Exam 2: Lecture 30 Flashcards
(47 cards)
1
Q
What is an enzyme defect?
A
- an enzyme that converts one substrate into another
- cause disease due to deficiency of a substance you were supposed to make; accumulation of a toxic substance
- defects in transporters or cofactors
2
Q
What are lysosomes
A
- breakdown and recycles a range of complex cellular components
- 70 different hydrolases
- broken down products are transported back to cytosol via transport proteins
3
Q
Describe lysosomal acid hydrolases
A
- function in the acidic environment in the lysosome
- special category of secretory proteins destined for intracellular organelles, not extracellular fluids
- synthesized in the ER and transported to the golgi
-post-translational modification–> attachment of terminal mannose-6 phosphate to oligosaccharide side chains - mannose 6 phosphate is recognized by receptors on the inner surface of golgi –> lysosomal enzyme segregate
- small transport vesicles containing these enzymes are pinched off from golgi and fuse with the lysosome
4
Q
What happens if lysosomal enzyme is not working?
A
- accumulation of macromolecules/metabolites in the lysosome
- large/numerous lysosomes within the cell interfere with normal function
- secondary dysfunction of mito–> production of free radicals and triggers apoptosis (inflammatory response later)
5
Q
Discuss the schematic of gene mutation of lysosomal enzymes
A
1) gene mutation
2) lysosomal enzyme and non-enzymatic lysosomal protein deficiency
3) lysosomal storage
4) steric hinderance
5) cell dysfunction, secondary enzyme deficiency, impairment autophagy; accumulation of toxic proteins and extra lysosomal storage
6) ER and golgi dysfunction; mito dysfunction; plasma membrane dysfunction; neuropathological changes in neurons
7) cellular damage/oxidative distress/ inflammatory response
8) cell death
6
Q
What are lysosomal storage disorders?
A
- cause by a genetic defects in lysosomal acid hydrolyases, or receptor, activator, membrane or transporter proteins
- most autosomal recessive; 3 are x linked
- newborn screening cnaging previoous frequencies
7
Q
Manifestation
A
- depends on what tissue the stored material is founds in and degraded in
- ex. brain: rich in gangliosides, defective hydrolysis of gangliosides leads to mainly neurologic manifestations
- ex. mucopolysaccrides are distributed throughout the body, therefor defective hydrolysis of these lead to widespread features–> hepatomegaly, skeletal abnormalities, and neurological features
8
Q
What is sphingolipidoses?
A
- deficiency of enzymes that break down lipids that contain ceramide; ceramide is found in cellular membrane
- ceramide is composed of sphingosine and FA ( impt for structure and signaling)
- consequences reflect distribution of stored lipid: peripheral tissues–> organomegaly (Gaucher disease); CNS –> neurologic deterioration (Tay Sachs); Both–> organomegaly and neurologic (Niemann-Pick)
9
Q
Tay- SACHs
A
- ganglioside metabolism
- gangliosides: one or more sialic acids linked to sphingolipid–> mostly in nervous system
- caused by deficiency in B -hexosaminidase, the enzyme that degrade GM2 ganglioside (requires HexA and Hex B isoenzymes and activator protein (gm2a)
- degradation of GM2 requires all 3
- problem with HexA gene, so you cannot make the alpha unit, so you cannot breakdown GM2 gangliosides
10
Q
What is the pathology of Tay- Sachs?
A
- GM2 accumulates in neurons and retina
- neurons balloon with lysosomes filled with gangliosides
- progressive destruction of these neurons, proliferation of microglia, and accumulation of complex lipids within brain and retina
- looks red because fovea comparatively looks redder because area in retina looks more white/ milky halo.. loss of retinal transparency (CHERRY RED SPOT)
11
Q
What is the clinical picture of Tay-Sachs?
A
- typically, babies are healthy 6-12 months
- gradual neurological deterioration @ 6-12 months
- developmental; retardation
- motor weakness
- hyperacusis (startled response)
- seizures
- blindness, cherry red spot
- spasticity
- death by 2-5 years, no effective treatment
12
Q
How do you diagnose Tay-Sachs?
A
- enzyme assay
- molecular testing
- gene: HEXA (autosomal recessive)
- increased prevalence in Ashkenazi Jewish population (3 common pathogenic variants)
- founder mutations in Cajun and French Canadians
13
Q
Distinguish the 3 types of Niemann- Pick
A
- 3 different types: A, B,C
- A and B –> deficiency of sphingomyelinase
- A –> severe infantile form with extensive neurologic and somatic involvement
- B–> generally no CNS involvement
- C–> problem with transport if free cholesterol from lysosome to cytoplasm; can present with hydrops fetalis/still birth
14
Q
Type A (Acute infantile form)
A
- deficiency of sphingomyelinase leads to accumulation of sphingomyelin (component of cell and organelle membrane)
- accumulates in mononuclear phagocyte system
- enlarged cells; small vacuoles appear imparting foaminess to the cytoplasm (foamy cells)
- phagocytic foam cells distributed in spleen, liver, lymph nodes, bone marrow, tonsils, GI tract, and lungs
- also have cherry red spots
15
Q
Type A Niemann Pick clinical manifestation
A
- evident by 6 months
- hepatosplenomegaly
- progressive failure to thrive, feeding difficulties
- generalized lymphadenopathy
- progressive neurologic deterioration
- death by 3-4 yrs
16
Q
Type B (non- neuropathic) clinical features
A
- milder, more chronic, non- neuropathic
- hepatosplenomegaly
- growth delay
17
Q
Niemann- pick genetics and diagnosis
A
- diagnosis: enzyme assay and molecular testing
- autosomal recessive
increased prevalence in certain populations - 3 genes acting on 2 pathways
- Type A/B–> sphingomyelin hydrolysis: SMPD1
- Type C: lipid transport–> NPC 1 and NPC2
18
Q
What is the basis of Gaucher?
A
- deficiency of glucocerebrosidase
- accumulation of glucocerebroside within macrophage cells primarily located within reticuloendothelial system (bone marrow, liver, spleen)
- some subtypes also in nervous system
- activation of macrophages and secretion of cytokines contribute to pathogenesis
19
Q
What is the normal function of glucocerebrosidase?
A
- glucocerebrosides are continually formed from catabolism of glycolipids from cell membranes of leukocytes and RBC
- glucocerebrosidase cleaves glucose residues from ceramide
20
Q
What happens when you have a deficiency in glucocerebrosidase?
A
- accumulation of glucocerebroside within macrophage cells primarily located within reticuloendothelial system (bone marrow, liver, spleen)
- some subtypes also in nervous system
- activation of macrophages and secretion of cytokines contribute to pathogenesis
21
Q
What is the pathogenesis of Gaucher?
A
- glucocerebrosides accumulate in massive amounts in phagocytic cells, “Gaucher cells”
- see it in the spleen, liver, bone, lymph nodes, tonsils, etc.
- fibrillary type of cytoplasm looks like “CRUMPLED TISSUE PAPER”
22
Q
What are the three types of Gaucher, based on neurologic involvement?
A
- Type 1: most common, non- neuronopathic–> no neurologic involvement
- Type 2: acute neuronopathic–> infantile cerebral form
- Type 3: Chronic neuronopathic–> starts in adolescence/ adulthood
23
Q
What are the clinical features of Gaucher?
A
- enlarged spleen and liver (hepatosplenomegaly)
- cytopenias causing bruising, bleeding, and fatigue
- liver dysfunction
- bone issues due to expansion of marrow space–> pain and thinner and weaker than normal, fractures
- loss of appetite, intestinal complaints
- CNS dysfunction: progressive neurologic deterioration, seizures
- Parkinson disease: 20x risk of developing
24
Q
Describe the genetics and diagnoses of Gaucher
A
- Gene GBA1
- autosomal recessive
- genetic variant correlated to type of Gaucher
- heterozygotes have increased risk of Parkinson’s disease
- founder mutations in Ashkenazi Jewish, Spanish, Portuguese, Swedish, and Mediterranean populations
- enzyme assay
- molecular testing
25
Mucopolysaccharidoses (MPS)
- deficient degradation of glycosaminoglycans = GAG or mucopolysacchrides =MPS
26
What is a glycosaminoglycan?
- a long chain complex sugar consisting of a repeating disaccharide unit, usually linked to a protein to form proteoglycan
- major constituent of CT ground substance, allowing CT to act as glue for cells attached to matrix
- major GAGs: Dermatan sulfate, Heparan sulfate, Keratan sulfate, Chondroitin sulfate--> MPS occurs by deficiencies of breaking these molecules down
27
Pathophysiology
- GAGs accumulated throughout the body in various cells like phagocytic cells, endothelial cells, intimal smooth muscle cells, and fibroblast
- affected cells are distended with apparent "clearing" of cytoplasm.. looks like little balloons in them, which are vacuoles
28
Clinical feature
- appears normal at birth
- between 6 months and 2 yrs features becomes apparent
- developmental delay or regression
- Hydrocephalus( build-up of CSF in the ventricles)
- hepatosplenomegaly
- skeletal deformities
- valvular lesions
- coarse facial features (storage material builds up in their face)
- corneal clouding
29
Compare and contrast the different types of Mucopolysacchridoses syndromes
- MPS 1: Hurler syndrome --> Classic MPS
- MPS 2: Hunter Syndrome --> no corneal clouding and is X-LINKED
- MPS 3: San Filippo--> primarily neurological disease, kid presents with ADHD and has learning/behavioral problems, neurologic decline
-MPS 4: Morquio--> normal intelligence; may present with short stature (skeletal dysplasia)
- a spectrum of these disorders; where you may not see symptoms until later in childhood or adolescence
30
Describe the Genetics and diagnoses of mucopolysacchridoses
- various genes based on disorders
- all autosomal recessive, except Hunter's (X-linked)
- Diagnosis: enzyme assays, Blood or urine GAG, molecular testing; newborn screening
31
Treatments of lysosomal storage disorders
- enzyme replacement therapy
- substrate reduction
- chaperone therapy
- stem cell transplants
- gene therapy
32
What are glycogen storage diseases?
- can be due to problem forming glycogen or in breaking down glycogen
- glycogenesis vs glycolysis
- cause disease by accumulation of abnormal glycogen molecules
- glycogen depletion
- accumulation of normal structure glycogen
- autosomal recessive
- liver and muscles are commonly involved; hepatic or myopathic form
33
What is glycogen?
- storage form of glucose
- branched polysacchride of glucose
- quick release storage form of glucose
- cannot have free glucose because accumulation would cause uptake of considerable amounts of water to be taken up, leading to cell lysis
34
Describe GSD-1 Von Gierke Disease (distinguish type a from type b)
- deficiency in glucose 6 phosphatase activity (converts glucose 6 phosphate to glucose in gluconeogenesis in liver)
- Type a: caused by mutated enzyme
- Type B: caused by a transport protein that is not working
- both lead to excessive accumulation of glycogen and the inability to release free glucose... so body cannot keep blood sugar up
35
What is the clinical manifestation of GSD-1: Von Gierke Disease?
- hypoglycemia when fasting (after a meal) --> irritability, pallor, feeding difficulties, and seizures (could lead to sudden death)
- hepatomegaly ( no splenomegaly)--> protuberant abdomen --> risk of hepatic adenomas that can lead to hepatocellular carcinoma
- delayed growth, short stature, thin limbs, and a doll face with big cute cheeks
- deficient platelet function, bleeding
- in 1b; neutrophil dysfunction/recurrent infections and GI dysfunctions
36
How is GSD-1: Von Gierke disease diagnosed?
- metabolic acidosis (lactic acidosis), ketosis, hyperuricemia, hyperlipidemia +/- neutropenia
- molecular testing: G6PC1 (GSD1a) or SLC37A4 (GSD1b)
- enzyme testing in liver biopsy
37
What is the treatment of GSD-1: Von Gierke Disease?
- frequent feeds, cornstarch overnight or continuous feeds
- avoid sucrose, galactose, fructose, and more
- liver imaging and blood work
38
GSD- 2: Pompe disease
- lysosomal disease because glycogen is stored in lysosome
- deficiency of alpha 1,4 glucosidase, which breaks down maltose to glucose
- 3 types: infantile, early childhood, and adult
- based on age of onset and severity, which correlates with enzyme activity and amount of lysosomal storage of glycogen
39
What are the clinical manifestations of GSD2: Pompe's disease?
- infantile form: rapidly progressive --> most die in infancy from cardiomyopathy w/o early diagnosis and treatment; glycogen increased in heart, muscle, liver, and kidney, macroglossia (large tongue)
Early childhood form: primarily skeletal muscle (muscle weakness), not cardiac--> slower progression but death by 20 y/o
- Adult form: myopathy--> diaphragmatic weakness and respiratory distress; slowly progressive
40
How can GSD-2 : Pompe's disease be diagnosed?
- lab findings: elevated CK, evidence of muscle issues, urinary oligosaccrides (urinary glucose, tetrasacchride)
- enzyme: leukocytes, muscle or fibroblasts
- molecular: GAA (acid alpha- glucosidase--> causes hydrolysis of 1,4 and 1,6 bonds in glycogen)--> would be absent or reduced
- Newborn screening: GAA enzyme
40
What is the treatment for GSD-2: Pompe's disease?
- enzyme replacement therapy
41
GSD-5: McArdle disease
- defective activity of phorphorylase in muscle, blocking muscle glycogen breakdown to glucose
42
What are the clinical manifestations of McArdle disease?
- muscle cramps and exercise intolerance
- severe myoglobinuria (presence of myoglobin in the urine), increased creatine phosphokinase--> rhabdomyolysis (skeletal muscle breakdown)
- second wind phenomenon--> get muscle pain after they work out, rest and then can go again
- fixed muscle weakness occurs in approx. 25% --> more involved in proximal muscles
- symptoms are present in childhood, most aren't diagnosed until adulthood
43
How is GSD- 5: McArdle disease diagnosed?
- genetic testing of PYGM gene
- enzyme: myophosphorylase enzyme activity in the muscle
44
How is GSD-5: McArdle disease treated?
- moderate- intensity aerobic training to increase cardiorespiratory fitness and muscle oxidative capacity
- pre-exercise ingestion of sports drinks containing simple carbs improves exercise tolerance and may protect against exercise-induced rhabdomyolysis
45
Name lysosomal storage defects
- Tay-Sachs: developmental regression, neurologic only
- Niemann - Pick: somatic changes (Hepatosplenomegaly) +/- neurologic
-Gaucher: Hepatosplenomegaly + bone issues + cytopenias
- MPS:
46
Name glycogen storage defects
- hypoglycemia
- myopathy
- cardiomyopathy
