Mucopolysaccharidoses

Mucopolysaccharidoses
Prof. Dr. Saad S Al Ani
Senior Pediatric Consultant
Head of Pediatric Department
Khorfakkan Hospital
Sharjah ,UAE
saadsalani@aol.com

Hereditary, progressive diseases caused by
mutations of genes coding for lysosomal
enzymes needed to degrade glycosaminoglycans
(GAGs) (acid mucopolysaccharides).
3/1/2015
Prof.Dr.Saad S Al Ani Khorfakkan Hospital
2

Glycosaminoglycan(GAG)
A long-chain complex
carbohydrate composed
of:
1. Uronic acids
2. Amino sugars
3. Neutral sugars.
www.mun.ca
3/1/2015
3

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
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Glycosaminoglycans (GAGs) (cont.)
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Major constituents of the ground substance of connective
tissue, as well as nuclear and cell membranes

Proteoglycans degradation
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www.glycoforum.gr.jp
Proteoglycans
Protein core
Proteolytic
Stepwise
degradation GAG moiety

Proteoglycans degradation disturbance
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Absent or grossly reduced activity
of mutated lysosomal enzymes
Proteoglycans
Glycosaminoglycans (GAGs)
Intralysosomal

Proteoglycans degradation disturbance
(cont.)
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Prof.Dr.Saad S Al Ani Khorfakkan Hospital8
printablecolouringpages.co.uk
Distended
lysosomes
cell
function
Characteristic pattern of clinical, radiologic, and
biochemical abnormalities
Specific diseases can be recognized that evolve from the
intracellular accumulation of different degradation products

Rule of fingers
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Heparan sulfate
(impaired degradation)
Mental
deficiency
Dermatan sulfate,
Chondroitin
sulfates,
Keratan sulfate
(impaired degradation)
Mesenchymal
abnormalities

Mucopolysaccharidoses are autosomal recessive
disorders, with the exception of Hunter disease,
which is X- linked recessive.
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Mucopolysaccharidoses (cont.)
Overall frequency is between
3.5/100,000 and 4.5/100,000
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teamsanfilippo.org
http://dxline.info/
Diseases /hurler-
syndrome
flipper.diff.org
The most common subtype is
Sanfilippo disease (MPS-III)
followed by Hurler disease
( MPS-I )
And Hunter disease (MPS II

Sanfilippo Syndrome(MPSIII)
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)
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http://www.primehealthchannel.com/sanfilippo-syndrome
A rare form of lysosomal storage disease
Inherited in an autosomal recessive pattern
www.primehealthchannel.com

Sanfilippo Syndrome (cont.)
• The incidence vary geographically, One per:
- 50000 people in the Netherlands
- 66000 people in Australia
- 280000 cases in Northern Ireland
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13
http://www.primehealthchannel.com/sanfilippo-syndrome
www.internationalstudentinsurance.com
www.gapyear.com
www.carhirecomparison.ie

Deficiency in one of the four enzymes:
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1. Heparan N- sulfatase (type A)

2.Alpha-N- acetylglucosaminidase (type B)
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3. Acetyl -Co Alpha- glucosaminide
acetyltransferase (type C)
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4.N- acetylglucosamine 6-sulfatase (type D)
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Patients are characterized by slowly progressive,
severe CNS involvement with mild somatic
disease
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Onset of clinical features usually occurs between
2 and 6 yr in a child who previously appeared
normal.

Presenting features include:
– Delayed development
– Hyperactivity with aggressive behavior
– Coarse hair
– Hirsutism
– Sleep disorders
– Mild hepatosplenomegaly
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articleactive.com

Severe neurologic deterioration occurs in most
patients by 6-10 yr of age, accompanied by rapid
deterioration of social and adaptive skills
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ellendelbloggolo.blogspot.com

3/1/2015
21
ellendelbloggolo.blogspot.com
Severe behavior problems such as:
- Sleep disturbance
- Uncontrolled hyperactivity
- Temper tantrums
- Destructive behavior
- Physical aggression
are common

Delays in diagnosis of MPS III are common
due to :
- Mild physical features
- Hyperactivity
- Slowly progressive neurologic disease
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rareshare.org

MPS 1
MPS I is caused by mutations of the IUA
gene on chromosome 4p16.3 encoding α-L-
iduronidase
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www.patienthelp.org

MPS1 (cont.)
Deficiency of α-L- iduronidase results in a
broad clinical spectrum, from severe Hurler
disease to mild Scheie diseases
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www.patienthelp.org

Hurler Disease (MPS I)
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
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www.eyecalcs.com

Hurler Disease (cont.)
An infant with Hurler syndrome appears
normal at birth, but inguinal hernias are often
present
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www.eyecalcs.com

3/1/2015
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www.eyecalcs.com
Most patients have:
• Recurrent upper respiratory tract and
ear infections
• Noisy breathing
• Persistent copious nasal discharge

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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.

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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

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www.eyecalcs.com
Headache and sleep disturbance due to:
Progressive ventricular enlargement with
increased intracranial pressure caused by
communicating hydrocephalus

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www.eyecalcs.com
Common eye involvement include:
• Corneal clouding
• Glaucoma
• Retinal degeneration

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www.eyecalcs.com
Skeletal abnormalities include:
• Enlarged, coarsely trabeculated diaphyses
of the long bones
• Irregular metaphyses and epiphyses

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www.eyecalcs.com
Radio-graphs show a
characteristic skeletal
dysplasia known as
dysostosis multiplex
The earliest radiographic
signs are thick ribs and
ovoid vertebral bodies
http://www.keywordpicture.com/keyword/arthrogryposis%20multiplex
http://www.maroteaux-lamy.com/Turkish/HCP/Bones.aspx

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www.eyecalcs.com
With progression of the disease macrocephaly
develops, with:
• Thickened calvarium
• Premature closure of lambdoid and
sagittal sutures
• Shallow orbits

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www.eyecalcs.com
Cont.
• Enlarged J-shaped sella
• Abnormal spacing of teeth with
dentigenous cysts

Hurler Disease (cont.) Diagnosis
Usually made between 6 and 24 mo of age
with evidence of:
– Hepatosplenomegaly
– Coarse facial features
– Corneal clouding
– Large tongue
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www.eyecalcs.com
nlm.nih.gov

Hurler Disease (cont.) Diagnosis
-Prominent forehead
– Joint stiffness
– Short stature
– Skeletal dysplasia
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www.eyecalcs.com
http://www.scripps.org/articles/99-frontal-bossing
http://www.nemours.org/service/medical/skeletal-dysplasia
http://doctorsgates.blogspot.ae
http://emedicine.medscape.com/article/951148-overview

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www.eyecalcs.com
Common causes of death:
• Obstructive airway disease
• Respiratory infection
• Cardiac complications

Hunter disease (MPS II)
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Is an X-linked disorder caused by the
deficiency of iduronate-2-sulfatase (IDS)
flipper.diff.org

Hunter disease (MPS II) (cont.)
3/1/2015
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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

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www.treypurcell.com

3/1/2015
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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

3/1/2015
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flipper.diff.org
Clinical manifestations:
• Coarse facial features
• Short stature
• Dysostosis multiplex
• Joint stiffness
• Mental retardation manifest between
2 and 4 yr of age.

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flipper.diff.org
The following may present
• Grouped skin papules
• Extensive Mongolian spots
• Chronic diarrhea
• Communicating hydrocephalus and
spastic paraplegia

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Patients with the mild form have:
• Prolonged life span
• Minimal CNS involvement
• Slow progression of somatic deterioration
with preservation of intelligence in adult
life
flipper.diff.org

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In severely affected patients:
• Extensive, slowly progressive neurologic
involvement
• Death, which usually occurs between 10
and 15 yr of age.
flipper.diff.org

3/1/2015
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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
flipper.diff.org

Diagnosis of MPS
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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

Differential diagnosis
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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:
• Hurler- like facial features
• Joint contractures
• Dysostosis multiplex
• Elevated urinary GAG excretion

Treatment of MPS
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• 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.

Hematopoietic stem cell transplantation
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Clinical effects include :
• Increased life expectancy
• Resolution or improvement of growth
failure
• Upper airway obstruction
• Hepatosplenomegaly
• Joint stiffness
• Facial appearance

(Cont.)
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• Pebbly skin changes
• Obstructive sleep apnea
• Heart disease
• Communicating hydrocephalus
• Hearing loss

(Cont.)
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Enzyme activity in serum and urinary GAG
excretion is normalized
Transplantation prevents neurocognitive
degeneration

Hematopoietic stem cell transplantation (Cont.)
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Transplantation does not correct :
• Existent cerebral damage
• Skeletal and ocular anomalies

Enzyme replacement
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-It reduces :
• Organomegaly
• Number of episodes of sleep apnea
• Urinary GAG excretion

Enzyme replacement (Cont.)
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- It ameliorates :
• rate of growth
• joint mobility
• Physical endurance.

Enzyme replacement (Cont.)
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-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

Prevention
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• Primary prevention
Through genetic counseling
• Tertiary prevention
To avoid or treat complications remains the
mainstay of supportive pediatric care

Prevention (Cont.)
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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

Prevention (Cont.)
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The progressive nature of clinical involvement
in MPS patients dictates the need for specialized
and coordinated evaluation

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noahstjohn.com

Mucopolysaccharidoses

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