Mucopolysaccharidoses

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

3. 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.

4. 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.

5. • 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.

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
• 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.

8. • 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

9. • 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

10. 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.

11. Classification

12. 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)

13. 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.

14. 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

15. 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

16. 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 hand
function

17. • 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:

18. 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

19. • 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).

20. 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

21. 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.

22. 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 + + + + + + +

23. 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.

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.
• 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

25. 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.

26.  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

27. • Multispecialty care is mandatory for these patients and
should include:
• pediatrician (internist),
• neurologist,
• cardiologist,
• ophthalmologist,
• audiologist,
• orthopedic surgeon, and a physical and
• occupational therapist.

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