Term
| Characteristics of Lysosomal Storage Diseases |
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Definition
- Deficiency of one or more of the lysosomal hydrolases leads to inability to break down particular macromolecule
- Abnormal intracellular accumulation of undigested material
- Site of storage depends on normal distribution of substrate
- Progressive clinical course - born normal; progressive regression
- Recessive inheritance
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Term
| I-Cell (Inclusion Cell) Disease |
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Definition
- Autosomal recessive deficiency of N-acetylglucosamine-phophotransferase
- Functional deficiency of multiple lysosomal enzymes intracellulary
- Rapid progressive course, including coarse facial features and severe psychomotor retardation
- Death by age 5-7 years
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Term
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Definition
- Inherited disorder where a sphingolipid is stored because of missing activity of a particular lysosomal enzyme
- Ceramide - common building block of sphingolipids =
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Term
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Definition
Derived from sphingosine (fatty alcohol)
Sphingosine + fatty acid = ceramide
Cermaide + sugar residue(s) = glycolipid
Specific glycolipids
- Cerebrosides - ceramide + monosugar
- Sulfatides - sulfated cerebroside
- Gangliosides - complex glycolipid with n-acetyl neuraminic acid component
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Term
| Normal Lysosomal Structure and Function |
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Definition
- Single membrane-bound organelles
- Contain hydrolytic (degradative) enzymes
- Acidic pH; pH optima of enzymes around 4-6
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Term
| Macromolecules Degraded in Lysosomes |
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Definition
Sphingolipids - Gangliosides
- Cerebrosides
- Sulfatides
Mucopolysaccharides (Glycosaminoglycans) Oligosaccharides
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Term
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Definition
- Abnormal storage of GM2 ganglioside (present mainly in brian, important components of normal membranes)
- Deficiency of hexosaminidase A (Hex A) activity
- Mutations in hex A alpha-chain gene
- Carrier frequency among Ashkenazi Jews is ~1/30
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Term
| Characteristics of Tay-Sachs Disease |
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Definition
Clinical and molecular heterogeneity Infantile form: - "Startle reaction" to sharp noises
- "Cherry red spot" on retina
- Deterioration post one year leading to paralysis, blindness, hearing loss, large head, seizures, death by around 2-4 years
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Term
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Definition
Abnormal storage ofGlucocerebroside in reticuloendothelial cells (macrophages) Three clinical types: -Type 1: Non-neuronopathic -Type 2: Acute neuronopathic -Type 3: Subacute neuronopathic All forms characterized by deficient activity of beta-glucocerebrosidase (beta-glucosidase)
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Term
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Definition
- Carrier frequency among Ashkenazi Jews estimated at 1/10
- No neurologic involvement
- Hepatosplenomegaly, pancytopenia, bone involvement, presenting at any age
- Enzyme replacement therapy available
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Term
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Definition
Long, unbranched polysaccharide chains of repeating disaccharide units Components of cartilage, extracellular matrix, bone, specific tissue distribution. Three major forms stored in disease: -Dermatan sulfate -Heparan sulfate -Keratan sulfate Heterogeneious group of disorders where MPS are stored in lysosomes
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Term
| Clinical features seen in disorders where MPS are stored in lysosomes |
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Definition
Clinically variable; some or all of these features can be seen: -Skeletal changes (dysotosis multiples) -Organomegaly -Corneal clouding -Coarse facial features -Progressive mental retardation
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Term
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Definition
Autosomal recessive inheritance
Excretion of dermatan and heparan sulfate
Two distinct phenotypes:
Hurler syndrome (MPS 1A) - severe Sheie syndrome (MPS 1B) - mild disorder, no MR Deficient activity of alpha-iduronidase
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Term
MPS Type II (Hunter Syndrome) |
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Definition
- X-Linked Recessive Inheritance
- Excretion of dermatan sulfate and heparan sulfate
- Phenotype similar to Hurler syndrome without corneal clouding
- Deficient activity of iduronate sulfatase
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Term
MPS III (Sanfilippo Syndrome) |
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Definition
- Types A, B, C, D
- four different enzymes involved in breaking down heparan sulfate
- deficiency in any of these results in MPS III - San Filipo syndrome
- clinically, all four are similar - same material stored
- Classic example of genetic (locus) heterogeneity
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Term
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Definition
- Only MPS disorder storing Keratan Sulfate.
- Two subtypes caused by deficiencies to two different enzymes
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Term
MPS VI (Maroteaux-Lamy Syndrome) |
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Definition
- Deficient activity of arylsulfatase B enzyme leading to storage of dermatan sulfate.
- Similar clinically to MPS IH but no mental retardation
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Term
| Evaluation of Suspected Lysosomal Storage Disorder |
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Definition
Clinical history, progression Family history Clinical exam, X-rays, neurologic evaluation, CT/MRI Lab Screeing: -MPS spot test/TLC -Oligosaccharide screen ENZYME DIAGNOSIS -Molecular testing to find mutation if possible
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