Mucopolysaccharidosis Notes

NOTES NOTES MUCOPOLYSACCHARIDOSIS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Metabolic disorder: dysfunction of lysosomal enzymes involved in glycosaminoglycans (GAG) breakdown ▪ Lysosomal storage disease ▪ Impaired glycosaminoglycans metabolism → GAGs (heparan, dermatan, keratan, chondroitin sulfate) accumulation within lysosomes → damage of cells, tissues, organs ▫ Heparan (in nervous tissue): decline of neurological function ▫ Keratan (in skeletal system): skeletal abnormalities ▫ Dermatan (in skin, lungs, heart valves): skin changes, mitral valve damage, lung diseases ▪ Residual enzyme activity determines life expectancy MPS VI: Maroteaux–Lamy syndrome ▪ Dermatan, chondroitin sulfate accumulation ▪ Mild to severe forms MPS VII: Sly syndrome ▪ Heparan, dermatan, chondroitin sulfate accumulation ▪ Mild to severe forms MPS IX: Natowicz syndrome (rarest type) ▪ Hyaluronidase deficit → hyaluronan accumulation CAUSES ▪ Inherited autosomal recessive, except for MPS II (X-linked) TYPES COMPLICATIONS MPS I: Hurler syndrome ▪ Attenuated MPS I ▪ Severe MPS I ▫ Associated with progressive intellectual disability, earlier onset ▪ ▪ ▪ ▪ ▪ ▪ ▪ MPS II: Hunter syndrome ▪ Mild to severe forms MPS III: Sanfilippo syndrome ▪ Four forms: A, B, C, D ▪ Early life clinical presentation ▪ Lack of appropriate enzymes → accumulation heparan sulfate → neurological damage → adolescent death MPS IV: Morquio syndrome ▪ Two forms: A, B ▪ Keratan, chondroitin sulfate accumulation Hearing, vision loss Skeletal abnormalities, limited movement Valve dysfunction Recurrent respiratory infections Joint stiffness Behavioral problems, intellectual disability C1-C2 subluxation → cord compression → central apnea ▪ Hydrocephalus SIGNS & SYMPTOMS MPS III: Sanfilippo syndrome ▪ Three stages ▫ Mental, motor skills delays (usually between ages two–six) ▫ Sleep disorders, hyperactivity with aggressiveness, dementia ▫ Inability to walk until age of ten OSMOSIS.ORG 287

▪ Visual, hearing problems; CNS degeneration; intellectual disability; excessive hair growth MPS IV: Morquio syndrome ▪ Skeletal abnormalities, joint stiffness, blurry cornea, common ear infections, hearing loss, breathing difficulties ▪ Severe forms: life expectancy of four decades ▪ Mild forms: life expectancy up to seven decades MPS VI: Maroteaux–Lamy syndrome ▪ Large head, tongue; rough facial features; corneal cloudiness; heart, hearing problems; short growth; progressive, limiting skeletal disorders; spinal cord damage from spinal stenosis ▪ Mild form: slower progression MPS VII: Sly syndrome ▪ Hydrops fetalis; skeletal, soft tissue abnormalities MPS IX: Natowicz syndrome ▪ Pain, swelling nodular masses of soft tissue around joints DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Maroteaux–Lamy: spinal canal stenosis, cord compression X-ray ▪ Sanfilippo syndrome: dysostosis multiplex ▪ Morquio syndrome: dysostosis multiplex, vertebra flattening, pectus carinatum, odontoid dysplasia ▪ Sly syndrome: flared ribs, pectus carinatum LAB RESULTS ▪ Prenatal diagnosis: enzyme activity measurement in amniotic cells ▪ Enzyme test: ↓ activity 288 OSMOSIS.ORG Urine analysis ▪ ↑ glycosaminoglycans ▫ Sanfilippo syndrome: ↑ heparan sulfate ▫ Morquio syndrome: ↑ keratan sulfate ▫ Maroteaux-Lamy syndrome: ↑ dermatan sulfate ▫ Sly syndrome: ↑ dermatan, heparan sulfate TREATMENT OTHER INTERVENTIONS ▪ ▪ ▪ ▪ ▪ ▪ No definitive cure Enzyme replacement therapy Hematopoietic bone marrow transplant Home exercises Gene therapy in development Treat associated complications

Chapter 50 Mucopolysaccharidosis HUNTER SYNDROME osms.it/hunter-syndrome PATHOLOGY & CAUSES ▪ X-linked disorder ▫ Impaired metabolism of glycosaminoglycans (GAG) → heparan, dermatan sulfate accumulation TYPES MPS II A (severe form) ▪ Affects children in early life MPS II B (mild form) ▪ Symptoms later in life; life expectancy up to seventy years CAUSES ▪ Mutation of IDS gene → enzyme iduronate2-sulfatase dysfunction → ineffective breakdown of GAG in lysosomes → accumulation; cell, tissue, organ damage COMPLICATIONS MPS II A ▪ Carpal tunnel syndrome ▪ Airway obstruction ▪ Heart problems ▫ Heart valve leaflet dysfunction; thickening of the myocardium → coronary blood vessel compression ▪ Intellectual disability ▪ Seizures MPS II B ▪ Valvular heart disease, hydrocephalus SIGNS & SYMPTOMS ▪ Death due to heart and lung problems ▪ Lack of blurry cornea differentiates Hunter syndrome from Hurler syndrome MPS II A ▪ Early life ▫ Rough facial features (enlarged head, flat bridge of nose, bulging forehead) ▫ Skeletal abnormalities, stiff joints, limited movement ▫ Intellectual disability ▫ Skin (ivory colored lesions) ▪ Later life ▫ Progressive neurological decline ▫ Hydrocephalus ▫ Seizures MPS II B ▪ Later onset: milder symptoms ▪ Rough facial features ▪ Rigid joints ▪ Hearing, pulmonary disorders DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Skeletal abnormalities CT scan/MRI ▪ Cord compression level, odontoid hypoplasia assessment LAB RESULTS ▪ Prenatal diagnosis ▫ ↓ enzyme activity in amniocytes ▪ Enzyme-linked immunosorbent assay (ELISA) ▫ ↑ heparan, dermatan sulfate in blood, urine ▪ Enzyme activity test on leucocytes/ fibroblasts ▫ ↓ activity ▪ Bone marrow cells histology ▫ Alder–Reilly granulations OSMOSIS.ORG 289

OTHER DIAGNOSTICS ▪ Physical examination ▫ Characteristic findings ECG, pulmonary testing ▪ Determination of functions TREATMENT OTHER INTERVENTIONS ▪ No definitive cure ▪ Address complications ▪ Recombinant human iduronate sulfatase ▫ dursulfase; enzyme replacement therapy ▪ Hematopoietic bone marrow transplant HURLER SYNDROME (MPS I) osms.it/hurler-syndrome PATHOLOGY & CAUSES ▪ Autosomal recessive disorder; glycosaminoglycans buildup ▪ Alpha-L iduronidase deficiency → heparan sulfate accumulation in lysosomes → cell, tissue, organ damage TYPES Attenuated form ▪ Better prognosis ▪ Presentation: age two–adolescence ▪ Life expectancy: twenties–middle age Severe form ▪ Presentation: within first two years ▪ Life expectancy: about 10 years CAUSES ▪ IDUA gene mutation COMPLICATIONS ▪ Carpal tunnel syndrome ▪ Heart valve abnormalities → heart failure ▪ Thick secretions → frequent sinopulmonary infections ▪ Enlargement of tonsils, adenoids → airway obstruction → sleep apnea ▪ Vision, hearing loss 290 OSMOSIS.ORG ▪ C1-C2 subluxation → spinal cord compression → central apnea ▪ Hydrocephalus SIGNS & SYMPTOMS ▪ Developmental delays; in severe form, progressive intellectual disability ▪ Attenuated form; normal intelligence ▪ Rough facial features ▫ Enlarged head, nose, cheeks, lips, tongue ▪ Repeated ear, respiratory infections ▪ Retinal degeneration, corneal blurriness ▪ Hepatosplenomegaly ▪ Hernias (umbilical, inguinal) ▪ Rib, hip, pelvis, vertebral abnormalities ▪ Stiff joints, claw-like hands ▪ Long bones thicken ▪ Thickened skin, short neck DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Enlargement of skull, frontal bulging ▪ Lumbar, thoracic vertebral hypoplasia ▪ Pelvis hypoplasia, small femoral heads ▪ Metacarpals narrow proximally, widen distally

Chapter 50 Mucopolysaccharidosis LAB RESULTS ▪ Enzyme activity in fibroblasts ▫ ↓alpha-L iduronidase ▪ ↑ heparan sulfate OTHER DIAGNOSTICS ▪ Physical examination ▫ Characteristic findings TREATMENT SURGERY ▪ Hand, foot abnormalities Figure 50.1 An X-ray image of the head of an infant with Hurler syndrome, showing a J-shaped sella turcica. OTHER INTERVENTIONS ▪ No definitive cure ▪ Address complications ▪ Recombinant human alpha-L-iduronidase ▫ Laronidase (replaces missing enzyme) ▪ Bone marrow transplant Figure 50.2 X-ray image of the hands of an infant with Hurler syndrome. The metacarpals are pointed at the proximal ends. OSMOSIS.ORG 291