplex Elevated urinary GAG excretion

50. Treatment of MPS 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 50 Hematopoietic stem cell transplantation results in significant clinical improvement of somatic disease in MPS I, II, and VI Enzyme replacement using recombinant enzymes is approved for patients with MPS I, MPS II, and MPS VI.

51. Hematopoietic stem cell transplantation 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 51 Clinical effects include : Increased life expectancy Resolution or improvement of growth failure Upper airway obstruction Hepatosplenomegaly Joint stiffness Facial appearance

52. Hematopoietic stem cell transplantation (Cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 52 Pebbly skin changes Obstructive sleep apnea Heart disease Communicating hydrocephalus Hearing loss

53. Hematopoietic stem cell transplantation (Cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 53 Enzyme activity in serum and urinary GAG excretion is normalized Transplantation prevents neurocognitive degeneration

54. Hematopoietic stem cell transplantation (Cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 54 Transplantation does not correct : Existent cerebral damage Skeletal and ocular anomalies

55. Enzyme replacement 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 55 - It reduces : Organo megaly Number of episodes of sleep apnea Urinary GAG excretion

56. Enzyme replacement (Cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 56 - It ameliorates : rate of growth joint mobility Physical endurance.

57. Enzyme replacement (Cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 57 -The enzymes do not : Cross the blood-brain barrier Prevent deterioration of neurocognitive involvement. -This therapy is the domain for patients with mild central nervous involvement

58. Prevention 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 58 Primary prevention Through genetic counseling Tertiary prevention To avoid or treat complications remains the mainstay of supportive pediatric care

59. Prevention (Cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 59 Multidisciplinary attention to: Respiratory and cardiovascular complications Hearing loss Carpal tunnel syndrome Spinal cord compression Hydrocephalus , and other problems Can greatly improve the quality of life for patients and their families

60. Prevention (Cont.) 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 60 The progressive nature of clinical involvement in MPS patients dictates the need for specialized and coordinated evaluation

61. 3/1/2015 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 61 noahstjohn.com