Biochemical Genetics II
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| show | N-terminal amphipathic helix
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| Nucleus targeting signal | show 🗑
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| ER targeting signal | show 🗑
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| Lysosome targeting signal | show 🗑
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| show | C-terminal -SKL
near N-terminal -RLX5H/QL
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| size of mitochondrial genome | show 🗑
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| show | 7-10X nuclear
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| copies of mt in cel | show 🗑
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| show | 37 genes (13 resp chain protein, 2 rRNAs, 22 tRNAs)
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| NuDNA mito-assoc genes | show 🗑
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| Mitochondrial disease incidence | show 🗑
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| show | nuclear and mt DNA
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| mito disease | show 🗑
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| heteroplasmy | show 🗑
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| Mito disease CNS | show 🗑
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| show | RP, optic atrophy, nystagmus, ophthalmoplegia
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| show | weakness, exercise intolerance, red ragged fibers
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| Mito disease cardiac | show 🗑
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| Mito disease hematologic | show 🗑
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| Mito disease endocrine | show 🗑
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| Mito disease GI | show 🗑
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| show | dysfx, failure
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| Mito disease renal | show 🗑
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| show | 80-90% pts have nuclear defects (e- transport chain)
AR inheritance
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| Mt disorders of Resp chain assembly factors | show 🗑
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| show | AR
defect in TYMP gene (nuclear)
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| show | 5 nuclear genes
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| Leigh syndrome | show 🗑
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| show | heterogeneous with nuclear & mt mutations
~50% SURF1 (inv assembly cyt oxidase, comple IV)
PDH mutations
Complex I,II,IV def
NARP mt DNA mut
mt DNA depletion
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| show | AR
decrease in ratio mt/nuclear DNA
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| show | POLG1
TK2
DGUOK
TWINKLE
others
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| Mito depletion syndrome clinical presentation | show 🗑
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| LHON | show 🗑
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| show | Neuropathy, ataxia and RP;
mostly heteroplasmic missense mutations in ATP synthase (Complex V)
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| show | point mutations in MT-rRNA; also associated with susceptibility to aminoglycoside ototoxicity
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| mt tRNA mutations cause | show 🗑
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| heteroplasmic point muts in mt tRNA(lys) | show 🗑
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| heteroplasmic point muts in mt tRNA(leu) | show 🗑
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| show | inability to translate several mt proteins and lack of nl processing of transcripts
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| show | episodes of metabolic decompensation assoc/ w/ high risk for stroke;
acute rx to Arg;
3243A>G tRNA(Leu) 80%
3271T>C tRNA(Leu)7%
heteroplasmic
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| show | Diabetes and deafness; Pearson syndrome (anemia, 2ndary marrow failure, lactic acidosis, exoncrine pancreatic failure, RTA);
CPEO (chronic progressive external ophthalmoplegia);Kearns-Sayre (PEO,cardiac conduction block,RP,ataxia,lacticacidosis,sporadic)
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| show | increase ratio of lactate to pyruvate or vice versa(peripheral, CNS);
inrease of alanine;
Brain MRI;
Muscle and/or liver biopsy;
OxPhos analysis (+enzyme assays)
Molecular testing (mt/nuclear DNA, exome)
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| show | symptomatic for involved organs;
carnitine, coenzyme Q10, riboflavin (comp 1 and 2), antioxidants (vit C, K deravitives)
L-arg for MELAS to reduce stroke risk;
diet manipulation
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| show | CNS, eye, skeletal, skin, clotting, immune system, endocrine, GI, liver, and more
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| Classes of Glycosylation Disorders | show 🗑
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| show | amide linkage to Aspargine
N-glycan assembly ER or cytosol; sugars transferred en bloc from dolichol; processing in ER or Golgi
~50% of all known proteins have 1+ N-gly site
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| show | linkage through -OH on Ser or Thr; transfer single sugars onto growing glycan backbone
includes ABO blood grps, exostoses 1&2 proteins; proteoglycans (with skeletal & connective tissue sx), some congenital muscular dystrophies (POMT1&2, Fukutin, etc.)
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| show | Multisystem disorder: 1.hypotonia, IDD, szs, ataxia (cerebellar hypoplasia) 2. RP,strabismus 3.liver disease, coagulopathy 4.FTT, inverted nipples, lipodystrophy 5.death <1yrs to adulthood w/ range of cognitive skills
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| show | most common CDG (60-70% of pts)
AR
phosphomannomutase 2 def
abnormal transferrin isoelectric focusing
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| show | hepatic/GI symptoms with vomiting, GI bleeding, protein loss enteropathy, liver disease, coagulopathy, hepatic fibrosis
minimal neurologic involvement
treatment: oral mannose
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| SRD5A3-CDG (Iq) Steroid 5-a-3 reductase deficiency | show 🗑
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| show | transferrin isoelectric focusing (N-linked only)
mass spec protein(Tf, apoCIII,...) and urine (N and O linked disorders)
false positives (in <30 day old): galactosemia, HFI, recent EtOH use, liver dis, hemolytic uremic syn, Tf prot polymorphisms
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| show | cytoplasmic organelles that contain ~50 acidic degradative enzymes
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| show | accum of macromolecules usually degraded
stored material may cause enlargement of organs and may be visualized in membrane bound vesicles by EM
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| Lysosomal storage disorders (inheritance) | show 🗑
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| show | normal at birth; as material accumulates there is a plateau and then regression: progressive and often fatal; there are milder forms
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| LSD classes | show 🗑
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| show | coarse facies; organomegaly (liver, spleen); eye abnormalities (corneal clouding, cherry red spot, optic atrophy, pigmentary retinopathy), skeletal abnormalities, non-immune hydrops
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| show | serum lysosomal enzymes; blood smear; radiological exam; opthalmologic exam; urine mucopolysaccharides and glycoproteins, bone marrow, biochemical studies of fibroblasts +/-leukocytes; molecular; others dis specific
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| Mucopolysaccharidoses general clinical presentation | show 🗑
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| show | AR (1/100,000)
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| show | onset 6-12 months, death by 5-10 yrs;
milder w/o CNS (Scheie IS)
Typical MPS presentation; CORNEAL clouding
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| show | +ve MPS spot test
enzyme assay
DNA testing
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| show | HSCT transplantation with match donor (slows disease if performed early but no effect on skeletal sx, corneal clouding
ERT- improved somatic sx, no effect on CNS
(ERT before HSCT)
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| show | prominent deafness
NO corneal clouding
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| Hunter syndrome (MPS II) inheritance | show 🗑
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| show | +ve MPS spot; enzyme assay;
females best diagnosed by DNA (may be neg for MPS spot)
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| Hunter syndrome (MPS II) treatment | show 🗑
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| show | AR
4 distinct loci (A and B most common)
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| Sanfilippo syndrome (MPS III) presentations | show 🗑
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| show | MPS may be + or -; enzyme assay/DNA
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| Sanfilippo syndrome (MPS III) treatment | show 🗑
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| Morquio syndrome (MPS IVA and B) | show 🗑
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| Maroteaux-Lamy syndrome (MPS VI) | show 🗑
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| show | severe infantile form; prenatal form with hyrdops/fetal ascites
defect in beta-glucuronidase
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| MPS disorders other features | show 🗑
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| Gaucher disease | show 🗑
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| Gaucher disease (type I) | show 🗑
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| show | acute neuronopathic- rapidly progressive neurologic disease with hepatosplenomegaly
all ethnic groups
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| Gaucher disease (type III) | show 🗑
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| Gaucher disease (diagnostic) | show 🗑
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| show | GBA (glucoside-b acid) on chr 1
protective allele against CNS: N370S
L444P usually type II or III
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| show | splenectomy
ERT for type I (no effect on type II
substrate reduction therapy (miglustat; D-glu analog)
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| Tay Sachs disease (GM2 gangliosidosis) incidence | show 🗑
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| Tay Sachs presentation | show 🗑
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| show | Tay Sachs
Sandhoff
Sialidase deficiency
Niemann-Pick disease type A
GM1 gangliosidosis
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| show | hexoseaminidase A (HEXA)
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| Sandhoff disease molecular defect | show 🗑
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| Tay Sachs/Sandhoff diagnosis | show 🗑
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| treatment | show 🗑
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| show | Sandhoff disease
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| show | X-linked
1/40,000-60,000 males
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| Fabry presentation (males) | show 🗑
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| Fabry presentation (females) | show 🗑
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| show | enzyme assay (may miss females)
heterogeneous mutation analysis (DNA testing best for females)
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| Fabry treatment | show 🗑
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| show | onset <6 mos, hypotonia, irritability, optic atrophy, occ, macrocephaly, elevated CSF prot; leukodystrophy on MRI
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| Krabbe disease diagnosis | show 🗑
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| Krabbe disease gene | show 🗑
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| Krabbe disease treatment | show 🗑
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| Lysosomal proceesing defects | show 🗑
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| show | AR
defect in targeting enzymes to lysosome via mannose-6-P (1st step in 2 step Golgi rxn)
*MLIII is allelic, milder variant
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| show | like Hurler
may see neonatal or prenatal onset
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| I cell dis diagnosis | show 🗑
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| I cell dis treatment | show 🗑
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| Lysosomal transport disorders | show 🗑
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| show | cystinosis
sailic acid storage disease (infantile and adult forms)
Niemann-Pick type C (NPC) disease
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| show | AR
1/150,000
NPC1 (95%) and NPC2 (~5%): these play role in intracellular cholesterol trafficking
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| show | infantile form with neonatal jaundice
later onset forms with ataxia and progressive dementia, psychosis
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| Niemann-Pick type C diagnosis | show 🗑
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| Niemann-Pick type C treatment | show 🗑
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| show | macrophages
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| Fabry cells with defect | show 🗑
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| Tay Sachs cells with defect | show 🗑
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| ERT for Gaucher (I, III) | show 🗑
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| show | Fabrazyme, Replagal
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| show | Myozyme
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| ERT for Hurler (MPSI) | show 🗑
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| ERT for Hunter(MPSII) | show 🗑
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| show | Naglazyme
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| ERT for Lysosomal acid lipase def (Wolman) | show 🗑
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| show | 1.substrate reduction
2.enzyme enhancement-chaperone therapy
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| substrate reduction for LSDs | show 🗑
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| Perixosomes (features) | show 🗑
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| show | degredation of VLCFA
early steps of plasmalogen biosynthesis
degredation of phytanic acid
selected steps in chol biosynthesis
degradation of pipecolic acid, synthesis of bile acid intermediated, glyoxylate metabolism
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| show | biogenesis of peroxisomes (16 proteins)
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| show | PTS1 - C terminal SKL most common
PTS2 - N-terminal
membrane unknown
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| Peroxisomal disorders classes | show 🗑
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| show | Zellweger syndrome spectrum;
Rhizomelic chondrodysplasia punctata (RCDP)
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| Px single enzyme defects | show 🗑
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| Zellweger syndrome spectrum | show 🗑
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| Zellweger syndrome presentation | show 🗑
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| show | all peroxisomal functions abn
no peroxisomes or ghost membranes seen by EM
biochemical then molecular
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| show | 1/100,000
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| show | skeletal dysplasia, cataracts, ichthyotic skin rash, IDD, occ CHD, cleft palate
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| RCDP gene | show 🗑
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| show | low plasmalogens, elevated phytanic acid
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| show | progressive x-linked neurodegenerative disorder assoc w/ adrenal involvement
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| X-linked ALD penetrance | show 🗑
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| show | highly variable
childhood cerebral-childhood onset, rapid progression
adrenomyeloneuropathy (AMN) - onset 20's - 30's with spastic parparesis
adrenal only
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| X-linked ALD presentation (female) | show 🗑
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| X-linked ALD genetics | show 🗑
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| show | VLCFA
molecular esp in females
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| X-linked ALD treatment | show 🗑
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| X-linked ALD diagnosis | show 🗑
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| Zellweger spectrum | show 🗑
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| show | decrease plasmalogens
VLCFA normal
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| Refsum disease presentation | show 🗑
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| Refsum disease genetics | show 🗑
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| Refsum disease diagnosis | show 🗑
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| Refsum disease treatment | show 🗑
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| Px clinical features (suggestive) | show 🗑
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| Laminopathies genes | show 🗑
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| show | Hutchinson-Gilford progeria
Emery-Dreifuss muscular dystrophy
Mandibuloacral dyspasia
Generalized lipodystrophy
Restrictive dermopathy
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| Niemann-Pick Disease, types A and B genetics/inheritance | show 🗑
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| Neimann-Pick dis presentation | show 🗑
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| show | enzyme assay
molecular
sea blue histiocytes in marrow
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| show | none
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| show | somatic + CNS affected
hypotonia, szs, MR
~50% have cherry red spot
milder juvenile and adult forms exist
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| show | foamy histiocytes in bone marrow
enzyme assay of beta-galactosidase (GLB1 gene)
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| show | pregnancy, oral contraceptives and some illness can make test inconclusive
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| show | late infantile - most pts walk, regression before age of 2; white matter changes, elevated CSF prot
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| Metachromatic Leukodystrophy gene | show 🗑
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| Metachromatic Leukodystrophy diagnosis | show 🗑
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| show | mannosidosis, aspartylglycosaminuria (AGU), sialidosis, fucosidosis
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| show | like mild/mod MPS; fucosidosis has false + sweat test & andiokeratomas; congenital form of sialidosis with fetal ascites
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| show | MPS spot -ve
enzyme assay
characteristic urine oligosaccharides
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| show | common in Finland (C163S in 95% of Finnish alleles)
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| Multiple sulfatase deficiency presentation | show 🗑
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| show | AR
SUMF1 gene (sulfatase modifying factor 1)
def of formylglycine enzyme (catalyzes posttranslational modification of conserved cys in all sulfatases)
very rare
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| show | +ve urine MPS,
enzyme assays
molecular
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| show | very rare
painful deformed joints + subcutaneous nodules
IDD
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| show | GI disorder with hepatosplenomegaly
FTT
adrenal Ca++
mild variant is cholesterol ester storage disease
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| show | progressive IDD, blindness, szs, hypotonia, a rare cause of neuraxonal dystrophy due to deficiency in lysosomal N-acetylgalactosaminidase
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| Pycnodysostosis | show 🗑
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| Sphingolipid activator protein (SAPs) | show 🗑
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| Other single gene Px disorders | show 🗑
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amrs
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