Mucopolysaccharidoses Hereditary, progressive diseases caused by mutations of genes coding for lysosomal enzymes needed to degrade glycosaminoglycans (GAGs) (acid mucopolysaccharides). 2 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Glycosaminoglycan(GAG) A long-chain complex carbohydrate composed of: 1. Uronic acids 2. Amino sugars 3. Neutral sugars. www.mun.ca 3 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Glycosaminoglycans(GAGs) The major GAGs are: 1. Chondroitin -4- sulfate 2. Chondroitin -6- sulfate 3. Heparan sulfate 4. Dermatan sulfate 5. Keratan sulfate 6. Hyaluronan 4 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Glycosaminoglycans (GAGs) (cont.) Major constituents of the ground substance of connective tissue, as well as nuclear and cell membranes 5 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Proteoglycans degradation Proteoglycans Proteolytic Stepwise degradation Protein core GAG moiety www.glycoforum.gr.jp 6 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Proteoglycans degradation disturbance Proteoglycans Absent or grossly reduced activity of mutated lysosomal enzymes Glycosaminoglycans (GAGs) Intralysosomal 7 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Proteoglycans degradation disturbance (cont.) Distended lysosomes cell function printablecolouringpages.co.uk Characteristic pattern of clinical, radiologic, and biochemical abnormalities Specific diseases can be recognized that evolve from the intracellular accumulation of different degradation products 8 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Rule of fingers Heparan sulfate (impaired degradation) Dermatan sulfate, Chondroitin sulfates, Keratan sulfate (impaired Mental deficiency 9 degradation) Mesenchymal abnormalities Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Mucopolysaccharidoses Mucopolysaccharidoses are autosomal recessive disorders, with the exception of Hunter disease, which is X- linked recessive. 10 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Mucopolysaccharidoses (cont.) Overall frequency is between 3.5/100,000 and 4.5/100,000 The most common subtype is Sanfilippo disease (MPS-III) followed by Hurler disease ( MPS-I ) And Hunter disease (MPS II 11 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital teamsanfilippo.org http://dxline.info/ Diseases /hurlersyndrome flipper.diff.org 3/1/2015 Sanfilippo Syndrome(MPSIII) A rare form of lysosomal storage disease Inherited in an autosomal recessive pattern 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) http://www.primehealthchannel.com/sanfilippo-syndrome www.primehealthchannel.com 12 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Sanfilippo Syndrome (cont.) • The incidence vary geographically, One per: - 50000 people in the Netherlands - 66000 people in Australia - 280000 cases in Northern Ireland http://www.primehealthchannel.com/sanfilippo-syndrome www.internationalstudentinsurance.com www.gapyear.com www.carhirecomparison.ie 13 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Sanfilippo Syndrome (cont.) Deficiency in one of the four enzymes: 1. Heparan N- sulfatase (type A) 14 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Sanfilippo Syndrome (cont.) 2.Alpha-N- acetylglucosaminidase (type B) 15 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Sanfilippo Syndrome (cont.) 3. Acetyl -Co Alpha- glucosaminide acetyltransferase (type C) 16 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Sanfilippo Syndrome (cont.) 4.N- acetylglucosamine 6-sulfatase (type D) 17 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Sanfilippo Syndrome (cont.) Patients are characterized by slowly progressive, severe CNS involvement with mild somatic disease Onset of clinical features usually occurs between 2 and 6 yr in a child who previously appeared normal. 18 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Sanfilippo Syndrome (cont.) Presenting features include: articleactive.com – Delayed development – Hyperactivity with aggressive behavior – Coarse hair – Hirsutism – Sleep disorders – Mild hepatosplenomegaly 19 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Sanfilippo Syndrome (cont.) ellendelbloggolo.blogspot.com Severe neurologic deterioration occurs in most patients by 6-10 yr of age, accompanied by rapid deterioration of social and adaptive skills 20 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Sanfilippo Syndrome (cont.) ellendelbloggolo.blogspot.com Severe behavior problems such as: - Sleep disturbance - Uncontrolled hyperactivity - Temper tantrums - Destructive behavior - Physical aggression are common 21 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Sanfilippo Syndrome (cont.) rareshare.org Delays in diagnosis of MPS III are common due to : - Mild physical features - Hyperactivity - Slowly progressive neurologic disease 22 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 MPS 1 www.patienthelp.org MPS I is caused by mutations of the IUA gene on chromosome 4p16.3 encoding α-Liduronidase 23 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 MPS1 (cont.) www.patienthelp.org Deficiency of α-L- iduronidase results in a broad clinical spectrum, from severe Hurler disease to mild Scheie diseases 24 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hurler Disease (MPS I) www.eyecalcs.com 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 25 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hurler Disease (cont.) www.eyecalcs.com An infant with Hurler syndrome appears normal at birth, but inguinal hernias are often present 26 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hurler Disease (cont.) www.eyecalcs.com Most patients have: • Recurrent upper respiratory tract and ear infections • Noisy breathing • Persistent copious nasal discharge 27 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hurler Disease (cont.) 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. 28 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hurler Disease (cont.) 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 29 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hurler Disease (cont.) www.eyecalcs.com Headache and sleep disturbance due to: Progressive ventricular enlargement with increased intracranial pressure caused by communicating hydrocephalus 30 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hurler Disease (cont.) www.eyecalcs.com Common eye involvement include: • Corneal clouding • Glaucoma • Retinal degeneration 31 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hurler Disease (cont.) www.eyecalcs.com Skeletal abnormalities include: • Enlarged, coarsely trabeculated diaphyses of the long bones • Irregular metaphyses and epiphyses 32 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hurler Disease (cont.) www.eyecalcs.com Radio-graphs show a characteristic skeletal dysplasia known as dysostosis multiplex http://www.keywordpicture.com/keyword/arthrogryposis%20multiplex The earliest radiographic signs are thick ribs and ovoid vertebral bodies http://www.maroteaux-lamy.com/Turkish/HCP/Bones.aspx 33 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 (cont.) With progression of the disease macrocephaly develops, with: • Thickened calvarium • Premature closure of lambdoid and sagittal sutures • Shallow orbits 34 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 www.eyecalcs.com Hurler Disease (cont.) www.eyecalcs.com Hurler Disease Cont. • Enlarged J-shaped sella • Abnormal spacing of teeth with dentigenous cysts 35 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 (cont.) Diagnosis Usually made between 6 and 24 mo of age with evidence of: – Hepatosplenomegaly – Coarse facial features – Corneal clouding – Large tongue nlm.nih.gov 36 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital www.eyecalcs.com Hurler Disease 3/1/2015 (cont.) Diagnosis -Prominent forehead – Joint stiffness http://www.scripps.org/articles/99-frontal-bossing www.eyecalcs.com Hurler Disease http://doctorsgates.blogspot.ae – Short stature http://emedicine.medscape.com/article/951148-overview – Skeletal dysplasia http://www.nemours.org/service/medical/skeletal-dysplasia 37 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hurler Disease (cont.) www.eyecalcs.com Common causes of death: • Obstructive airway disease • Respiratory infection • Cardiac complications 38 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hunter disease (MPS II) Is an X-linked disorder caused by the deficiency of iduronate-2-sulfatase (IDS) 39 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital flipper.diff.org 3/1/2015 Hunter disease (MPS II) (cont.) 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 40 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 www.treypurcell.com 41 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hunter disease (MPS II) (cont.) 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 42 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hunter disease (MPS II) (cont.) Clinical manifestations: • Coarse facial features • Short stature • Dysostosis multiplex • Joint stiffness • Mental retardation manifest between 2 and 4 yr of age. 43 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital flipper.diff.org 3/1/2015 Hunter disease (MPS II) (cont.) The following may present • Grouped skin papules • Extensive Mongolian spots • Chronic diarrhea • Communicating hydrocephalus and spastic paraplegia 44 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital flipper.diff.org 3/1/2015 Hunter disease (MPS II) (cont.) flipper.diff.org Patients with the mild form have: • Prolonged life span • Minimal CNS involvement • Slow progression of somatic deterioration with preservation of intelligence in adult life 45 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hunter disease (MPS II) (cont.) flipper.diff.org In severely affected patients: • Extensive, slowly progressive neurologic involvement • Death, which usually occurs between 10 and 15 yr of age. 46 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hunter disease (MPS II) (cont.) 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 47 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital flipper.diff.org 3/1/2015 Diagnosis of MPS Any individual who is suspected of an MPS disorder based on: • Clinical features • Radiographic results • Urinary GAG screening tests Should have a definitive diagnosis established by enzyme assay 48 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Differential diagnosis 1.Mucolipidoses 2.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: • • • • 49 Hurler- like facial features Joint contractures Dysostosis multiplex Elevated urinary GAG excretion Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Treatment of MPS • 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. 50 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hematopoietic stem cell transplantation Clinical effects include : • Increased life expectancy • Resolution or improvement of growth failure • Upper airway obstruction • Hepatosplenomegaly • Joint stiffness • Facial appearance 51 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hematopoietic stem cell transplantation (Cont.) • • • • • 52 Pebbly skin changes Obstructive sleep apnea Heart disease Communicating hydrocephalus Hearing loss Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hematopoietic stem cell transplantation (Cont.) Enzyme activity in serum and urinary GAG excretion is normalized Transplantation prevents neurocognitive degeneration 53 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Hematopoietic stem cell transplantation (Cont.) Transplantation does not correct : • Existent cerebral damage • Skeletal and ocular anomalies 54 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Enzyme replacement -It reduces : • Organomegaly • Number of episodes of sleep apnea • Urinary GAG excretion 55 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Enzyme replacement (Cont.) - It ameliorates : • rate of growth • joint mobility • Physical endurance. 56 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Enzyme replacement (Cont.) -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 57 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Prevention • Primary prevention Through genetic counseling • Tertiary prevention To avoid or treat complications remains the mainstay of supportive pediatric care 58 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Prevention (Cont.) 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 59 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015 Prevention (Cont.) The progressive nature of clinical involvement in MPS patients dictates the need for specialized and coordinated evaluation 60 Mucopolysaccharidoses Prof.Dr.Saad S Al Ani Khorfakkan Hospital 3/1/2015
