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28 Cards in this Set
- Front
- Back
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Gaucher Disease
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• Most prevalent LSD (1/40,000)
• Ashkenazi Jewish predilection (1/500-1/1000) • Autosomal recessive • Clinical spectrum – Type I – non-neuronopathic (most common) – Type II – acute, neuronopathic – Type III – chronic neuronopathic • Clinical heterogeneity – With same genotype, within family • Diagnosis by enzyme assay of WBC (or other) |
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Gaucher Disease – Clinical features
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• Hepatosplenomegaly
– Mean liver ~2x normal, mean spleen ~20x normal • Thrombocytopenia ! bruising or bleeding • Anemia ! transfusions • Bony lesions ! fractures, pain crises • Aseptic necrosis of hip • Growth retardation • Delayed puberty • Fatigue • Reduced quality of life |
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Avascular necrosis
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Avascular necrosis (also osteonecrosis, bone infarction, aseptic necrosis, ischemic bone necrosis, and AVN) is a disease where there is cellular death (necrosis) of bone components due to interruption of the blood supply. Without blood, the bone tissue dies and the bone collapses. If avascular necrosis involves the bones of a joint, it often leads to destruction of the joint articular surfaces
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Gaucher Type 1: Non-neuronopathic Highly variable phenotype
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• Typically comes to medical attention as painless splenomegaly
• Spleen may not be very large • Usually smooth, mobile, and nontender • Enlargement of the liver and spleen may cause abdominal pain |
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Fabry disease
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• Similar in frequency to Gaucher disease
• X-linked disorder • Variable expression in females • US prevalence estimated at 2000-4000 pts • Deficient α-galactosidase A (α-GAL) activity • Progressive globotriaosylceramide (GL-3) accumulation in tissues • Key affected cell type is vascular endothelium |
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Multisystemic Manifestations of Fabry
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Progressive accumulation of GL-3 causes increasing
involvement of multiple organ systems. Nervous System TIA/stroke pain Ocular Corneal Opacities Skin Hypohidrosis Angiokeratomas Gastrointestinal Diarrhea/Constipation Pain Heart LVH Valvular disease Conduction abnormalities Kidney Proteinuria Renal insufficiency Renal failure |
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Fabry Disease - Diagnosis
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• Clinical diagnosis
• Characteristic signs and symptoms • Family history/medical pedigree • Definitive diagnosis • Males - enzyme assay in plasma, WBC, other • Females - gene mutation or linkage analysis • Screening of males with HCM, renal failure |
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Mucopolysaccharidosis I (MPS I)
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• Incidence ~1/100,000 births
• Deficiency α-L-iduronidase • Progressive accumulation of glycosaminoglycans (GAG) – (heparan and dermatan sulfate) • Multi-systemic, heterogeneous • Spectrum of severity • Significant morbidity and early mortality All patients typically have <1% of normal enzyme levels |
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MPS I - Disease Spectrum
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Hurler -- MPS I H
Hurler-Scheie -- MPS I H/S Scheie -- MPS I S |
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Hurler
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[• Severe mental retardation]
• More progressive disease • Severe respiratory disease • Obstructive airway disease • Death before age 10 years |
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Hurler--Scheie
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NRO CJS HDD
• Little or no intellectual defect • ENT/respiratory disease • Obstructive airway disease • Cardiovascular disease • Joint stiffness/contractures • Skeletal abnormalities • Hernias • Decreased vision and hearing • Death in teens and 20’s |
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Schieie
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NSC JHD
• Normal intelligence • Slowly progressive physical problems • Corneal clouding • Joint stiffness • Valvular heart disease • Death in later decades |
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Eye Disease in MPS I
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• Corneal clouding
• Optic nerve compression • Retinal disease • Glaucoma • Myopia • Blindness is common final outcome |
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MPS II (Hunter Syndrome)
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• X-linked
• No corneal clouding • +/- CNS • Hepatosplenomegaly • Dysostosis multiplex • Connective tissue • Iduronate-2-sulftase deficiency (heparan sulfate) |
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MPS III (Sanfilippo syndrome)
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4DSMM
• 4 subtypes – A, B, C, D (different enzymes, genes) • Developmental delay/behavior problems • Sleep disturbance • Mild coarse features • Mild dysostosis multiplex |
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MPS IV (Morquio syndrome)
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Morkios
• 2 subtypes – A, B (different enzymes, genes) • Severe dysostosis multiplex • Urine excretion of keratan/chondroitin sulf A), keratan sulfate (B) • Motor dysfunction • Normal intelligence • No corneal clouding |
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MPS VI (Maroteaux Lamy)
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NUD CHCCI
• N-acetylgalactosamine 4-sulfatase • Urine excretion of dermatan sulfate • Dysostosis multiplex • Coarse features • Hepatosplenomegaly • Corneal opacities • Connective tissue involvement • Normal intelligence |
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MPS VII (Sly Syndrome)
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DDDUCCH
• Deficiency of β-glucuronidase • Urine excretion of heparan, dermatan, chondroitin sulfate • Dysostosis multiplex • Coarse features • Developmental delay • Hepatosplenomegaly • Corneal opacities |
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Pompe Disease
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Infant (<1% GAA activity)
--Death in first year of life --Cardiomegaly and severe hypertrophy cardiomyopathy --Severe myopathy (hypotonia, muscle weakness) Juveniles and Adults (<1-30% GAA activity) --Onset in childhood to adulthood --Little to no cardiac involvement --Progressive myopathy ***proximal limbs, respiratory muscles ***biopsy may appear normal, but low GAA activity --Outcomes ***May become ventilator-dependent or wheelchair bound |
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Niemann-Pick A and B
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• allelic mutations 11p 15.4-15.1
– Deficiency of acid sphingomyelinase – Hepatosplenomegaly, pulmonary infiltrate – Type A: infantile onset, neuoronopathic – Type B: juvenile onset, min/no neuro sx – Pan ethnic – Severity usually due to residual enzyme activity |
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Niemann-Pick A & B
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• Acid sphingomyelinase (ASM) deficiency
• NPD-A (acute) and NPD-B (chronic) allelic • Phenotypic continuum • Incidence ~1/250,000 • More common in Ashkenazi (A), North African (B), and New Mexico Spanish (B) • Accumulation of sphingomyelin and cholesterol in macrophages of liver, spleen, lung (A and B), and brain (A only) • NPD-A: 3 mutations in Ashkenazi Jews >90% alleles • NPD-B: R608del > 20% alleles |
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Clinical Features of NPD-A
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• Onset of symptoms in first few months of life
• Massive hepatosplenomegaly • Pulmonary infiltration • Cherry red macula seen in 50% • Hypotonia, weakness, feeding difficulty • Neurodegeneration, rarely with seizures • Death by age 3 |
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Clinical Features of NPD-A
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• Onset of symptoms in first few months of life
• Massive hepatosplenomegaly • Pulmonary infiltration • Cherry red macula seen in 50% • Hypotonia, weakness, feeding difficulty • Neurodegeneration, rarely with seizures • Death by age 3 |
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Clinical Features of NPD-B
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• Variable onset from early childhood to adulthood
• Massive hepatosplenomegaly – Liver ~2x normal; spleen ~10x normal • Bleeding, thrombocytopenia • Growth delay, short stature, delayed puberty • Abnormal lipid profiles (low HDL) • Interstitial lung disease, dyspnea on exertion • Little to no neurologic involvement • Death in adulthood from recurrent pulmonary infections |
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Niemann-Pick C and D
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• Allelic mutations NPC1 18q11-12
– NPD Nova Scotia variant • Defect of cholesterol trafficking – dx filipin staining, cholesterol uptake (fibroblasts) • Neuronopathic (wide spectrum) – Ataxia, spasticity, seizures, vertical gaze palsy, dystonia, dementia, little/no hepatosplenomegaly – Death in childhood-adulthood |
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Treatment for LSDs
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Enzyme Replacement Therapy (ERT)
--Gaucher --Fabry --Pompe --MPS I, II, IV, VI Drawbacks: --IV infusions (weekly/biweekly) --Infusion associated reactions/IgE mediated reactions --High antibody titers-can be neutralizing --Poor tissue penetration (bone, kidney, muscle) --No penetration of the blood brain barrier --Most effective for Gaucher Clinical trials --Niemann-Pick B --MPS VII --San Filippo --Acid lipase defiicency |
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Treatment for LSDs (cont'd)
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• Small Molecule Therapy (oral)
– Substrate reduction ** Zavesca ### Gaucher type 3, +/- type I ###Niemann-Pick Type C **GZ-112638 (Eliglustat) ###Gaucher Type I – Chaperone Therapy **Iminosugars ###Fabry: ph 3 ###Gaucher ###Pompe **Pyramethamine ###Late-onset Tay Sachs **Cyclodextran ###Niemann Pick C |
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Newborn Screening for LSDs
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• MS/MS
– Multiplexed • Pompe, Gaucher, Fabry, Krabbe, Niemann-Pick, MPS I • Fluorometric – Single enzyme • Pompe, Fabry • Microfluidics • Protein Quantification |
