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Mucopolysaccharidoses in children

Mucopolysaccharidoses in children

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Mucopolysaccharidoses in children

  1. 1. Contents • Introduction • Pathophysiology • Mode of Inheritance • Classification • Clinical presentation • Diagnosis • Management • Complications
  2. 2. Lysosome • Function: • Found only in cells • Filled with enzymes for intercellular digestion • Waste Disposal System that is inside of cell • If it is not functioning properly, there would be an accumulation of unwanted materials, which would lead to the death of the cell • Relevant Structures: • Filled with hydrolytic and digestive enzymes • Spherical bag-like structure that are bound by a single layer membrane that surrounds it • The membrane acts as a protective barrier that protects the rest of the cell from the enzymes that are contained within the lysosome.
  3. 3. Disorders of Lysosome Metabolism • Functions of cellular organelles can be disrupted by accumulation of a toxic substance within the organelle or malformation/lack of formation of the entire organelle. • Disorders of lysosome metabolism include: • mucopolysaccharidoses, • lipidoses, and • MucoLipidosis ;ML.
  4. 4. • The mucopolysaccharidoses result from a deficiency of degradation of acid mucopolysaccharides leading to lysosomal accumulation and include Hunter, Hurler, and Sanfilippo disease. • The lipidoses include mannosidosis and sialidosis. • The ML include Niemann-Pick, Krabbe, Fabry, Gaucher, and Tay-Sachs disease.
  5. 5. Mucopolysaccharidoses • 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.
  6. 6. Pathophysiology • Mucopolysaccharidoses are hereditary, progressive diseases caused by mutations of genes coding for lysosomal enzymes leading to defects in stepwise breakdown of glycosaminoglycans (GAGs). • Glycosaminoglycan (GAG) widely distributed in most of the tissues. • Glycosaminoglycan (GAG) is a long-chain complex carbohydrate composed of uronic acids, amino sugars, and neutral sugars. • The major GAGs are chondroitin-4-sulfate, chondroitin-6-sulfate, heparan sulfate, dermatan sulfate, keratan sulfate, and hyaluronan.
  7. 7. • These substances are synthesized and, with the exception of hyaluronan, linked to proteins to form proteoglycans, major constituents of the ground substance of connective tissue, as well as nuclear and cell membranes. • Failure of this degradation due to absent or grossly reduced activity of mutated lysosomal enzymes results in the intralysosomal accumulation of GAG fragments Pathophysiology
  8. 8. • Distended lysosomes accumulate in the cell, interfere with cell function, and lead to a characteristic pattern of clinical, radiologic, and biochemical abnormalities. • Within this pattern, specific diseases can be recognized that evolve from the intracellular accumulation of different degradation products. • As a general rule, the impaired degradation of heparan sulfate is more closely associated with mental deficiency and the impaired degradation of dermatan sulfate, chondroitin sulfates, and keratan sulfate with mesenchymal abnormalities. Pathophysiology
  9. 9. Mode of Inheritance • Mucopolysaccharidoses are autosomal recessive disorders, with the exception of Hunter disease, which is X-linked recessive. • Their overall frequency is between 3.5/100,000 and 4.5/100,000. • The most common subtype is MPS- III, followed by MPS-I and MPS-II.
  10. 10. Classification
  11. 11. 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)
  12. 12. 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.
  13. 13. Common Presentations • CNS disease – Hydrocephalus; cervical spine myelopathy, Mental retardation, Developmental delay, Severe behavioral problems. • Cardiovascular disease –valvular dysfunction; hypertension; congestive heart failure • Pulmonary disease – Airway obstruction, potentially leading to sleep apnea, severe respiratory compromise, or cor pulmonale • Ophthalmologic disease – Corneal clouding; glaucoma; chronic papilledema; retinal degeneration. • Hearing impairment – Deafness • Musculoskeletal disease – Short stature; Skeletal irregularities, joint stiffness; symptoms of peripheral nerve entrapment, Dysostosis multiplex. • Others: Coarse facial features, Hepatosplenomegaly, Hernias
  14. 14. Findings from examination may include the following: • MPS IH – Corneal clouding, hepatosplenomegaly, skeletal deformities (dysostosis multiplex), coarse facial features, large tongue, prominent forehead, joint stiffness, and short stature; upper airway obstruction, recurrent ear infections, noisy breathing, and persistent nasal discharge; hirsutism, hearing loss, hydrocephalus, and mental retardation • MPS I-H/S - Milder features; normal intelligence and micrognathia; corneal clouding, joint stiffness, and heart disease • MPS IS - Aortic valve disease, corneal clouding, and joint stiffness; normal intelligence and stature
  15. 15. Findings from examination may include the following: • MPS II (severe) – Pebbly ivory skin lesions on the back, arms, and thighs; coarse facial features, skeletal deformities, and joint stiffness; retinal degeneration with clear cornea and hydrocephalus, mental retardation, and aggressive behavior • MPS II (mild form) – Similar features, but with much slower progression; normal intelligence and no hydrocephalus; hearing impairment and loss of
  16. 16. • MPS III – The most common MPS disorder; severe central nervous system (CNS) involvement and only minimal somatic involvement; coarse hair, hirsutism, mild hepatosplenomegaly, and enlarged head; occasionally, mild dysostosis multiplex and joint stiffness; eventually, by age 8-10 years, profound retardation with severely disturbed social behavior • MPS IV (severe) – Orthopedic involvement (eg, spondyloepiphyseal dysplasia) as the primary finding; preservation of intelligence; genu valgum, short stature, spinal curvature, odontoid hypoplasia, ligamentous laxity, and atlantoaxial instability • MPS IV (mild) – Much slower progression of skeletal dysplasia • MPS VI – Features very similar to MPS IH • MPS VII – Features similar to MPS IH Findings from examination may include the following:
  17. 17. Diagnosis • Clinical feature: MPS disorder should be suspected in a child with coarse facial features, bone disease, developmental delay, short stature, hepatosplenomegaly, corneal clouding. • 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
  18. 18. • Imaging studies that may be warranted are as follows: • Plain radiography (to detect dysostosis multiplex) • Computed tomography (CT) of the cranium (to help diagnose hydrocephalus) • Echocardiography (to monitor ventricular function and size in MPS patients with cardiovascular disease) • Other tests to be considered are as follows: • Hearing assessment (Audiologic assessment) • Ophthalmologic examination (Electroretinography).
  19. 19. Dysostosis multiplex • Dysostosis multiplex refers to a constellation of skeletal abnormalities in MPS conditions diagnosed based on plain radiographs. Dysostosis multiplex is classic in Hurler syndrome . These findings include the following: • Large skull with thickened calvaria, premature suture closure, j- shaped sella turcica, and shallow orbits • Abnormal spacing of teeth. • Short, thickened and irregular clavicles • Short, wide, and trapezoid shaped phalanges • Oar-shaped ribs • Anterior hypoplasia of the lumbar vertebrae with kyphosis • Poorly formed pelvis with small femoral heads and coxa valga • Enlarged diaphyses of long bones and irregular metaphyses
  20. 20. 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.
  21. 21. RECOGNITION PATTERN OF MUCOPOLYSACCHARIDOSES MANIFESTATIONS MUCOPOLYSACCHARIDOSIS TYPE I-H I-S II III IV VI VII Mental deficiency + – ? + – – ? Coarse facial features + (+) + + – + ? Corneal clouding + + – – (+) + ? Visceromegaly + (+) + (+) – + + Short stature + (+) + – + + + Joint contractures + + + – – + + Dysostosis multiplex + (+) + (+) + + + Mucopolysacchariduria + + + + + + +
  22. 22. 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.
  23. 23.  Enzyme-replacement therapy (ERT): • Currently (ERT) available for MPS type I ,II and VI. • The therapeutic products laronidase (for MPS I), idursulfase (for MPS II) and galsulfase (for MPS VI . • It reduces organomegaly and ameliorates rate of growth, joint mobility, and physical endurance. It also reduces the number of episodes of sleep apnea and urinary GAG excretion. • The enzymes do not cross the blood-brain barrier and do not prevent deterioration of neurocognitive involvement. Consequently, this therapy is the domain for patients with mild central nervous involvement. • To stabilize extraneural manifestations, it is also recommended in young patients before stem cell transplantation. • The combination of enzyme replacement therapy and early stem cell transplantation may offer the best treatment. Management
  24. 24. 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.
  25. 25.  Surgical care for specific conditions may include the following: • Hydrocephalus – Ventriculoperitoneal shunting • Corneal clouding – Corneal transplantation • Cardiovascular disease – Valve replacement • Obstructive airway disease – Tracheostomy • Orthopedic conditions – Carpal tunnel release; soft tissue procedures to release hip, knee, and ankle contractures; hip containment surgeries; corrective osteotomy for progressive valgus deformity at the knee; posterior spinal fusion
  26. 26. • Multispecialty care is mandatory for these patients and should include: • pediatrician (internist), • neurologist, • cardiologist, • ophthalmologist, • audiologist, • orthopedic surgeon, and a physical and • occupational therapist.
  27. 27. Complications • Complications of mucopolysaccharidosis include the following: • Hearing loss • Joint stiffness • Hydrocephalus • Corneal clouding • Cardiovascular disease • Obstructive airway disease

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Mucopolysaccharidoses in children

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