Mucopolysaccharidoses

Mucopolysaccharidoses

Prof. Dr. Saad S Al Ani

Senior Pediatric Consultant

Head of Pediatric Department

Khorfakkan Hospital

Sharjah ,UAE

[email protected]

mailto:[email protected]


Hereditary, progressive diseases caused by

mutations of genes coding for lysosomal

enzymes needed to degrade glycosaminoglycans

(GAGs) (acid mucopolysaccharides).

3/1/2015Mucopolysaccharidoses

Prof.Dr.Saad S Al Ani Khorfakkan Hospital2

Glycosaminoglycan(GAG)

A long-chain complex

carbohydrate composed

of:

1. Uronic acids

2. Amino sugars

3. Neutral sugars.

www.mun.ca



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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



Glycosaminoglycans (GAGs) (cont.)



Major constituents of the ground substance of connective

tissue, as well as nuclear and cell membranes

Proteoglycans degradation



www.glycoforum.gr.jp

Proteoglycans

Protein coreProteolytic

Stepwise

degradation GAG moiety

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Proteoglycans degradation disturbance



Absent or grossly reduced activity

of mutated lysosomal enzymes

Proteoglycans

Glycosaminoglycans (GAGs) Intralysosomal

Proteoglycans degradation disturbance(cont.)



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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

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Rule of fingers



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.



Mucopolysaccharidoses (cont.)

Overall frequency is between

3.5/100,000 and 4.5/100,000



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

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http://dxline.info/diseases/hurler-syndrome

http://dxline.info/diseases/hurler-syndrome

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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)



http://www.primehealthchannel.com/sanfilippo-syndrome

A rare form of lysosomal storage disease

Inherited in an autosomal recessive pattern

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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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Deficiency in one of the four enzymes:



1. Heparan N- sulfatase (type A)


2.Alpha-N- acetylglucosaminidase (type B)




3. Acetyl -Co Alpha- glucosaminide

acetyltransferase (type C)




4.N- acetylglucosamine 6-sulfatase (type D)




Patients are characterized by slowly progressive,

severe CNS involvement with mild somatic

disease



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



articleactive.com

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Severe neurologic deterioration occurs in mostpatients by 6-10 yr of age, accompanied by rapiddeterioration of social and adaptive skills



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elle

ndel

blo

ggolo

.blo

gsp

ot.

comSevere behavior problems such as:

- Sleep disturbance

- Uncontrolled hyperactivity

- Temper tantrums

- Destructive behavior

- Physical aggression

are common

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Delays in diagnosis of MPS III are commondue to :

- Mild physical features

- Hyperactivity

- Slowly progressive neurologic disease



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MPS 1

MPS I is caused by mutations of the IUA

gene on chromosome 4p16.3 encoding α-L-

iduronidase



www.patienthelp.org

http://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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http://www.patienthelp.org/

Hurler Disease (MPS I)

This is a severe form of MPS I ,and it isprogressive disorder with multiple organ andtissue involvement that results in prematuredeath, usually by 10 yr of age



www.eyecalcs.com

http://www.eyecalcs.com/

Hurler Disease (cont.)

An infant with Hurler syndrome appears

normal at birth, but inguinal hernias are often

present



www.eyecalcs.com





www.eyecalcs.com

Most patients have:

• Recurrent upper respiratory tract and

ear infections

• Noisy breathing

• Persistent copious nasal discharge





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.





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





www.eyecalcs.com

Headache and sleep disturbance due to:

Progressive ventricular enlargement with

increased intracranial pressure caused by

communicating hydrocephalus





www.eyecalcs.com

Common eye involvement include:

• Corneal clouding

• Glaucoma

• Retinal degeneration





www.eyecalcs.com

Skeletal abnormalities include:

• Enlarged, coarsely trabeculated diaphyses

of the long bones

• Irregular metaphyses and epiphyses





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


http://www.keywordpicture.com/keyword/arthrogryposis multiplex

http://www.maroteaux-lamy.com/Turkish/HCP/Bones.aspx




ww

w.e

yec

alcs

.com

With progression of the disease macrocephaly

develops, with:

• Thickened calvarium

• Premature closure of lambdoid and

sagittal sutures

• Shallow orbits





ww

w.e

yec

alcs

.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



ww

w.e

yec

alcs

.com

nlm.nih.gov


Hurler Disease (cont.) Diagnosis

-Prominent forehead

– Joint stiffness

– Short stature

– Skeletal dysplasia



ww

w.e

yec

alcs

.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


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




www.eyecalcs.com

Common causes of death:

• Obstructive airway disease

• Respiratory infection

• Cardiac complications


Hunter disease (MPS II)



Is an X-linked disorder caused by the

deficiency of iduronate-2-sulfatase (IDS)

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Hunter disease (MPS II) (cont.)



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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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





flipper.diff.org

Clinical manifestations:

• Coarse facial features

• Short stature

• Dysostosis multiplex

• Joint stiffness

• Mental retardation manifest between

2 and 4 yr of age.





flipper.diff.org

The following may present

• Grouped skin papules

• Extensive Mongolian spots

• Chronic diarrhea

• Communicating hydrocephalus and

spastic paraplegia





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





In severely affected patients:

• Extensive, slowly progressive neurologic

involvement

• Death, which usually occurs between 10

and 15 yr of age.

flipper.diff.org





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



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



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



• 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



Clinical effects include :

• Increased life expectancy

• Resolution or improvement of growth

failure

• Upper airway obstruction

• Hepatosplenomegaly

• Joint stiffness

• Facial appearance

Hematopoietic stem cell transplantation (Cont.)



• Pebbly skin changes

• Obstructive sleep apnea

• Heart disease

• Communicating hydrocephalus

• Hearing loss




Enzyme activity in serum and urinary GAG

excretion is normalized

Transplantation prevents neurocognitive

degeneration




Transplantation does not correct :

• Existent cerebral damage

• Skeletal and ocular anomalies

Enzyme replacement



-It reduces :

• Organomegaly

• Number of episodes of sleep apnea

• Urinary GAG excretion

Enzyme replacement (Cont.)



- It ameliorates :

• rate of growth

• joint mobility

• Physical endurance.

Enzyme replacement (Cont.)



-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



• Primary prevention

Through genetic counseling

• Tertiary prevention

To avoid or treat complications remains the

mainstay of supportive pediatric care

Prevention (Cont.)



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.)



The progressive nature of clinical involvement

in MPS patients dictates the need for specialized

and coordinated evaluation



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Mucopolysaccharidoses

Health & Medicine

Transcript of Mucopolysaccharidoses