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17 Cards in this Set
- Front
- Back
Mucopolysaccharidoses
(General) |
- Mucopolysaccharides or glycosaminoglycans (GAG). Macromolecules- structural integrity of extracellular matrix w/ varied tissue involvement & cells (mast cells & neutrophils) & plateletes
- Enzyme defect results in tissue accumulation & urine excretion Clinical features: - Chronic & Progressive Course - Multisystem involvement - Organomegaly - Dysostosis Multiplex - Abnormal facies Diagnosis: - GAGS Urinary age dependent (present in normal infants up to 1 year) Normal urine contains mostly chondroitin sulfate, with small amounts of heparan and dermatan sulfate Screening tests qualitative and quantitative analysis - Amniotic fluid - Enzyme assays Prenatal Cultured cells from amniotic fluid Chorionic villous biopsy is less suitable because normal villi have low enzyme activity Postnatal measure enzyme activity in plasma or leukocytes Enzyme activity from skin fibroblast |
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Hurler
MPS I |
- α-1-iduronidase deficiency
- Lysosomal accumulation of GAGS (heparin & dermatan sulfate) - Autosomal recessive Onset in early infancy 6-8 months Death usually before ten years of age Clinical features: - respiratory - skeletal - cardiovascular - ocular Corneal clouding Retinal disease Glaucoma Results in blindness - neurologic: storage in neurons, macrophages & meninges Mental retardation Hydrocephalus Headaches Spinal cord compression Thicken leptomeninges - course facial features - alder-reilley anomaly Accumulation of course material in neutrophils |
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Hunter
MPS II |
- Deficiency in iduronate sulfatase
- Accumulation of heparin & dermatan sulfates - X-linked - Similar to Hurler syndrome but less severe - appear in late infancy & early childhood - lack corneal clouding - slower progression of somatic & CAN involvement than Hurler disease - Stacks of lipid profiles |
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Spingolipidoses
(General) |
- Membrane lipids
Phospholipids, cholesterol spingolipids |
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Niemann-Pick Disease
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Types I (A and B) caused by deficiency of
sphingomyelinase -> progressive accumulation of spingomyalin (ubiquitous component of cellular and organellar membranes) Type II (C & D) - foamy bubble looking cells - swirls lysosomes |
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Type A (severe infantile)
Spingolipidoses |
- 70 -80%
- first weeks of life Clinical features: - hypotonia - failure to thrive - Severe neurodegenerative course - 50 % will have macular cherry red spot - marked visceral accumulation of sphingomyelin - death within 3 years |
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Type B (chronic visceral)
Spingolipidoses |
- No CNS involvement
- Present with splenomegaly and ultimately develop generalized visceral involvement |
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Type C
Spingolipidoses |
- Defect involves NPC-1 (95%) and NPC 2 genes
which code for a protein involved in lipid transport (free cholesterol from the lysosomes cytoplasm) - More common than type I ( A and B combined) - Cholesterol accumulates in affected cells of the spleen, liver, bone marrow and accumulation of cholesterol in neurons ultimately causes destruction Clinical features: - Variable - Classic phenotype (neurovisceral) Presents in childhood Variable hepatosplenomegaly Vertical supranuclear opthalmoplegia (supranuclear palsy) Progressive ataxia Psychomotor regression Hydrops fetalis and stillbirth Fatal neonatal liver disease “giant cell hepatitis” Adult presentation with psychosis and dementia |
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Type D
Spingolipidoses |
variant of type C patients appear to be
less severely affected, Nova Scotia |
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Gangliosidoses
(General) |
- Autosomal recessive
- Normal component of cell membranes particularly neurons |
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GM1 Gangliosidoses
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- Β- Galactosidase deficiency
- Accumlation of ganglioside in neurons - in other sites - 3 isoenzymes A,B,C Type I: virtual absence of all three isoezymes Type II: Absence of A,B isoenzymes - clinical variability depends on amount of residual enzyme activity - Transcription of β- galactosidase requires an activator which may also be deficient & thus cause similar features Type I (Generalized gangliosidosis): infantile, birth to 6 months Type II (juvenile): later onset 1-2 years Clinical features: Type I: - neurodegeneration - accumulation of gangliosides in neurons, liver, spleen, and renal tubular epithelium, macular “cherry red spots” - Skeletal deformities Features of both neurolipidoses & mucopolysaccharidoses “pseudo-Hurler phenotype” Type II: - slower progressive psychomotor retardation - less visceromegaly - milder skeletal disease - death occurs by age 3-10 years Diagnosis: Lab studies Measurement of β galactosidase activity in peripheral blood leukocytes Type I: virtually no enzyme activity Type II: 5-10% activity Peripheral blood smear: vacuolization of lymphocytes (crude method as many lysosomal storage diseases may have this feature) |
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GM2 Gangliosidoses
Tay-sachs α Sandhoff diseases β GM2activator deficiency |
- Inability to catabolize GM2 ganglioside which requires 3 poypeptides (αβ active enzyme complex + activator) encoded by 3 separate loci
- Phenotypic effects are similar bc they are all result in accumulation of GM2 ganglioside GM2 ganglioside accumulates in many tissues (CNS & retinal represent the dominant features of the disease) Clinical features: - loss of motor skills at 3-6 months - macular cherry red spot - progressive neurodegeneration, seizures, blindness and death by 2-4 yrs of age - Ashkenazi Jewish decent carrier rate 1/30 |
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Metachromatic Leukodystrophy
(Sulfatidoses) |
- Deficiency of Arylsulfatase A
- characterized by accumulation of non-degradable (cerebroside sulfate) - white matter of brain - peripheral nerves - liver, kidney - causes breakdown of myelin sheaths which leads to demyelination & gliosis - Primarily a neurodenerative disorder Clinical features: Three types: • late infantile (most common form): present with regression of motor skills,mental deterioration, rigidity and convulsions, unusual loss of white matter on CNS imaging -> death before 5 years • juvenile: change in gait, cognitive skills, and progressive regression of all skills death 6-8 years after diagnosis • adult onset: psychiatric or cognitive symptoms, with motor symptoms occurring later Diagnosis: Urine -spot screening test -> confirms the presence of sulfatides -Quantitative measurement Imaging studies: unusual loss of white matter due to demyelination Biopsy (usually of a sural nerve): demyelination and metachromatic granules -PAS + -Alcian blue -Acidified Crystal violet Arylsulfatase A activity levels Genetic testing (gene located on long arm of chromosome 22) |
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Multiple sulfatase deficiency
(Sulfatidoses) |
Deficiency of arylsulfatase A,B,C as well as other sulfatases
Combined clinical features of metachromatic leukodystrophy & mucopolysaccaridosis |
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Gaucher Disease
Type I |
Defect in glucocerebrosidase
Type I: - chronic non-neuropathic form, most common (99%) - reduced levels of glucocerebrosidase - Children & adults - Ashkenzai Jewish Clinical features: Type I: Accumulation of glucocerebroside limited to mononuclear phagocytes throughout the body, without brain involvement - splenomegaly/hepatomegaly -cytopenias secondary to hypersplenism & bone involvement - Bone involvement • Avascular necrosis esp of hip • Osteopenia w/ fractures • Lytic lesion • Bone crises: occur when collections of Gaucher cells interfere w/ vascularization causing severe pain Erlenmeyer flask deformity: abnormality in new bone formation resulting in flattened ends of femurs |
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Gaucher Disease
Type 2 |
Defect in glucocerebrosidase
Type 2: - Acute, neuropathic form - no predilection for Ashkenazi Jewish (panethic) - Absent glucocerebrosidase progressive CNS involvement with death at an early age (usually by 2 years of age) Hepatomegaly/splenomegaly cytopenias secondary to hypersplenism |
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Gaucher Disease
Type 3 |
Defect in glucocerebrosidase
Type 3: - subacute, intermediate, juvenile form - reduced glucocerebrosidase progressive CNS involvement beginning in teens and twenties Hepatomegaly / splenomegaly cytopenias secondary to hypersplenism bone involvement |