Mucopolysaccharidoses

for pediatrics UG teaching

1. DrM.Sanjeevappa
M.D.(paeds)
Asst.Professor
Dept. of Paediatrics GMC,ATP.

2. SPHINGOLIPIDOSES
GM2-gangliosidosis
Tay–Sachs
Sandhoff
Gaucherdisease
Fabrydisease
Metachromatic leukodystrophy
Krabbedisease
Farber syndrome
Mucolipidoses
Disorders involving sialicacid

3. MPS-I: Hurler disease
MPS-II: Hunter disease
MPS-III: Sanfilippodisease
MPS-IV: Morquiodisease
MPS-VI: Maroteaux-Lamydisease
MPS-VII: Sly Syndrome
MPS-IX : Hyaluronidasedeficiency

4. Overall frequency is between 3.5 to 4.5 in 100,000
births.
The most common subtype is MPS-III,
followed by MPS-I and MPS-II.
MPS III -80%.
Inheritance –AR ExceptMPS II(Hunter’s
syndrome )

5. Normal development initially.
Symptomatic in infancy and early childhood.
CNS :
Hydrocephalus , Atlantoaxial dislocation
MUSCULOSKELETAL :
Short stature , Joint stiffness , peripheral nerve
entrapment ,Tendon entrapment.
CVS :
Valvular dysfunction , Hypertension ,CHF ,
Anginal pains , sudden cardiac deaths .

6. RS :
Obstructive airway disease
Sleep apnea
Corpulmonale
EYE :
Corneal clouding ,Glaucoma ,Chronic
papilledema , Retinal degeneration.
EAR :
Recurrent middle ear infections ,
Deformities of the ossicles.
Deafness.

7. MPS IH(Hurler syndrome):
mutations of the IDUA
gene on chromosome 4p16.3
encoding α-L-iduronidase.
Healthy at birth.
Inguinal and Umbilical hernias.
Corneal clouding
Hepatosplenomegaly .
Skeletal deformities .
Course facial features
Large tongue .
Prominent forehead .
Hirsutism .
Mental retardation.
Death usually occurs by 10 yrsof age

8. Intermediate form of mpsI.
Onset at 3 –8 yrsof age.
Normal intelligence.
Survive into 3
rd
decade of life.
Cardiac involvement and upper airway
obstruction.
Spondylolisthesis.

9. Onset is after the age of 5 yr.
Mild disorder.
Joint stiffness.
Aortic valve disease.
Mild dysostosis multiplex.
Normal intelligence and stature.
Ophthalmic features include corneal clouding,
glaucoma, and retinal degeneration.
Obstructive airway disease-sleep apnea

10. X-linked recessivedisorder caused by the
deficiency of iduronate2-sulfatase (IDS).
SEVERE CLINICAL PHENOTYPE:
Major deletions or rearrangements of the IDS gene
Manifests almost exclusively in males. it has been
observed in females also.
Manifest between 2 to 4 yrof age.
Features similar of Hurler disease
exceptions
lack of corneal clouding,
slow progression

11. Grouped skin papules.
Extensive mongolianspots at birth.
Chronic diarrhea.
Communicatinghydrocephalus and spastic paraplegia.
MILD FORM:
Point mutations of the IDS gene
normal life span,
minimal CNS involvement.
slow progression of somatic deterioration.
preservation of cognitive function in adult life.
Survival to ages 65 and 87 yr.

12. Genetically heterogeneous.
Characterized by slowly progressive, severe CNS
involvement with mild somatic disease.
Onset occurs between 2 to 6 yr.
Developmental delay
Hyperactivity with aggressive behavior.
Coarse hair.
Hirsutism.
Sleep disorders
Mild hepatosplenomegaly.

13. deficiency of N-acetylgalactosamine-6-sulfatase
or β-galactosidase.
defective degradation of keratansulfate.
short-trunk dwarfism.
skeletal dysplasia.
Intelligence preserved.
genuavalga, kyphosis.
growth retardation with short trunk and neck.
waddling gait with a tendency to fall.
Atlantoaxial instability and dislocation.
Extra skeletal manifestations:
mild corneal clouding,
small teeth with abnormally thin enamel.
hepatomegaly
Cardiac Valvular lesions.

14. mutations of the ARSB gene on
chromosome 5q11-13 encoding
N-acetylgalactosamine-4-sulfatase
(arylsulfataseB).
Intelligence preserved.
somatic involvement resembles MPS I
growth can be normal for the first few
years of life virtually stop after age 6-8
yr.
Spinal cord compression in upper
cervical canal.

15. Caused by mutations of the GUSB gene located
on chromosome 7q21.11.
Deficiency of β-glucuronidase, intracellular
storage of glycosaminoglycan fragments.
Most severe form:
Non-immune fetal hydrops.
Some severely affected newborns survive for
some months and developthick skin,
visceromegaly, and dysostosis multiplex.

16. Less-severe form:
present during the first years of life with features
of MPS-I but slower progression.
Patients with manifestation after 4 yrof life have
skeletal abnormalities of dysostosis Multiplex.
normal intelligence and usually clear corneae.
blood smear that shows coarse granulocytic
inclusions.

17. The disorder is caused by a mutation in the HYAL1
gene on chromosome 3p21.2-21.2 encoding one
of 3 hyaluronidases.
Clinical findings:
bilateral nodular soft-tissue periarticularmasses.
lysosomalstorage of GAGs in histiocytes.
mildly dysmorphiccraniofacial features.
short stature.
normal intelligence.
Small erosions in both acetabula.

18. skeletal survey.
assay the urinary excretion of GAG.
Quantitative analysis of single GAG by tandem
mass spectrometry.
Morquiodisease-monoclonal antibodies to
keratansulfate.
enzyme assay: Serum leukocytes, or cultured
fibroblasts are used as the tissue source for
measuring lysosomalenzymes.

19. Prenatal diagnosis is available for all MPSs and
is carried out on cultured cells from amniotic
fluid or chorionic villus biopsy.
Prenatal molecular analysis in a male fetus of a
proven female carrier of the IDS geneto prevent
MPS II.
MPSs I, II, and VI are candidates for neonatal
blood spot screening by tandem mass
spectrometry allowing early diagnosis and
enzyme replacement therapy.

20. Mucolipidoses.
Oligosaccharidoses.

21. Hematopoietic stem cell transplantation and enzyme
replacement therapy are performed in specialized
institutions.
Bone marrow transplantation and cord blood
transplantation have resulted in significant clinical
improvement of somatic disease in MPSs I, II, and VI.
Transplantation does not significantly improve the
neuropsychologicoutcome.
Stem cell transplantation does not correct
skeletal and ocular anomalies

22. Enzyme replacement therapy :
Recombinant α-L-iduronidaseapproved for
patients with MPS-I.
Recombinant iduronate-2-sulfatase ameliorates
the non neurologic manifestations of Hunter
disease.
Recombinant N-acetylgalactosamine-4-sulfatase
has been successfully tested in patients with
MPS-VI.

23. NEUROLOGIC:
Hydrocephalus-Ventriculoperitonealshunt
Disturbed sleep/wake circle MPS-III -Melatonin
Seizures-anticonvulsants
Odontoid hypoplasia MPS-IV -upper cervical
fusion
Spinal cord compression-Laminectomy, dural
excision
OPHTHALMOLOGIC:
Corneal opacity-Corneal transplant
Glaucoma-Medication, surgery

24. EARS, AIRWAYS:
Recurrent otitis media-Ventilating tubes.
Impaired hearing -Audiometry, hearing aids.
Obstruction of RS -tonsillectomy, bronchodilator
therapy, continuous positive airway pressure at
night, laser excision of tracheal lesions,
tracheotomy.
CARDIAC:
Cardiac valve disease -Endocarditis prevention,
valve replacement
Coronary insufficiency -Medical therapy
Arrhythmias-Antiarrhythmic medication,
pacemaker

25. ORAL, GASTROINTESTINAL:
Hypertrophic gums, poor teeth -Dental care
Chronic diarrhea MPS-II-Diet modification,
loperamide
MUSCULOSKELETAL:
Joint stiffness All except MPS-IV-Physiotherapy
Weakness -Physiotherapy, wheelchair
Gross long bone malalignment-Corrective
osteotomies
Carpal tunnel syndrome-Electromyography,
surgical decompression