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Biochemical Genetics II

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
Created by: amrs
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