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biochem_gen
Biochemical Genetics II
| Term | Definition |
|---|---|
| Mitochondria targeting signal | N-terminal amphipathic helix |
| Nucleus targeting signal | internal basic AA di-peptide |
| ER targeting signal | N-terminal hydrophobic peptide; binds signal recongnition particle (SRP) with co-translational import followed by cleavage |
| Lysosome targeting signal | Mannose-6-P (M6P) added post-translationally |
| Peroxisome targeting signal | C-terminal -SKL near N-terminal -RLX5H/QL |
| size of mitochondrial genome | 16,659 bp |
| mutation rate of mitocchondrial genome | 7-10X nuclear |
| copies of mt in cel | 100-1000s |
| mtDNA genes | 37 genes (13 resp chain protein, 2 rRNAs, 22 tRNAs) |
| NuDNA mito-assoc genes | >300 genes (resp chain, mtDNA replication, expression, and repair, antioxidant defense, FE homeostasis) |
| Mitochondrial disease incidence | 1/5000-8000 |
| Mito disease mutations in | nuclear and mt DNA |
| mito disease | affects tissue with high energy demands |
| heteroplasmy | threshold effect |
| Mito disease CNS | hypotonia, ataxia, IDD, seizures, migraines, dementia, snhl |
| Mito disease eyes | RP, optic atrophy, nystagmus, ophthalmoplegia |
| Mito disease muscle | weakness, exercise intolerance, red ragged fibers |
| Mito disease cardiac | HCM, arrhythmias, heart block |
| Mito disease hematologic | macrocytic anemia, pancytopenia |
| Mito disease endocrine | diabetes mellitus, diabetes insipidus, exocrine pancreatic dysfunction, short staturem |
| Mito disease GI | dysfx, intestinal psuedo-obstruction |
| Mito disease liver | dysfx, failure |
| Mito disease renal | RTA, Fanconi syndrome |
| Mt disorders of OxPhos | 80-90% pts have nuclear defects (e- transport chain) AR inheritance |
| Mt disorders of Resp chain assembly factors | mutation in nuc genes ACAD9 (complex 1) SURF1 (complex IV) SCO1&2 (Cu++ homeostasis, complex assembly) |
| Mt neurogastrointestinal encephalomyopathy (MNGIE) | AR defect in TYMP gene (nuclear) |
| CoQ synthesis defects | 5 nuclear genes |
| Leigh syndrome | onset late infancy with regression MRI abnormal with white matter and basal ganglia changes +/- increase in serum lactate |
| Leigh syndrome | 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 |
| Mitochondrial depletion syndrome | AR decrease in ratio mt/nuclear DNA |
| Genes that cause Mito depletion syndrome | POLG1 TK2 DGUOK TWINKLE others |
| Mito depletion syndrome clinical presentation | hepatic failure decrease glucose CNS involvement |
| LHON | adult onset optic neuropathy; mostly hmp missense mutations |
| NARP | Neuropathy, ataxia and RP; mostly heteroplasmic missense mutations in ATP synthase (Complex V) |
| Maternally inherited deafness | point mutations in MT-rRNA; also associated with susceptibility to aminoglycoside ototoxicity |
| mt tRNA mutations cause | MERRF MELAS |
| heteroplasmic point muts in mt tRNA(lys) | MERRF (~80%): myoclonic epilepsy with red ragged fibers |
| heteroplasmic point muts in mt tRNA(leu) | MELAS (most): myoclonic epilepsy with lactic acidosis and stroke |
| mt tRNA mutations pathogenesis | inability to translate several mt proteins and lack of nl processing of transcripts |
| MELAS presentation and genetics | 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 |
| Disorders caused by mtDNA del and/or dup | 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) |
| Lab diagnosis of mt disorders | 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) |
| Treatment of mitochondrial disorders | 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 |
| Congenital Disorders of Glycosylation (CDG) clinical spectrum | CNS, eye, skeletal, skin, clotting, immune system, endocrine, GI, liver, and more |
| Classes of Glycosylation Disorders | N-glycosylation defects (17) O-glycosylation defects (17) Lipid glycosylation defects (3+) Golgi COG (component of oligomeric Golgi) complex proteins (6) dolichol synthesis or recycling (6) |
| N-glycosylation defects | 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 |
| O-glycosylation defects | 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.) |
| Classical PMM2-CDG (Ia) presentation | 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 |
| Classical PMM2-CDG (Ia) genetics | most common CDG (60-70% of pts) AR phosphomannomutase 2 def abnormal transferrin isoelectric focusing |
| MPI-CDG (1b) Mannose-6-phosphate isomerase def | hepatic/GI symptoms with vomiting, GI bleeding, protein loss enteropathy, liver disease, coagulopathy, hepatic fibrosis minimal neurologic involvement treatment: oral mannose |
| SRD5A3-CDG (Iq) Steroid 5-a-3 reductase deficiency | dolichol synthesis defect 1st symptoms at 6 mo - 12 yrs severe IDD, ataxia, cerebellar hypoplasia eye: COLOBOMA, optic atrophy, cataracts, glaucoma, micro-ophthalmia heart defects, liver dysfx, ICTHYOSIS |
| CDG diagnosis | 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 |
| Lysosomes | cytoplasmic organelles that contain ~50 acidic degradative enzymes |
| Lysosomal storage disorders | accum of macromolecules usually degraded stored material may cause enlargement of organs and may be visualized in membrane bound vesicles by EM |
| Lysosomal storage disorders (inheritance) | all are recessive most are autosomal |
| LSDs (progression) | normal at birth; as material accumulates there is a plateau and then regression: progressive and often fatal; there are milder forms |
| LSD classes | 1.Mucopolysaccharidoses 2.Sphingolipidoses 3.Transport disorders 4.Mucolipidoses 5.Glycoprotein 6.Neutral Lipid 7.Glycogen Storage |
| LSD general clinical features | coarse facies; organomegaly (liver, spleen); eye abnormalities (corneal clouding, cherry red spot, optic atrophy, pigmentary retinopathy), skeletal abnormalities, non-immune hydrops |
| LSD general diagnostic approach | serum lysosomal enzymes; blood smear; radiological exam; opthalmologic exam; urine mucopolysaccharides and glycoproteins, bone marrow, biochemical studies of fibroblasts +/-leukocytes; molecular; others dis specific |
| Mucopolysaccharidoses general clinical presentation | 1.normal at birth 2.gradual slowing of dev > regression 3.coarses facies 4.+/- corneal clouding 5.macrosephaly, IDD 6.skeletal (dec ROM, claw hand) 7.dystosis multiplex on x-ray 8.otitis and HI 9.recurrent herniae, thickened mucous 10.late cardiac |
| Hurler syndrome (MPS I) inheritance/incidence | AR (1/100,000) |
| Hurler syndrome (MPS I) presentation | onset 6-12 months, death by 5-10 yrs; milder w/o CNS (Scheie IS) Typical MPS presentation; CORNEAL clouding |
| Hurler syndrome (MPS I)diagnosis | +ve MPS spot test enzyme assay DNA testing |
| Hurler syndrome (MPS I) treatment | 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) |
| Hunter syndrome (MPS II) presentations | prominent deafness NO corneal clouding |
| Hunter syndrome (MPS II) inheritance | X-linked (1/70,000-1/150,000); 20% of pts with complete gene deletion > have more severe IDD |
| Hunter syndrome (MPS II) diagnosis | +ve MPS spot; enzyme assay; females best diagnosed by DNA (may be neg for MPS spot) |
| Hunter syndrome (MPS II) treatment | ERT gives improved somatic function in pts w/ milder disease (reduces visceromegaly and GAG excretion, improves joint mobility, preserves linear growth); no effect on CNS *efficacy of HSCT not proven |
| Sanfilippo syndrome (MPS III) inheritance | AR 4 distinct loci (A and B most common) |
| Sanfilippo syndrome (MPS III) presentations | more CNS, less somatic features onset usually 2-4 yrs, chronic diarrhea, insomnia, szs, aggression prominent |
| Sanfilippo syndrome (MPS III) diagnosis | MPS may be + or -; enzyme assay/DNA |
| Sanfilippo syndrome (MPS III) treatment | none no benefit from HSCT |
| Morquio syndrome (MPS IVA and B) | short-trunk dwarfism with nl IQ; severe odontoid hypoplasia; clinical trials with ERT |
| Maroteaux-Lamy syndrome (MPS VI) | somatic sx may severe; usually nl IQ defects in arylsulfatase B ERT (Naglazyme) |
| Sly syndrome (MPS VII) | severe infantile form; prenatal form with hyrdops/fetal ascites defect in beta-glucuronidase |
| MPS disorders other features | hydrocephalus; obstructive airway disease; difficulty with intubation; excessive secretions; atlantoaxial instability; odontoid hypoplasia; cardiac-valvular, conduction disturbances, EFE, occ cardiomyopathy; pulmonary and systemic hypertension |
| Gaucher disease | most common lysosomal storage disease |
| Gaucher disease (type I) | nonneuronopathic, splenomegaly, pancytopenia, bone pain/lytic bone lesions 1:400 - 1:1000 US AJ |
| Gaucher disease (type II) | acute neuronopathic- rapidly progressive neurologic disease with hepatosplenomegaly all ethnic groups |
| Gaucher disease (type III) | subacute neuronpathic later onset |
| Gaucher disease (diagnostic) | "foam cells" in bone marrow, smear enzyme assay molecular carrier screening in AJ |
| Gaucher disease genetics | GBA (glucoside-b acid) on chr 1 protective allele against CNS: N370S L444P usually type II or III |
| Gaucher disease treatment | splenectomy ERT for type I (no effect on type II substrate reduction therapy (miglustat; D-glu analog) |
| Tay Sachs disease (GM2 gangliosidosis) incidence | AR ~1/100,000 general population ~1/4000 in AJ increased incidence in French Canadians |
| Tay Sachs presentation | classic infantile: onset 6-12 mos loss of milestones, hyperacusis, apathy, cherry red spot later onset of szs, blindness, spasticity death by 2-5 milder juvenile and adult forms |
| Cherry red spot seen in | Tay Sachs Sandhoff Sialidase deficiency Niemann-Pick disease type A GM1 gangliosidosis |
| Tay Sachs molecular defect | hexoseaminidase A (HEXA) |
| Sandhoff disease molecular defect | hexoseaminidase B (HEXB) |
| Tay Sachs/Sandhoff diagnosis | enzyme assay molecular testing |
| treatment | none |
| Tay Sachs + CNS involvement | Sandhoff disease |
| Fabry disease inheritance | X-linked 1/40,000-60,000 males |
| Fabry presentation (males) | median age 9 yrs peripheral neuropathy, acroparesthesias (painful sensation), angiokeratomas, lens/corneal opacities, late renal and cardiovascular disease,chronic lung disease with fibrosis accounts for 1% chr renal failure and 5% cryptogenic stroke |
| Fabry presentation (females) | median age 13 yrs fatigue, stroke, ~10% females develop renal failure, can be detected by slit lamp |
| Fabry diagnosis | enzyme assay (may miss females) heterogeneous mutation analysis (DNA testing best for females) |
| Fabry treatment | dilantin/tegretol for neuropathy; renal transplant; ERT - may decrease pain, GI sx, slow renal disease, does not decrease proteinuria |
| Krabbe disease (Globoid Cell Leukodystrophy) | onset <6 mos, hypotonia, irritability, optic atrophy, occ, macrocephaly, elevated CSF prot; leukodystrophy on MRI |
| Krabbe disease diagnosis | enzyme assay molecular testing of GALC gene pseudodeficiency can complicate prenatal dx and requires sulfatide loading assay |
| Krabbe disease gene | GALC galactosylceramidase |
| Krabbe disease treatment | HSCT has some efficacy in later onset or if performed very early in infantile cases |
| Lysosomal proceesing defects | I-cell disease (Mucolipidosis II) Multiple sulfatase deficiency |
| I cell disease (MLII) gene/inheritance | AR defect in targeting enzymes to lysosome via mannose-6-P (1st step in 2 step Golgi rxn) *MLIII is allelic, milder variant |
| I cell dis presentation | like Hurler may see neonatal or prenatal onset |
| I cell dis diagnosis | increase plasma activity multiple lysosomal enzymes with deficient activity in fibroblasts -ve MPS spot |
| I cell dis treatment | none |
| Lysosomal transport disorders | defect in transport of lysosomal degradation products out of lysosomes |
| Lysosomal transport disorders examples | cystinosis sailic acid storage disease (infantile and adult forms) Niemann-Pick type C (NPC) disease |
| Niemann-Pick type C genetics | AR 1/150,000 NPC1 (95%) and NPC2 (~5%): these play role in intracellular cholesterol trafficking |
| Niemann-Pick type C presentation | infantile form with neonatal jaundice later onset forms with ataxia and progressive dementia, psychosis |
| Niemann-Pick type C diagnosis | nl sphingomyelinase abn lysosomal accumulation of unesterified cholesterol |
| Niemann-Pick type C treatment | clinical trials with drugs to increase cholesterol removal from cells |
| Gaucher cells with defect | macrophages |
| Fabry cells with defect | endothelial cells |
| Tay Sachs cells with defect | neurons |
| ERT for Gaucher (I, III) | Cerezyme, Vpriv |
| ERT for Fabry | Fabrazyme, Replagal |
| ERT for Pompe | Myozyme |
| ERT for Hurler (MPSI) | Aldurazyme |
| ERT for Hunter(MPSII) | Elaprase |
| ERT for Maroteaux-Lamy (MPS VI) | Naglazyme |
| ERT for Lysosomal acid lipase def (Wolman) | Synageva |
| Other therapies for LSDs | 1.substrate reduction 2.enzyme enhancement-chaperone therapy |
| substrate reduction for LSDs | Zavesca (miglustat; Gaucher and others) iminosugar analog of glucose; crosses BBB |
| Perixosomes (features) | ubiquitous (except RBCs) single membrane no nucleic acid several 100/cell |
| Peroxisoms (function) | 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 |
| PEX proteins | biogenesis of peroxisomes (16 proteins) |
| target signals for matrix Px prot | PTS1 - C terminal SKL most common PTS2 - N-terminal membrane unknown |
| Peroxisomal disorders classes | 1.Peroxisome biogenesis disorders 2.Single enzyme defects |
| Px biogenesis disorders | Zellweger syndrome spectrum; Rhizomelic chondrodysplasia punctata (RCDP) |
| Px single enzyme defects | X-linked adrenoleukodystrophy; Refsum disease; 11 others |
| Zellweger syndrome spectrum | combined developmental and metabolic disorders overall ~1/50,000 incidence genetically heterogeneous (12 complementation grps) 50% defects in PEX1 encoding PTS1 receptor includes Zellweger syn, neonatal ADL, infantile Refsum dis |
| Zellweger syndrome presentation | dysmorphic facies, hypotonia, seizures, IDD, neuronal heterotopias, cataracts and/or glaucoma, renal cysts, 50% with epiphyseal calcifications early death by 6-12 months |
| Zellweger syn diagnosis | all peroxisomal functions abn no peroxisomes or ghost membranes seen by EM biochemical then molecular |
| RCDP incidence | 1/100,000 |
| RCDP presentation | skeletal dysplasia, cataracts, ichthyotic skin rash, IDD, occ CHD, cleft palate |
| RCDP gene | PEX7 encodes PTS2 receptor (most common cause) |
| RCDP diagnosis | low plasmalogens, elevated phytanic acid |
| X-linked adrenoleukodystrophy | progressive x-linked neurodegenerative disorder assoc w/ adrenal involvement |
| X-linked ALD penetrance | ~1/20,000 |
| X-linked ALD presentation | highly variable childhood cerebral-childhood onset, rapid progression adrenomyeloneuropathy (AMN) - onset 20's - 30's with spastic parparesis adrenal only |
| X-linked ALD presentation (female) | ~50% het female carriers develop mild neurological sx in adulthood 20% gait and spinal cord involvement like AMN |
| X-linked ALD genetics | ABCD1 gene encodes ABC transporter in the peroxisome membrane no geno/pheno corr (some males with sx and other assymp in same family) defective metabolism of VLCFA |
| X-linked ALD diagnosis | VLCFA molecular esp in females |
| X-linked ALD treatment | HSCT early in course for males as soon as MRI changes noted corticosteroids for adrenal insufficiency |
| X-linked ALD diagnosis | T1 MRI with gadolinium inflammatory demyelination with perivascular infiltration |
| Zellweger spectrum | increase VLCFA decrease plasmalogens inrease plasma pipecolic acid |
| RCDP | decrease plasmalogens VLCFA normal |
| Refsum disease presentation | cerebellar ataxia, polyneuropathy and RP, elevated CSF protein |
| Refsum disease genetics | AR deficiency of phytanoyl-CoA hydroxylase |
| Refsum disease diagnosis | increase phytanic acid molecular testing |
| Refsum disease treatment | phytanic acid-restricted diet |
| Px clinical features (suggestive) | FTT, DD hypotonia, cerebral atrophy, decreased myelination, neuronal heterotopia dysmophia cataracts, glaucoma, RP chondropdysplasia punctata, hepatomegaly, renal cysts |
| Laminopathies genes | LMNA, LMNB2, LMNB1 |
| Laminopathies disorders (LMNA) | Hutchinson-Gilford progeria Emery-Dreifuss muscular dystrophy Mandibuloacral dyspasia Generalized lipodystrophy Restrictive dermopathy |
| Niemann-Pick Disease, types A and B genetics/inheritance | AR deficiency of acid sphingomyelinase increase in AJ (carrier freq 1:60) |
| Neimann-Pick dis presentation | neurodegenerative with spleen > liver cherry red spot (~50% type A); pulmonary (type B) |
| Neimann-Pick diagnosis | enzyme assay molecular sea blue histiocytes in marrow |
| Neimann-Pick treatment | none |
| GM1 gangliosidosis presentations | somatic + CNS affected hypotonia, szs, MR ~50% have cherry red spot milder juvenile and adult forms exist |
| GM1 gangliosidosis diagnosis | foamy histiocytes in bone marrow enzyme assay of beta-galactosidase (GLB1 gene) |
| Tay Sachs serum screening | pregnancy, oral contraceptives and some illness can make test inconclusive |
| Metachromatic Leukodystrophy presentation | late infantile - most pts walk, regression before age of 2; white matter changes, elevated CSF prot |
| Metachromatic Leukodystrophy gene | arylsulfatase A (ARSA) inheritance is AR |
| Metachromatic Leukodystrophy diagnosis | enzyme assay psudodeficiency (2 singl bp changes) |
| Glycoprotein disorders | mannosidosis, aspartylglycosaminuria (AGU), sialidosis, fucosidosis |
| Glycoprotein disorders presentation | like mild/mod MPS; fucosidosis has false + sweat test & andiokeratomas; congenital form of sialidosis with fetal ascites |
| Glycoprotein disorders diagnossis | MPS spot -ve enzyme assay characteristic urine oligosaccharides |
| AGU | common in Finland (C163S in 95% of Finnish alleles) |
| Multiple sulfatase deficiency presentation | like severe MPS + ichthyosis, mild skeletal |
| Multiple sulfatase def gene/inheritance | AR SUMF1 gene (sulfatase modifying factor 1) def of formylglycine enzyme (catalyzes posttranslational modification of conserved cys in all sulfatases) very rare |
| Multiple sulfatase def dx | +ve urine MPS, enzyme assays molecular |
| Farber lipogranulomatosis (ceramide def) | very rare painful deformed joints + subcutaneous nodules IDD |
| Acid lipase def (Wolman) | GI disorder with hepatosplenomegaly FTT adrenal Ca++ mild variant is cholesterol ester storage disease |
| Schindler disease | progressive IDD, blindness, szs, hypotonia, a rare cause of neuraxonal dystrophy due to deficiency in lysosomal N-acetylgalactosaminidase |
| Pycnodysostosis | skeletal dysplasia, defect in lysosomal cathepsin K |
| Sphingolipid activator protein (SAPs) | small proteins that interact with some lys hydrolases to stabilize them or stimulate activity |
| Other single gene Px disorders | Px beta oxidation disorders Ether phospholipid synthetic defects (resemble RCDP) Mevalonate kinase - classic & hyper IgD periodic fever Catalase deficiency - oral ulcers Glyoxylate detoxification - hyperoxaluria type I |
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