for pediatrics UG teaching

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

2. SPHINGOLIPIDOSES
 GM2-gangliosidosis
 Tay–Sachs
 Sandhoff
 Gaucher disease
 Fabry disease
 Metachromatic leukodystrophy
 Krabbe disease
 Farber syndrome
Mucolipidoses
Disorders involving sialic acid

3.  MPS-I: Hurler disease
 MPS-II: Hunter disease
 MPS-III: Sanfilippo disease
 MPS-IV: Morquio disease
 MPS-VI: Maroteaux-Lamy disease
 MPS-VII: Sly Syndrome
 MPS-IX : Hyaluronidase deficiency

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 Except MPS 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
 Cor pulmonale
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 yrs of age

8.  Intermediate form of mps I.
 Onset at 3 – 8 yrs of age.
 Normal intelligence.
 Survive into 3rd 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 recessive disorder caused by the
deficiency of iduronate 2-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 yr of age.
 Features similar of Hurler disease
 exceptions
lack of corneal clouding,
slow progression

11.  Grouped skin papules.
 Extensive mongolian spots at birth.
 Chronic diarrhea.
 Communicating hydrocephalus 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 keratan sulfate.
 short-trunk dwarfism.
 skeletal dysplasia.
 Intelligence preserved.
 genua valga, 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
(arylsulfatase B).
 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 develop thick 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 yr of 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 periarticular masses.
 lysosomal storage of GAGs in histiocytes.
 mildly dysmorphic craniofacial 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.
 Morquio disease-monoclonal antibodies to
keratan sulfate.
 enzyme assay: Serum leukocytes, or cultured
fibroblasts are used as the tissue source for
measuring lysosomal enzymes.

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 gene to 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
neuropsychologic outcome.
 Stem cell transplantation does not correct
skeletal and ocular anomalies

22. Enzyme replacement therapy :
 Recombinant α-L-iduronidase approved 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- Ventriculoperitoneal shunt
 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- Physio therapy
 Weakness - Physio therapy, wheelchair
 Gross long bone malalignment -Corrective
osteotomies
 Carpal tunnel syndrome- Electromyography,
surgical decompression