Biochemical Genetics II
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| Mitochondria targeting signal | N-terminal amphipathic helix
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| Nucleus targeting signal | internal basic AA di-peptide
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| ER targeting signal | N-terminal hydrophobic peptide; binds signal recongnition particle (SRP) with co-translational import followed by cleavage
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| Lysosome targeting signal | Mannose-6-P (M6P) added post-translationally
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| Peroxisome targeting signal | C-terminal -SKL
near N-terminal -RLX5H/QL
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| size of mitochondrial genome | 16,659 bp
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| mutation rate of mitocchondrial genome | 7-10X nuclear
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| copies of mt in cel | 100-1000s
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| mtDNA genes | 37 genes (13 resp chain protein, 2 rRNAs, 22 tRNAs)
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| NuDNA mito-assoc genes | >300 genes (resp chain, mtDNA replication, expression, and repair, antioxidant defense, FE homeostasis)
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| Mitochondrial disease incidence | 1/5000-8000
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| Mito disease mutations in | nuclear and mt DNA
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| mito disease | affects tissue with high energy demands
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| heteroplasmy | threshold effect
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| Mito disease CNS | hypotonia, ataxia, IDD, seizures, migraines, dementia, snhl
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| Mito disease eyes | RP, optic atrophy, nystagmus, ophthalmoplegia
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| Mito disease muscle | weakness, exercise intolerance, red ragged fibers
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| Mito disease cardiac | HCM, arrhythmias, heart block
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| Mito disease hematologic | macrocytic anemia, pancytopenia
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| Mito disease endocrine | diabetes mellitus, diabetes insipidus, exocrine pancreatic dysfunction, short staturem
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| Mito disease GI | dysfx, intestinal psuedo-obstruction
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| Mito disease liver | dysfx, failure
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| Mito disease renal | RTA, Fanconi syndrome
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| Mt disorders of OxPhos | 80-90% pts have nuclear defects (e- transport chain)
AR inheritance
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| Mt disorders of Resp chain assembly factors | mutation in nuc genes
ACAD9 (complex 1)
SURF1 (complex IV)
SCO1&2 (Cu++ homeostasis, complex assembly)
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| Mt neurogastrointestinal encephalomyopathy (MNGIE) | AR
defect in TYMP gene (nuclear)
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| CoQ synthesis defects | 5 nuclear genes
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| Leigh syndrome | onset late infancy with regression
MRI abnormal with white matter and basal ganglia changes
+/- increase in serum lactate
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| 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
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| Mitochondrial depletion syndrome | AR
decrease in ratio mt/nuclear DNA
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| Genes that cause Mito depletion syndrome | POLG1
TK2
DGUOK
TWINKLE
others
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| Mito depletion syndrome clinical presentation | hepatic failure
decrease glucose
CNS involvement
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| LHON | adult onset optic neuropathy;
mostly hmp missense mutations
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| NARP | Neuropathy, ataxia and RP;
mostly heteroplasmic missense mutations in ATP synthase (Complex V)
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| Maternally inherited deafness | point mutations in MT-rRNA; also associated with susceptibility to aminoglycoside ototoxicity
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| mt tRNA mutations cause | MERRF
MELAS
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| heteroplasmic point muts in mt tRNA(lys) | MERRF (~80%): myoclonic epilepsy with red ragged fibers
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| heteroplasmic point muts in mt tRNA(leu) | MELAS (most): myoclonic epilepsy with lactic acidosis and stroke
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| mt tRNA mutations pathogenesis | inability to translate several mt proteins and lack of nl processing of transcripts
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| 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
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| 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)
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| 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)
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| 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
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| Congenital Disorders of Glycosylation (CDG) clinical spectrum | CNS, eye, skeletal, skin, clotting, immune system, endocrine, GI, liver, and more
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| 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)
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| 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
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| 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.)
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| 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
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| Classical PMM2-CDG (Ia) genetics | most common CDG (60-70% of pts)
AR
phosphomannomutase 2 def
abnormal transferrin isoelectric focusing
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| 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
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| 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
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| 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
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| Lysosomes | cytoplasmic organelles that contain ~50 acidic degradative enzymes
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| 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
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| Lysosomal storage disorders (inheritance) | all are recessive
most are autosomal
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| LSDs (progression) | 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 | 1.Mucopolysaccharidoses 2.Sphingolipidoses 3.Transport disorders 4.Mucolipidoses 5.Glycoprotein 6.Neutral Lipid 7.Glycogen Storage
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| 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
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| 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
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| 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
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| Hurler syndrome (MPS I) inheritance/incidence | AR (1/100,000)
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| 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
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| Hurler syndrome (MPS I)diagnosis | +ve MPS spot test
enzyme assay
DNA testing
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| 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)
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| Hunter syndrome (MPS II) presentations | prominent deafness
NO corneal clouding
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| Hunter syndrome (MPS II) inheritance | X-linked (1/70,000-1/150,000);
20% of pts with complete gene deletion > have more severe IDD
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| Hunter syndrome (MPS II) diagnosis | +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 | 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
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| Sanfilippo syndrome (MPS III) inheritance | AR
4 distinct loci (A and B most common)
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| Sanfilippo syndrome (MPS III) presentations | more CNS, less somatic features
onset usually 2-4 yrs, chronic diarrhea, insomnia, szs, aggression prominent
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| Sanfilippo syndrome (MPS III) diagnosis | MPS may be + or -; enzyme assay/DNA
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| Sanfilippo syndrome (MPS III) treatment | none
no benefit from HSCT
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| Morquio syndrome (MPS IVA and B) | short-trunk dwarfism with nl IQ; severe odontoid hypoplasia; clinical trials with ERT
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| Maroteaux-Lamy syndrome (MPS VI) | somatic sx may severe; usually nl IQ
defects in arylsulfatase B
ERT (Naglazyme)
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| Sly syndrome (MPS VII) | severe infantile form; prenatal form with hyrdops/fetal ascites
defect in beta-glucuronidase
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| 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
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| Gaucher disease | most common lysosomal storage disease
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| Gaucher disease (type I) | nonneuronopathic, splenomegaly, pancytopenia, bone pain/lytic bone lesions
1:400 - 1:1000 US AJ
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| Gaucher disease (type II) | acute neuronopathic- rapidly progressive neurologic disease with hepatosplenomegaly
all ethnic groups
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| Gaucher disease (type III) | subacute neuronpathic
later onset
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| Gaucher disease (diagnostic) | "foam cells" in bone marrow, smear
enzyme assay
molecular carrier screening in AJ
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| Gaucher disease genetics | GBA (glucoside-b acid) on chr 1
protective allele against CNS: N370S
L444P usually type II or III
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| Gaucher disease treatment | 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 | AR
~1/100,000 general population
~1/4000 in AJ
increased incidence in French Canadians
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| 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
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| Cherry red spot seen in | Tay Sachs
Sandhoff
Sialidase deficiency
Niemann-Pick disease type A
GM1 gangliosidosis
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| Tay Sachs molecular defect | hexoseaminidase A (HEXA)
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| Sandhoff disease molecular defect | hexoseaminidase B (HEXB)
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| Tay Sachs/Sandhoff diagnosis | enzyme assay
molecular testing
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| treatment | none
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| Tay Sachs + CNS involvement | Sandhoff disease
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| Fabry disease inheritance | X-linked
1/40,000-60,000 males
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| 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
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| Fabry presentation (females) | median age 13 yrs
fatigue, stroke, ~10% females develop renal failure, can be detected by slit lamp
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| Fabry diagnosis | enzyme assay (may miss females)
heterogeneous mutation analysis (DNA testing best for females)
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| Fabry treatment | dilantin/tegretol for neuropathy; renal transplant; ERT - may decrease pain, GI sx, slow renal disease, does not decrease proteinuria
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| Krabbe disease (Globoid Cell Leukodystrophy) | onset <6 mos, hypotonia, irritability, optic atrophy, occ, macrocephaly, elevated CSF prot; leukodystrophy on MRI
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| Krabbe disease diagnosis | enzyme assay
molecular testing of GALC gene
pseudodeficiency can complicate prenatal dx and requires sulfatide loading assay
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| Krabbe disease gene | GALC
galactosylceramidase
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| Krabbe disease treatment | HSCT has some efficacy in later onset or if performed very early in infantile cases
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| Lysosomal proceesing defects | I-cell disease (Mucolipidosis II)
Multiple sulfatase deficiency
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| 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
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| I cell dis presentation | like Hurler
may see neonatal or prenatal onset
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| I cell dis diagnosis | increase plasma activity multiple lysosomal enzymes with deficient activity in fibroblasts
-ve MPS spot
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| I cell dis treatment | none
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| Lysosomal transport disorders | defect in transport of lysosomal degradation products out of lysosomes
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| Lysosomal transport disorders examples | cystinosis
sailic acid storage disease (infantile and adult forms)
Niemann-Pick type C (NPC) disease
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| Niemann-Pick type C genetics | AR
1/150,000
NPC1 (95%) and NPC2 (~5%): these play role in intracellular cholesterol trafficking
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| Niemann-Pick type C presentation | infantile form with neonatal jaundice
later onset forms with ataxia and progressive dementia, psychosis
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| Niemann-Pick type C diagnosis | nl sphingomyelinase
abn lysosomal accumulation of unesterified cholesterol
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| Niemann-Pick type C treatment | clinical trials with drugs to increase cholesterol removal from cells
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| Gaucher cells with defect | macrophages
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| Fabry cells with defect | endothelial cells
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| Tay Sachs cells with defect | neurons
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| ERT for Gaucher (I, III) | Cerezyme, Vpriv
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| ERT for Fabry | Fabrazyme, Replagal
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| ERT for Pompe | Myozyme
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| ERT for Hurler (MPSI) | Aldurazyme
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| ERT for Hunter(MPSII) | Elaprase
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| ERT for Maroteaux-Lamy (MPS VI) | Naglazyme
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| ERT for Lysosomal acid lipase def (Wolman) | Synageva
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| Other therapies for LSDs | 1.substrate reduction
2.enzyme enhancement-chaperone therapy
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| substrate reduction for LSDs | Zavesca (miglustat; Gaucher and others) iminosugar analog of glucose; crosses BBB
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| Perixosomes (features) | ubiquitous (except RBCs)
single membrane
no nucleic acid
several 100/cell
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| 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
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| PEX proteins | biogenesis of peroxisomes (16 proteins)
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| target signals for matrix Px prot | PTS1 - C terminal SKL most common
PTS2 - N-terminal
membrane unknown
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| Peroxisomal disorders classes | 1.Peroxisome biogenesis disorders
2.Single enzyme defects
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| Px biogenesis disorders | Zellweger syndrome spectrum;
Rhizomelic chondrodysplasia punctata (RCDP)
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| Px single enzyme defects | X-linked adrenoleukodystrophy;
Refsum disease;
11 others
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| 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
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| 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
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| Zellweger syn diagnosis | all peroxisomal functions abn
no peroxisomes or ghost membranes seen by EM
biochemical then molecular
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| RCDP incidence | 1/100,000
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| RCDP presentation | skeletal dysplasia, cataracts, ichthyotic skin rash, IDD, occ CHD, cleft palate
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| RCDP gene | PEX7 encodes PTS2 receptor (most common cause)
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| RCDP diagnosis | low plasmalogens, elevated phytanic acid
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| X-linked adrenoleukodystrophy | progressive x-linked neurodegenerative disorder assoc w/ adrenal involvement
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| X-linked ALD penetrance | ~1/20,000
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| X-linked ALD presentation | 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) | ~50% het female carriers develop mild neurological sx in adulthood
20% gait and spinal cord involvement like AMN
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| 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
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| X-linked ALD diagnosis | VLCFA
molecular esp in females
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| X-linked ALD treatment | HSCT early in course for males as soon as MRI changes noted
corticosteroids for adrenal insufficiency
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| X-linked ALD diagnosis | T1 MRI with gadolinium
inflammatory demyelination with perivascular infiltration
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| Zellweger spectrum | increase VLCFA
decrease plasmalogens
inrease plasma pipecolic acid
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| RCDP | decrease plasmalogens
VLCFA normal
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| Refsum disease presentation | cerebellar ataxia, polyneuropathy and RP, elevated CSF protein
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| Refsum disease genetics | AR
deficiency of phytanoyl-CoA hydroxylase
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| Refsum disease diagnosis | increase phytanic acid
molecular testing
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| Refsum disease treatment | phytanic acid-restricted diet
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| Px clinical features (suggestive) | FTT, DD
hypotonia, cerebral atrophy, decreased myelination, neuronal heterotopia
dysmophia
cataracts, glaucoma, RP
chondropdysplasia punctata,
hepatomegaly, renal cysts
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| Laminopathies genes | LMNA, LMNB2, LMNB1
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| Laminopathies disorders (LMNA) | 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 | AR
deficiency of acid sphingomyelinase
increase in AJ (carrier freq 1:60)
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| Neimann-Pick dis presentation | neurodegenerative with spleen > liver
cherry red spot (~50% type A); pulmonary (type B)
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| Neimann-Pick diagnosis | enzyme assay
molecular
sea blue histiocytes in marrow
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| Neimann-Pick treatment | none
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| GM1 gangliosidosis presentations | somatic + CNS affected
hypotonia, szs, MR
~50% have cherry red spot
milder juvenile and adult forms exist
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| GM1 gangliosidosis diagnosis | foamy histiocytes in bone marrow
enzyme assay of beta-galactosidase (GLB1 gene)
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| Tay Sachs serum screening | pregnancy, oral contraceptives and some illness can make test inconclusive
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| Metachromatic Leukodystrophy presentation | late infantile - most pts walk, regression before age of 2; white matter changes, elevated CSF prot
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| Metachromatic Leukodystrophy gene | arylsulfatase A (ARSA)
inheritance is AR
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| Metachromatic Leukodystrophy diagnosis | enzyme assay
psudodeficiency (2 singl bp changes)
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| Glycoprotein disorders | mannosidosis, aspartylglycosaminuria (AGU), sialidosis, fucosidosis
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| Glycoprotein disorders presentation | like mild/mod MPS; fucosidosis has false + sweat test & andiokeratomas; congenital form of sialidosis with fetal ascites
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| Glycoprotein disorders diagnossis | MPS spot -ve
enzyme assay
characteristic urine oligosaccharides
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| AGU | common in Finland (C163S in 95% of Finnish alleles)
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| Multiple sulfatase deficiency presentation | like severe MPS + ichthyosis, mild skeletal
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| 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
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| Multiple sulfatase def dx | +ve urine MPS,
enzyme assays
molecular
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| Farber lipogranulomatosis (ceramide def) | very rare
painful deformed joints + subcutaneous nodules
IDD
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| Acid lipase def (Wolman) | GI disorder with hepatosplenomegaly
FTT
adrenal Ca++
mild variant is cholesterol ester storage disease
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| Schindler disease | progressive IDD, blindness, szs, hypotonia, a rare cause of neuraxonal dystrophy due to deficiency in lysosomal N-acetylgalactosaminidase
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| Pycnodysostosis | skeletal dysplasia, defect in lysosomal cathepsin K
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| Sphingolipid activator protein (SAPs) | small proteins that interact with some lys hydrolases to stabilize them or stimulate activity
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| 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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You may also shuffle the rows of the table by clicking on the "Shuffle" button.
Or sort by any of the columns using the down arrow next to any column heading.
If you know all the data on any row, you can temporarily remove it by tapping the trash can to the right of the row.
To hide a column, click on the column name.
To hide the entire table, click on the "Hide All" button.
You may also shuffle the rows of the table by clicking on the "Shuffle" button.
Or sort by any of the columns using the down arrow next to any column heading.
If you know all the data on any row, you can temporarily remove it by tapping the trash can to the right of the row.
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Created by:
amrs
Popular Genetics sets