Mucopolysaccharidoses in children

2. Contents
• Introduction
• Pathophysiology
• Mode of Inheritance
• Classification
• Clinical presentation
• Diagnosis
• Management
• Complications

3. Lysosome
• Organelle 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 defect & even death
of the cell.

4. Disorders of Lysosome Metabolism
• Disorders of lysosome metabolism include:
• mucopolysaccharidoses,
• lipidoses, and
• MucoLipidosis ;ML.

5. • The mucopolysaccharidoses :include Hunter,
Hurler, and Sanfilippo disease.
• The lipidoses include mannosidosis and
sialidosis.
• The ML include Niemann-Pick, Krabbe, Fabry,
Gaucher, and Tay-Sachs disease.

6. 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.

7. Pathophysiology
• Glycosaminoglycan (GAG) is a long-chain complex carbohydrate.
• The major GAGs are chondroitin-4-sulfate, chondroitin-6-sulfate, heparan
sulfate, dermatan sulfate, keratan sulfate, and hyaluronan.
• Glycosaminoglycan (GAG) widely distributed in most of the tissues.
• Glycosaminoglycan (GAG) major constituents of connective tissue, as well as
nuclear and cell membranes.

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. 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)

10. Classification

11. 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.

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. 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. Findings from examination may include the following:
• MPS I H/S :
• skeletal deformities (dysostosis
multiplex),
• joint stiffness, and short stature
• prominent forehead
• Corneal clouding,
• coarse facial features, hirsutism
• large tongue, noisy breathing,
upper airway obstruction,
persistent nasal discharge.
• recurrent ear infections,
hearing loss.
• hydrocephalus,
• mental retardation.
• hepatosplenomegaly,

15. Findings from examination may include the following:
• MPS II (mild to severe)
• coarse facial features,
• skeletal deformities,
and joint stiffness;
• ivory skin lesions on the
back, arms, and thighs;
• retinal degeneration
with clear cornea.
• hydrocephalus, mental
retardation, and
aggressive behavior.

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; genu valgum,
short stature, spinal curvature,
odontoid hypoplasia, ligamentous
laxity, and atlantoaxial instability.
• preservation of intelligence.
• 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. 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
• Genetic testing

18. • Imaging studies that may be warranted are
as follows:
• Plain radiography (to detect dysostosis
multiplex).

19. Dysostosis multiplex
• Dysostosis multiplex refers to a constellation of skeletal
abnormalities in MPS conditions diagnosed based on plain
radiographs. 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. 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

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. Management
 Treatment of Manifestations:
 Supportive management can improve the quality of life
for affected individuals and their families.
 Enzyme-replacement therapy (ERT)
 Stem Cell Transplantation (HSCT)
 Gen therapy.

23. Occupational
therapist
Orthopaedic
consultant
Physiotherapist
Physician
Psychologist
Acute care
clinicians
Consultant
neurologist
Gastroenterologist
Neuromuscular
care specialist
Nutritionist
Pulmonologist
Speech-language
pathologist
The MDT can
consist of:
Supportive management
• A multidisciplinary approach is key for the management of individuals
with MPS.
• In MPS, it is important to monitor the various aspects that are known to
be involved in disease progression and, when possible, provide
anticipatory care.

24.  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.
Management

25.  Enzyme-replacement therapy (ERT):
• 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

26. Management
 Hematopoietic Stem Cell Transplantation (HSCT)
• 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.

27.  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

28. Complications
• Complications of mucopolysaccharidosis
include the following:
• Hearing loss
• Joint stiffness
• Hydrocephalus
• Corneal clouding
• Cardiovascular disease
• Obstructive airway disease