Basics of MPS in children

1. Basics of
Mucopolysaccharidosis
(MPS)
Fatima Farid
Ped Resident Yr 3

2. 2
https://oncofertility.msu.edu/resources/hurler-syndrome-mps-i

3. Overview
● MPS are hereditary progressive diseases caused by mutations of genes coding for lysosomal
enzymes
● These enzymes are needed to degrade glycosaminoglycans (GAGs) as part of the natural process
● Failure to intra- lysosomal GAG break- down leads to accumulation of distended lysosomes in
various body tissues & this in turn interferes with the normal function
● Within this pattern, specific diseases evolve from the intra- cellular accumulation of different
degradation products
3

4. 4
https://doi.org/10.3390/ijms21072515

5. 5
https://www.mpsreference.com.au/management-and-treatment-of-mps/mps-vi-maroteaux-lamy-syndrome/

6. Types
6
MPS Type Common Name Associated Gene Enzyme Deficiency
I
Hurler
Hurler- Scheie
Scheie
IDUA Alpha- L- iduronidase
II Hunter IDS Iduronate sulfatase
III
Sanfillippo A
Sanfillippo B
Sanfillippo C
Sanfillippo D
SGCH
NAGLU
HGSNAT
GNS
Heparan N- sulfatase
Alpha- N-
acetylglucosaminidase
Acetyl CoA alpha-
glycosaminide
N- acetylglucosamine- 6-
sulfatase
IV
Morquio A
Morquio B
GALNS
GLB1
Galactose 6- sulfatase
Beta- galactosidase
VI Maroteaux- Lamy ARSB
N- acetylgalactosamine
4- sulfatase
VII Sly GUSB Beta- glucuronidase
IX Natowicz HYAL1 Hyaluronidase

7. 7
https://doi.org/10.1186/s13052-018-0553-2

8. Frequency
8
MPS III MPS I MPS II

9. Incidence & Inheritance
● Rare disease with an overall frequency between 3.5-
4.5 per 100,000 births
● Autosomal recessive inheritance in all except MPS II
(Hunter Disease) which is X- linked recessive
● MPS display variable expressivity of disease due to
allelic mutations and variable residual activity of the
mutated enzymes
9

10. General Pathogenesis
● Tissue accumulation of GAG leads to hepatosplenomegaly & course facial features
● Disruption of growth plate leads to skeletal disease
● Valvular heart disease occurs due to primary GAG storage followed by secondary fibrosis
● Airway disease results from GAG storage in soft tissues & tracheal ring formation
● Mechanism of CNS disease unclear with possible multiple secondary events such as inflammation
and apoptosis
10

11. 11
https://doi.org/10.1007/s12017-019-08559-1

12. Presenting Features
● Hydrops fetalis
● Hernias
● Hepatosplenomegaly
● Bone dysplasia
● Joint stiffness/ restriction
● Heart murmur
● Recurrent pneumonias
● Skin lesions (nodules)
● Hearing loss
● Cognitive impairment or developmental delay
12

13. Major MPS Manifestations
13
CVS
• Valvular heart
disease
• Cardiomyopathy
Respiratory
• Obstructive
sleep apnea
• Restrictive lung
disease
• Reactive airway
disease
Deafness
• Combined
conductive &
sensorineural
Musculoskeletal
• Joint stiffness &
contracture
• Joint pain
• Short stature
• Spinal deformity

14. Major MPS Manifestations
14
Vision
• Corneal clouding
• Glaucoma
GI
• Hepatomegaly
• Inguinal/ umbilical
hernia
Chronic
infections
• Pneumonia and
otitis media
Dental
• Abnormal gums,
teeth and enamel
• Frequent caries
and risk of
abscesses

15. “Dysostosis Multiplex” in MPS
● Macrocephaly with thickened skull
● Odontoid hypoplasia with cervical instability
● Flattened vertebrae with anterior beaking
● Kyphosis/ scoliosis
● “Bullet- shaped” phalanges
● Oar shaped ribs
● Dysplastic hips
● Genu valgum
15

16. 16
Nelson Textbook of Pediatrics 20th edition

17. 17
Nelson Textbook of Pediatrics 20th edition

18. E.g – MPS I
18
http://www.sanofimedicalaffairs.com/rarediseases/index.php/21-mps-i

19. Specific Pathogenesis
● Deficiency of a lysosomal enzyme results in GAG accumulation, but storage in tissue specific for each type
● General rules:
○ Impaired degradation of heparan sulfate is more closely associated with intellectual disability
○ Impaired degradation of dermatan sulfate, chondrotoin sulfate and keratan sulfate lead to
mesenchymal abnormalities
19

20. 20
http://www.sanofimedicalaffairs.com/rarediseases/index.php/21-mps-i

21. Characteristics
● MPS I, II & VII have multi-systemic somatic disease
and CNS involvement, but never isolated CNS disease
● MPS III is a primarily neurological disorder & mild
forms are most likely not detected
● MPS IV has skeleton as the main organ of involvement
with normal intelligence
● MPS VI has multi-systemic somatic involvement but
with preserved intelligence
21
Table Source: Journal of Pediatric Research

22. 22
I, II, VII =
Systemic +
CNS
III = CNS
only
IV =
Skeleton
mainly
VI =
Systemic
only

23. MPS- I
● Deficiency of α-L-iduronidase results in a wide range of
clinical involvement from severe Hurler disease to mild
Scheie disease, which are ends of a broad clinical spectrum
● Homozygous nonsense mutations result in severe forms of
MPS-I, whereas missense mutations are more likely to
preserve some residual enzyme activity associated with a
milder form of the disease
23

24. 24
https://www.mps1disease.com/patients/about/disease-spectrum

25. Hurler (MPS- I H)
● Severe intellectual disability
● Progressive deterioration
● Characteristic dysmorphic features
● Corneal clouding
● Severe respiratory distress
● Obstructive airway disease
● Death before age of 10 years
25
I, II, VII =
Systemic +
CNS

26. Scheie (MPS I S)
● Normal intelligence
● Less progressive physical problems
● Corneal clouding
● Joint stiffness
● Aortic valve disease
● Death in later decades
26
I, II, VII =
Systemic +
CNS

27. Hurler- Sheie (MPS I H/S)
● Little or no intellectual defect
● Respiratory disease
● Obstructive airway disease
● Cardiovascular disease
● Joint stiffness & contractures
● Skeletal abnormalities
● Decreased visual acuity
● Death in teens & 20’s
27
I, II, VII =
Systemic +
CNS

28. Hunter Syndrome (MPS II)
● Deficiency of lysosomal enzyme iduronate-2- sulfatase
● Onset of symptoms between 1 and 3 years in severe form
● Early mortality in severe form
● Rare (estimated incidence 1:100,000)
● X- linked recessive disorder – carrier females have no evidence of disease
● Small number of females are reported with MPS II
28
I, II, VII =
Systemic +
CNS

29. Hunter Syndrome (MPS II)
● Similar features to Hurler syndrome but with clear cornea & milder
severity
● Extensive Mongolian spots especially among Asian patients has been
shown to be an early marker
● Common CNS manifestations include:
○ Progressive cognitive impairment
○ Seizures
○ Communicating hydrocephalus
○ Hearing loss
○ Decreased night and peripheral vision loss
29
I, II, VII =
Systemic +
CNS

30. Hunter Syndrome (MPS II)
● In general, the earlier the onset of physical disease the more severe
the phenotype
● DNA mutation analysis allows prediction of severe phenotype in
patients with large rearrangements or deletions
● Determination of clinical severity for most patients cannot be made
at the time of diagnosis
30
I, II, VII =
Systemic +
CNS

31. Sanfillippo Syndrome (MPS III)
● Major manifestations include: profound intellectual deterioration,
hyperactivity, relatively mild somatic features and coarse hair
● Cornea is clear
● Severe neurologic degeneration occurs in most patients by 6- 10 years old
● Milder forms are known to exist
● Death in teenage years
31
III = CNS
only

32. Morquio Syndrome (MPS IV)
● Includes 2 different enzymatic disorders with the same clinical phenotype
● MPS IV- A is more common
● There is a wide spectrum of clinical involvement with both types
● Skeleton is the major organ of involvement with normal intelligence
● Joint laxity is a hallmark symptom
32
IV = Skeleton
mainly

33. Morquio Syndrome (MPS IV)
Morquio A
● Short trunk dwarfism
● Fine corneal opacities
● Characteristic bone dysplasia
● Final height below 125 cm
Morquio B
● Same features as A, but final
height more than 120 cm
33

34. Maroteaux- Lamy Syndrome (MPS VI)
● Deficiency of lysosomal enzyme arylsulfatase B
● Multi-systemic involvement but have normal intelligence
● Hurler like phenotype but with marked corneal clouding
● Moderate to severe expression in different families
● Early mortality (life span up to second decade) in severe form
due to cardiac and airway disease
34
VI =
Systemic
only

35. Sly Syndrome (MPS VII)
● A rare form of MPS
● Varies from fetal hydrops to mild
dysmorphism
● Dense inclusion granules present in
granulocytes (Alder–Reilly granules)
35
DOI: 10.32677/IJCR.2020.v06.i10.016

36. Recap
36
Nelson Textbook of Pediatrics 20th edition

37. Diagnosis
1. Skeletal survey for features of dysostosis multiplex
2. Urine analysis for GAG
3. If Morquio suspected, would need to do serum monoclonal antibodies to keratin sulfate (missed on
urine GAG screen)
4. Lysosomal enzyme essay
5. Molecular genetic testing for attributable pathogenic variant
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38. Treatment Options
● Hematopoietic stem cell or cord blood transplantation
● Enzyme replacement therapy
● Symptomatic management
● Primary prevention by family counseling & further planning
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39. Transplant
● Proven to be of benefit in MPS I, II & VI
● Increases life expectancy; improves growth parameters, hepatosplenomegaly, OSA, joint stiffness, skin
appearance, coarse facies, hydrocephalus and hearing loss
● Enzyme activity in serum & urine GAG levels normalize
● Intellectual disability may improve in the case of MPS I who have undergone transplantation before 24
months age with baseline development index more than 70
● Ocular & skeletal involvement do not improve with transplant
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40. Enzyme Replacement
● Proven benefit in MPS I
● Aldurazyme: ideally used before & after transplantation
● Reduces organomegaly, improves growth, joint mobility, OSA & urine GAG levels
● Enzyme does not cross BBB, so it cannot prevent deterioration in neurologic status
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41. Symptomatic Mx
41
Nelson Textbook of Pediatrics 20th edition

42. Thanks!