Lysosomal storage diseases: An inborn errors of metabolism

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Lysosomal storage diseases An inborn errors of
metabolism

• Damayanti Rusli Sjarif
• Div Pediatric Nutrition and Metabolic Diseases
• Dept of Child Health FKUI/RSCM
• Jakarta - Indonesia

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Genetic diseases

• Single gene disorders
• Caused by individual mutant gene
• Example Inborn errors of metabolism
• Chromosomal disorders
• Numerical disorders
• Structural disorders
• Multifactorial disorders

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Inborn Errors of Metabolism a genetic
disease also known as biochemical
genetics Gene-level Gene mutation Protein-l
evel Abnormal protein
Transport Other Enzyme protein protein
Metabolic-level Abnormal metabolites
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Classification IEM

• Clinical presentations
• neurological syndrome
• - metabolic acidosis
• hepatic syndrome
• cardiovascular syndrome
• storage syndrome dysmorphism
• acute metabolic disorders (neonatus)

• Type/location of disorders
• small molecule disease (amino acids,
  carbohydrates, fatty acids, etc)
• organelle diseases (lysosomal, peroxisomal,
  mitochondrial)

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Lysosomes

• Isolated by Christian de Duve in 1949 ? extracted
  from rat liver
• small cellular organelles 0.25 and 0.5mm in size
  ?
• consist of a fragile membranous bag encircling a
  mixture of hydrolytic enzymes
• that breakdown macromolecules into smaller
  subunits that can be utilized by the cell for its
  own biosynthesis.

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Lysosomes are each cell's 'recycling centre' ?
Their role is to break down complex material to
simple products for recycling within the cell to
build new complex material
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Acid Hydrolases

• Lysosomes contain about 40 types of hydrolytic
  enzymes (acid hydrolases),
• For optimal activity they require an acid
  environment by maintaining a pH of about 5 in its
  interior.
• The membrane of the lysosome normally keeps the
  digestive enzymes out of the cytosol, but even if
  they should leak out, they can do little damage
  at the cytosolic pH of about 7.2.

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Delivering Hydrolytic Enzymes to the Lysosome
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Delivering Hydrolytic Enzymes to the Lysosome
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Lysosomes function defect ? storage
diseasesendocytosis (foods), phagocytosis,
autophagy (damaged organelles)
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Lysosomal storage diseases

• Prevalence 1 to 5000-8000 live birth
• Classified into 2 groups
• Enzymatic
• Deficient or defective acid hydrolases
• Defective metabolism of glycosaminoglycans
• Defective degradation of glycan portion of
  glycoproteins
• Defective degradation of glycogen
• Defective degradation of sphingolipid components
• Defective degradation of polypeptides
• Defective degradation or transport of
  cholesterol, cholesterol esters, or other complex
  lipids
• Absence of crucial activator (M6PR )
• Multiple deficiencies of lysosomal enzymes
• Non-enzymatic
• Transport defects through the lysosomal membrane
• Transport and trafficking defects

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Defect of acid hydrolases enzymes M6PR marker
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Transport and trafficking defects
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Lysosomal storage disorders by affected lysosomal
function
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Lysosomal Storage DiseasesClinical features

• Coarse facial features (sometimes with
  macroglossia)
• Corneal clouding or related ocular
  abnormalities
• Angiokeratoma
• Umbilical/inguinal hernias
• Short stature
• Developmental delays
• Joint or skeletal deformities
• Organomegaly (especially liver and spleen)
• Muscle weakness or lack of control (ataxia,
  seizures, etc.)
• Neurologic failure/decline or loss of gained
  development

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Pathogenesis of clinical features

• Babies with LSD usually appear normal at birth ?
  progressively in the first few years
• lysosomes are each cell's 'recycling centre' ? to
  break down complex material to simple products ?
  recycling within the cell ? to build new complex
  material.

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Radiological features
Metacarpal II-IV taper at proximal Wide and short
metacarpals and phalangs
Thickening of bone skull J shaped sella
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Lysosomal Storage Diseasesbone marrows features
Gaucher
MPS I
Sea-blue histiocytes
Niemann-Pick Cell
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Optimal Path to Diagnosis
Clinical Suspicion
Urgent Referral
Definitive Diagnosis

• Finding of a unique sign or symptom
• Presentation of a cluster of common signs and
  symptoms

• Enzyme assay diagnostic test (gold standard)
• DNA testing

• To a geneticist or metabolic specialist

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Principles of treatment
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Treatable LSDs
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ERT in Pompe diseases
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Current Pharmacologic Therapies
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Clinical Investigational Initiatives
For more current information on investigational
initiatives, visit www.clinicaltrials.gov.
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Chemical chaperones
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Substrate Deprivation Therapy (Trickle-Down
Therapy)

• a)In most individuals the substrate (water) can
  be degraded efficiently by adequate enzyme
  (hole). 
•  b)In affected individuals the amount of enzyme
  is insufficient to degrade the substrate and it
  accumulates.   
• c)In affected individuals treated with substrate
  synthesis inhibitors the amount of substrate is
  decreased to match the amount of residual enzyme
  to prevent accumulation

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Call to Action

• Now that treatments exist for some LSDs, it is
  more important than ever for pediatricians to
• Become more knowledgeable about this family of
  diseases
• Increase the index of suspicion
• Become familiar with local experienced physicians
  and treatment centers

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Thank you