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133 Cards in this Set
- Front
- Back
Tyrosenemias I, II, III
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I - most severe
II - “oculocutaneous” tyrosinemia because of corneal findings, photophobia, and keratoderma III - variable from MR and ataxia to asymptomatic |
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Cherry red spot is ass'd with which diseases?
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Tay-Sachs
Sandhoff Sialidase deficiency Niemann Pick A GM1 gangliosidosis gangliosidosis |
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MPS I (Hurler vs. Scheie) vs. MPS II (Hunter)
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Hurler dx <18mo, Scheie dx >5yo
Hunter/MPS II similar to Hurler/MPS I but XR (vs. AR) Hunter - milder phenotype variable CNS disease Hunter - no corneal clouding (vs. Hurler) - hunter needs to see clearly to use gun Hurler and Scheie are alellic, Scheie mtn have residual activity Scheie - normal lifespan and IQ (vs. Hurler death by 10yo) Hunter - BMT less successful than Hurler |
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AA disorders
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toxic buildup of substrate - intoxication phenotype
don't necessarily present after illness or fasting (vs. OA, FAO) metabolic acidosis, mild ketotic hypoglycemia (vs. FAO - hypoketotic) generally less severe than OAD, generally chronic and not acute conditions: alkaptonuria, homocystinuria, nonketotic hyperglycinemia/glycine encephalopathy, PKU, tyrosinemia |
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OA disorders
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excretion of excess organic acids in urine (OA is AA minus NH4)
intoxication phenotype when catabolic & ∴ degrading AA newborn presentation: lethargy, poor feed, vomit'g, abnl muscle tone, encephalopathy, seizures, coma, death, metabolic acidosis (primary, due to build up of OA), resp alkalosis (secondary, to get pH up), hyperammonemia (secondary, b/c OA interfere w/ UC), ketotic hypoglycemia (vs. FAO), neutropenia, elevated glycine (OA block glycine oxidation) - ketotic hyperglycinemia, liver fxn usu normal conditions: IVA, MMA, PA, MMA w/ homocystinuria, GA, biotinidase deficiency, others |
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carbohydrate disorders
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energy deficient phenotype (not intoxication phenotyp)
lethargy, hypoglycemia, dysfxn due to low energy - brain, liver, muscle (myopathy), heart (CM) disorders: galactosemia, GSD |
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Fatty acid oxidation
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defect in beta oxidation of FA of different lengths
presents when energy demands high & body is trying to use fats lethargy, irritibality, encephalopathy myopathy (muscle weakness, rhabdomyolysis) - esp. older onset + longer chains CM (VLCAD/LCHAD only) hypoketotic hypoglycemia (vs. others) (except SCAD) UOA - dicarboxylic acid +/- ammonia b/c FA block UC +/- low carnitine abN blood acylcarnitine, abN urine acylglycines, abnl UOA conditions: SCAD, MCAD (most common), VLCAD (most severe), LCHAD & TFP (like VLCAD) LCHAD in fetus causes HELLP and acute fatty liver in pregnant mother |
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Urea Cycle disorder
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UC in liver, produces arginine, NH4→ urea for excretn. Lycine + benzoate→hippurate w/ NH4 for alt excretn
newborn- intoxicatn phenotype severe - hrs-days after birth mild - adult, avoid prtn lethargy, vomit, poor feed, FTT, cerebral edema (↑NH4), stupor, tremor, sz, coma, death, hyperammonemia, ↓plasma urea, resp alkalosis (1°-tachypnea frm ammonia vs. 2°-OA, AA) conditns: OTC, carbamyl phosphate synthetase deficiency, arginase defici, N-acetylglutamate synthetase defici tx: prtn restrictn, mt arginine requirmnts, alt pathway for NH4 excretn plasma >150mmol/L, N anion gap, N serum glucose, plasma AA to identify which conditoin |
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Lysosomal storage disorder
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storage of substrate in lysosome
distention of cell, disruption of cellular functions finally storage in tissues coarse* facies developmental regression**, MR hepatosplenomegaly CM* conditions: fabry, gaucher, MPS I, II, Pompe |
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biochemical/metabolic disorders that can be associated with congenital malformations and/or dysmorphic features due to prenatal onset?
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-disorders of glycosylation (esp. type 1)
-mtDNA (severe forms - brain malforamtions, ex. absence of corpus callosum -FAOD - CPTII deficiency ass'd with dysmorphic features, malformations -peroxismal disorders - zellweger has dysmorphic features and organ malformations |
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Ammonia levels in:
OAD UCD mitochondrial FAO LSD |
OAD - high (secondary to inhibition of UC by OA)
UCD - v. high, highest of all metabolic disorders mitochondrial - can be high b/c first part of UC is in mitoch. and abnromal enviroment can interfere FAO - high because FA block UC LSD - normal!! |
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Trichorrhexis nodosa (or “kinky hair”) is assocaited with what two diseases?
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Menkes
Argininosuccinic aciduria |
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what is the toxic compound in Maple Syrup Urine Ds (MSUD)?
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leucine.
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XL metabolic disorders?
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Fabry
OTC Adrenoleukodystrophy Hunter Lesch-Nyhan G6PD deficiency Menkes PDHC E1 alpha (mitochondrial) Barth syndrme 3-MCC - defect in leucine met'm |
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AD metabolic disorders?
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porphyrias
familial mediteranean fever forms of Kearns-Sayre syndrome caused by nuclear mutations that lead to mtDNA deletions |
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Which UCD is not ass'd with high ammonia?
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arginase deficiency.
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Which urea cycle defect can be associated with progressive liver disease?
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Argininosuccinic acid lyase deficiency
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Which FAOD is most often linked with fatty liver of pregnancy?
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LCHAD
|
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general inheritance of each of these mitochondrial DNA mutations:
-point -deletion -duplication |
point - usually inherited
deletion - usually sporadic duplication - usually inherited beware the del/dup combo |
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protein synthesis for all mtDNA-encoded polypeptides is defective in which conditions?
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A8344G, MERRF mutation in tRNAlys
7kb deletion in the greater arc |
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markers for possible mitochondrial disease?
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-lactate
-pyruvate -ketones -3-methylglutaconate -dicarboxylic acids (ethylmalonate and glutarate) -generalized organic aciduria (not one specific) -elevated 3-methylglutaconate -plasma carnitines - need for carnitine supplementation? -lactat in CSF in children with prominent neurological disease -tissue biopsy - findings are suggestive, but can be non-specific; fiber size variation, mitochondrial proliferaiton, bizarre mitoch shape, ragged red fibers are rarely foudn in children, enzyme testing on tissue can sometimes identify the deficiency, |
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is prenatal testing available for mitochondrial disease?
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no, not for the majority of cases
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what are the most common presentations of mtDNA depletion syndrome?
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liver failure
myopathy (infantile onset and encephalopathy are common) |
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cardinal features of Leigh disease?
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respiratory dysfunction
cranial nerve abnormalities ataxia hyperintense signals on MRI |
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mitochondrial dietary management?
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preventing fasting-related symptoms
shunting more electrons via complex I or II small, frequent, low-fat meals for GI motility issus |
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features of mitochondrial disease
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-energy deficient state
-neuromuscular or multi-system disease -lactic acidosis -abnormal findings on UOA and muscle biopsy |
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most subunits of the electron transport train are both nuclear-encoded and mtDNA-encoded, which one isn't?
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all subunits of complex 2 are nuclear-encoded (only, no mtDNA).
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what is the inheritance pattern for conditions that lead to multiple mtDNA deletions (and are a rare cause of KSS)?
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AR or AD
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pyruvate dehydrogenase complex
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-PDHC E1 alpha is most common
-XLD -birth defects -congenital 'overhwehelming' lactic acidosis -carbohydrate induced episodic ataxia -cystic brain lesions |
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pyruvate carboxylase
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mitochondrial disorder
similar to PDHC deficiency AR (vs. PDHC XLD) -severe lactic acidosis -high ammonia -high citrulline -high lysine |
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which tissues use FAO at all times?
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muscle (skeletal and cariac) and liver
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what shuttles long chain fatty acids across the mitochondrial inner membrane?
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carnitine. disorders of any of the 4 proteins in the carnitine cycle mimic long chain FAOD (i.e. skeletal myopathy, CM and/or fasting intolerance)
conditions: carnitne uptake deficinecy (defect of plasma membrane carnitine transporter), CPT I, CPT II |
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role of molecular analysis in mitochondrial disease?
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mutation remains unknown in most cases (also means that prenatal testing isn't an option).
cases with known mutations are generally mtDNA mutations (b/c genome is smaller), while nuclear-encoded diseases tend to not have identified mutations. |
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prenatal testing for electron transport genes?
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molecular - if nuclear-encoded mtn is known (ex. SURF1)
mtDNA - often not available prenatally, also genotype doesn't predict phenotype well b/c of heteroplasmy, so low utility. enzyme and/or metabolic testing is available for some disorders |
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what is involved in mitochondrial disorder treatment?
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individualized, may include:
-avoidance of catabolism -dietary manipulations - frequent feeding, low fat, high fat... -carnitine supplementation -v. high doses of vitamins - riboflavin (-> flavin, which is a component of ETC compelxes), coenzyme Q10 (shuttles electrons within ETC) -creatine - increase strength and bulk (high-energy store in muscle) -anti-oxidants -exercise -supportive therapy |
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mtDNA mutation rate compared to nuclear DNA?
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mtDNA has a 10-fold higher mtn rate
b/c of exposures to high concentratin of oxygen free radicals from ox phos, lack of protective histones, ineffective DNA repair no introns so random mutaitons usually affect dcoding sequences b/c of mtn rate, mitochondrial efficiency declines through adulthood - contributes to aging and to age-dependent penetrance/severity of mitochondrial disease |
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what odor is associated with untreated PKU?
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"mousy" odor (ACMG), musty, sweet (esp. ear wax)
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what odor is associated with IVA?
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sweaty feet
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what odor is associated with untreated MSUD?
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maple syrup in the urine! clearly.
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peroxisomes are...
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bound by a single (not double) membrane
many peroxismal proteins show minimal posttranslational processing ubiquitous in mammalian cells except RBC several hundred/cell some steps of bile acid metabolism occur here (ACMG q'n) |
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what is the typical presentation of type 1a glycogen storage disease (aka glucose-6-phosphatase deficiency, von Gierke)
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a 6 month old with hepatomegaly, renomegaly, hypoglycemia and lactic acidosis
also - doll like facies, thin extremities, short stature |
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what is the enzyme defect in Gaucher?
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alpha - glucosidase
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what common mutation for Gaucher is ass'd with the nonneuropnopathic phenotype?
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N370S (1226G)
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what are the ranges for phe levels?
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normal: 30-90umol/L (i.e. uM);
benign hyper: 120-600: hyper: 600-100; abnormal >1000-1200 (>20mg%) therapeutic target range -<12yo 2-6mg% ->12yo 2-10mg% -preconcept/pregnant: <6mg% |
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what are some causes of false positives for PKU on NBS?
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blood spot too thick
sample improperly prepared liver immaturity protein overload (newborns fed cow's milk) heterozygosity for PAH deficiency in premature babies a combo of any of these also, testing shouldn't be done until >24hr old b/c it takes that long for phe concentrations to manifest |
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NBS for galactosemia
*sensitivity? *what is tested? *results for G/G, G/N, D? |
*sensitivity ~100%
*tested: GALT (galactose-1-phosphate uridyltransferase) enzyme activity and total RBC galactose-1 phosphate conc and galactose *2nd tier: molecular GALT testing *enzyme activity: -classic: G/G <5% -het G/N 50% -G/D - may have positive NBS *galactose-1-phosphate conc (substrate of GALT, so builds up) -classic: 2-5mg/dL despite therapy |
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which metabolic disorders are well treated by BMT?
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hurler
x-linked adrenoleukodystrophy scheie adenosine deaminase deficiency Gaucher type 3 NOT - sanfilippo, hunter |
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key issues in Tay-Sachs carrier testing?
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-serum hexA enzyme analsysi is not accurate during pregnancy (must do WBC hexA)
-molecular testing is not helpful in non-AJ as most mutations won't be detected |
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What conditions involve defects in cholesterol biosynthesis?
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mevalonic aciduria (mevalonate kinase, early step in chol biosynth)
hyper IgD syndrome (mevalonate kinase, early step in chol biosynth) SLOS CHILD syndrome |
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what disorders are assocaited with an elevated plasma tyrosine?
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prematurity
liver disease inborn errors of tyrosine catabolism -tyrosinemia type I (hepatorenal) -tyrosinemia type II (oculocutaneous) -4HPPD deficiency other -NTBC tx -hyperthyroidism -scurvy |
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are cataracts typically seen in mitochondrial disease?
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no!
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Which metabolic diseases have ERT clinically available?
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Gaucher
Fabry Pompe MPS-1 (Hurler, Scheie) MPS-2 (Hunter) MPS-6 |
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Pycnodysostosis, a skeletal dysplasia, is caused by mutations in
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Cathepsin K, a lysosomal enzyme
actually a LSD (ACMG) |
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what metabolic disorders have a risk for malignancy?
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GSD type 1 (liver ca)
tyrosinemia (liver ca) hemochromatosis immunodeficiency disorders DNA repair disorders |
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neonatal hypotonia, seizures, apnea, and hiccups are features of?
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nonketotic hyperglycinemia
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features of disorders of creatine synthesis or transport include?
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MR
reduced creatinine excretion severely delayed language dev't abnl brain MR spectroscopy - decreased creatine autistic genetics - 2 AR, 1 XR (CRT transporter) treatment - creatine supplementation |
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B53. A lysosomal storage disease that does not involve the central nervous system is:
A. Hunter syndrome B. Type I Gaucher disease C. Niemann-Pick A D. Tay-Sachs disease E. Krabbe disease |
type 1 gaucher disease
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B54. A lysosomal storage disease in which hepatosplenomegaly is not prominent is:
A. Hurler disease B. Pompe disease C. Mannosidosis D. Wolman disease E. Tay-Sachs disease |
Tay-Sachs (vs. other storage disorders)
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clinical features of congenital defect in glycosylation?
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very broad clinical spectrum: CNS, eye, skeletal, clotting, immune system, more
inverted nipples progressive liver disease abnormal deposition of subcutaneous fat bleeding diathesis MR; ataxia; RP testing: transferrin isoelectric focusing most commonly recognized CDG: CDG-1a - phosphomannomutase 2 deficiency |
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Where do very long branch-chain fatty acids undergo beta-oxidation?
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in peroxisomes
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what is the differential dx for a newborn with poor feeding, vomiting and lethargy?
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sepsis
cardiac defect CNS catastrophe GI obstruction metabolic defect |
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what features of acute metabolic distress in infancy increase suspicion it's a metabolic defect?
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fhx neonatal deaths
initially normal poor feeding -> vomiting -> lethargy -> coma seizures peculiar odor ketonuria disturbed acid/base status - metabolic acidosis, respiratory alkalosis |
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differential diagnosis - hyerpammonemic newborn
lethargic, NH4 >50uM <24hrs |
preterm? --> THAN (transient hyperammonemia of the newborn)
full term? --> inborn error --> -pyruvate dehydrogenase deficiency -electron transport defects -others |
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differential diagnosis - hyerpammonemic newborn
lethargic, NH4 >50uM >24hrs |
with acidosis (+/- ketonuria) --> OAD
without acidosis (+/- ketonuria) --> UCD -which UCD? - check plasma citrulline ---high (>1000uM) - ASD ---100-300 uM - ALD ---low (<10uM) -------low urine orotic acid - CPSD -------high urine orotic acid - OTCD |
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what is the preferred substrate for cardiac and skeletal muscle?
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long chain fats - hence myopathy and cardiomyopathy in LCHAD and VLCAD but not shorter FAOD.
|
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what does liver oxidize FA to?
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ketone bodies
-provide energy for gluconeogenesis, ureagenesis -used as fuel in CNS |
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differential diagnosis - hyerpammonemic newborn
lethargic, NH4 >50uM <24hrs |
preterm? --> THAN (transient hyperammonemia of the newborn)
full term? --> inborn error --> -pyruvate dehydrogenase deficiency -electron transport defects -others |
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differential diagnosis - hyerpammonemic newborn
lethargic, NH4 >50uM >24hrs |
with acidosis (+/- ketonuria) --> OAD
without acidosis (+/- ketonuria) --> UCD -which UCD? - check plasma citrulline ---high (>1000uM) - ASD ---100-300 uM - ALD ---low (<10uM) -------low urine orotic acid - CPSD -------high urine orotic acid - OTCD |
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what is the preferred substrate for cardiac and skeletal muscle?
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long chain fats - hence myopathy and cardiomyopathy in LCHAD and VLCAD but not shorter FAOD.
|
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what does liver oxidize FA to?
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ketone bodies
-provide energy for gluconeogenesis, ureagenesis -used as fuel in CNS |
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MSUD (maple syrup urine disease)
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AR deficiency of BCKD
symptoms - poor feeding, vomiting, lethargy, coma, seizures characteristic odor second step in breakdown of branched chain amino acids Dx - Paa - increased lue, ile, val, alloisoleucine; decreased ala Uoa - increased branch chain keto acids tx - acute: restrict branch chain aa, may require hemofiltration -chronic: dietary restriction of branch chain aa, avoid deficiency of ile or val |
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VOMIT
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valine, odd chain FA, methionine, isoleucine, threonine
restrict in PA, MMA |
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complications of MMA and PA?
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pancreatitis
basal ganglia infarcts ('metabolic strokes') cardiomyopathy bone marrow suppression progressive renal disease |
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biotinidase deficiency
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AR
deficiency of biotinidase affects functioning of multiple enzymes symptoms - gradual, remitting onset; hypotonia; seizures; rash and alopecia; MR and hearing loss in late diagnosed pt dx - reduced biotin in plasma and urine -uoa: 3-oh-isovaleric acid tx: oral biotin (10-100mg/day) |
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UCD
symptoms? genetics? diagnosis/tests? treatment? |
-symptoms: PFVLCSz, tachypnea
-genetics: all AR, except OTC is XR -dx/tests: high ammonia, high glutamine, alanine and specific AA, cpds -treatment: protein restriction, meet arginine requirement, alternate pathways of waste nitrogen excretion (benzoate, phenylacetate |
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which UCD is ass'd with hepatomegaly?
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AS lyase deficiency
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which UCD is ass'd with spastic diplegia?
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arginase deficiency
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HHH syndrome
ORNT1 |
hyperornithinemia-hyperammonemia-homocitrullinuria
ornithine transporter, associated with urea cycle tests: high ornithine, high ammonia tx: restrict protein, supplement citrulline |
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nonketotic hyperglycinemia (NKH)
GLDC, AMT, GCSH |
AR
4 components to system defect in Gly -> NH4, CO2, etc. PFLCSz, hypotonia, apnea, hiccups, burst suppression EEG dx - respiratory acidosis; paa - high gly; csf - v. high gly tx - benzoate, NMDA channel blockers |
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how is diagnosis of classical PKU made?
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Plasma phe >1200uM (or 20mg%) on unrestricted diet
normal blood biopterin or urine pterin metabolites |
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When do you treat with a reduced phe diet?
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for phe levels >500uM
also do sapropterin (kuvan) trial (BH4 like?) |
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at what level of maternal Phe does the embryonopathy occur?
what are the features? what maternal Phe should aim for? |
maternal phe>1200, more than 90% of infants have:
-microcephaly and SGA -dysmorphic facies -increased incidence of other malformations (CHD etc.) -MR aim for maternal phe <300uM with diet restriction supplement with tyr |
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biopterin (BH4) defects
|
AR
symptoms - DD, microcephaly, dystonia, seizures BH4 is cofactor for several enzymes - PAH, TyrH, TrpH, NO synthase dx - paa: high phe corrected by BH4 administration -abnl blood and urine biopterin metabolites tx - control phe levels with diet or BH4; amine replacement for synthetic defects |
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hepatorenal tyrosinemia
FAH |
AR deficiency of fumarylacetoacetate hydrolase
liver failure with bleeding diathesis (increased PT) and increased AFP renal fanconi syndrome with rickets neurologic crises - secondary to porphrin disturbances increased risk hepatic ca (40% by 5yo) dx-paa - high tyr, high met, bld spot succinylacetone uoa - high succinylacetone tx - NTBC, restrict phe and tyr in diet, liver transplant |
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type 1 glutaric aciduria
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AR deficiency of glutaryl-CoA dehydrogenase
symptoms - macrocephaly, acute encephalopathic crisis followed by choreoathetosis (involuntary movements), dystonia dx - metabolic acidosis, high ammonia during episode -uoa- glutaric acid -MRI - atrophy of frontal lobe with basal ganglia changes tx - fluids, glucose, carinitie in episode; riboflavin, trial lys-restricted diet |
|
canavan disease
aspartoacylase deficiency |
AR
increased incidence in AJ symptoms - loss of skills starting 2-4mo hypotonia, poor head control, seizures macrocephaly dx - uoa: n-acetylaspartate (NAA) -MRI: diffuse white matter abnl -MRS: increased NAA -molecular: E285A tx - supportive |
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how is galactosemia diagnosed?
|
NBS - high galactose, low GALT
high RBC Gal-1-P (GALT substrate) high urine RS molecular - Q188R common mtn |
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hereditary fructose intolerance
|
AR deficiency of aldolase B
symptoms - asymptomatic in absence of dietary fructose -nausea, vomiting, hypoglycemia, metabolic acidosis after fructose intake (sucrose, fruits, honey) dx - controlled fructose load; molecular (A149P ~70% of alleles) tx - fructose avoidance |
|
GSD type 1
G6Pase (90%, type 1a) G6P translocase (10%, type 1b) |
AR
symptoms - irritable infant with chubby cheeks, hepatomegaly dx - hypoglycemia 3-4hr post feed; dose not respond to glucagon; metabolic acidosis with high lactate; high uric acid; high chol and TG tx - freq't feeding; cornstarch type 1b - antibiotics, GCSF |
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inborn errors with malformations.
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excess substrate or insufficient product interferes with morphogenesis, causing malformations
sterol synthetic defects peroxisomal disorders glutaric acidemia type II pdh deficiency some ETC disorders |
|
what proportion of defects in OxPhos are nuclear-encoded?
|
~80-90%
all complexes of ETC have subunits encoded in nuclear genome AR inheritance ex. Leigh syndrome - nuclear and mt mutations; 50% SURF1 |
|
mitochondrial depletion syndromes
|
AR
genetically heterogeneous including deficiency of: mt thymidine kinase; mt deoxyguanosine kinase; twinkle - mtDNA helicase; mt polymerase gamma; adenine nucleotide translocator; reduced ration of mt to nuclear DNA content |
|
ciliopathies
|
-BBS types 1-14
-orofaciodigital syndrome (OFD1) -meckel-gruber syndrome (MGS) -joubert syndrome (types 1-7) -senior-loken syndrome (SLS) -AD PKD -AR PKD -nephronophthisis (types 1-9) -almstrom syndrome |
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nuclear membrane disorders - laminopathies
|
LMNA, LMNB2, LMNB1
lamins - multifunctional filamentous proteins of nucler lamina, just under inner nuclear membrane LMNA mtn: progeria; emery-dreifuss MD; mandibuloacral dysplasia; generalized lipodystrophy; restrictive dermopathy |
|
disorders of ER
|
rough ER: translocation; glycosylation; folding; sorting
smooth and rough ER: phospholipid synthesis; ion transport |
|
general characteristics of lysosomal storage disorders
|
-progressive clinical course
-variability in clinical course -abnl cellular storage -heterogeneity in stored material -secondary enzyme alterations -variability of organ and cellular manifestations -theoretical basis for therapy |
|
general phenotypic features of LSDs
|
-onset: in utero to several years
-loss of milestones -coarse facies -eye: corneal clouding, cherry red spots, pigmentary retinopathy -ogranomegaly -early and recurrent hernia -skeletal abnormalities -non-immune hydrops |
|
diagnostic approach to LSDs
|
-blood smear
-radiologic exam -ophthalmologic exam, fundoscopic and slit lamp -uring mucopolysaccharides and glycoproteins -serum lysosomal enzymes -consider bone marrow -biochemical studies of fibroblast +/o luekocytes -other - depending on specific disorder |
|
LSD - types/groups of disorders
|
hydrolase deficiencies (>40)
-MPS (hurler, hunter) -sphingolipidoses (niemann-pick) -GSD type II (pompe) trafficking disorders -mucolipidoses II and III lysosomal transport disorders -cystinosis -sialic acid storage |
|
MPSs - general phenotype
|
usually nl at birht
gradual slowing of dev't coarse facies with (hurler) and without (hunter) corneal clouding macrocephaly skeletal inv't (decreased ROM, claw hand); dysostosis multiplex otitis and hearing loss recurrent herniae cardiac involvement |
|
MPS 1- Hurler
|
prototypical MPS
AR - onset 6-12mo, rarely live to age 10 dx - corneal involv't (vs. hunter), MPS spot iduronidase deficiency in WBC or fibrobalsts tx - symptomatic, early BMT, ERT |
|
MPS II - Hunter
|
XLR (vs. hurler!)
variable pheno, similar to hurler on the severe end no corneal involvement dx - +MPS spot iduronate sulfatase deficiency |
|
MPS III - Sanfilipo
|
AR - 4 loci, 2 more common
more CNS involvement - hyperactive, aggresive, insomnia dx - MPS spot +/-; enzyme assay tx - symptomatic |
|
Niemann-Pick A & B
|
AR, increased frequency in AJ
A- poor feeding, respiratory problems before 6mo, hepatosplenomegaly, cherry red spot (50%) dx - foam cells in marrow, sphingomyelinase deficiency, molecular studies tx - supportive B - later onset, hepatosplenomegaly, diffuse pulmonary involvement |
|
Niemann-Pick C
NPC1 (95%), NPC2 (5) |
AR
similar pheno to A & B childhood onset forms with ataxia, dysarthria, progressive dx - foam cells in marrow, sphingomyelinase normal, abnl accumulation of unesterified cholesterol in lysosomes tx - supportive |
|
Gaucher
|
AR deficiency of glucocerebrosidase
sphingolipidosis, LSD N370S - protective for CNS type I - non-neuronopathic; (1/400-1/1000 AJ); splenomegaly, hypersplenism, bone pain (pseudo-osteomyelitis)/lytic lesions; abn pigmentation type II - acute neuronopathic; rapidly progressive w onset in first year; opisthotonus; no AJ predilection type III - adolescent neuronopathic dx - gaucher cell infiltrate marrow and other tissues, 'crumpled paper' cytoplasm tx - ERT for type I |
|
Tay-Sachs disease
HEXA |
AR - hexosaminidase A deficiency
sphingolipidosis, LSD onset: 6-12mo with slowing development; hyperacusis, apathy, cherry red macular, progressing to seizures, blindness, spasticity and death by 2-5y **no hepatosplenomegaly tx - none carrier screening in high risk pop'n (AJ, French canadian) - molecular testing only useful for AJ/common mtn hexosaminidase A enzyme composed of alpha and beta subunits. HEXA = Tay-Sachs, HEXB = Sandhoff w pheno similar to Tay-Sachs |
|
with which disorders do you see a cherry red spot?
|
Tay-Sachs
Sandhoff Sialidase deficiency Niemann-Pick A GM1 gangliosidosis |
|
Fabry
|
XL - nearly all females affected
Sphingolipidosis, LSD males - neuropathy, acroparesthesias, provoked by exercise and temperature changes, angiokeratomas, corneal opacities, renal & cardiac disease dx - gb3 levels, alpha-galactosidase activity, molecular tx - ERT, for certain alleles - galactose |
|
peroxisome functions?
|
-beta-oxidation of VL and L chain FA, straight and branched chain
-peroxidase-based respiration -plasmalogen and bile acid synthesis -glyoxylate transamination |
|
disorders of peroxisomes
|
multiple deficiencies - peroxisome biogenesis disorders:
-zellweger syndrome spectrum -rhizomelic chondrodysplasia punctata (RCDP) single function deficiencies: -x-linked adrenoleukodystropyhy (ALD) -refsum disease |
|
zellweger syndrome spectrum
12 PEX genes PEX1 most common (68%) |
AR
sig locus heterogenetiy - 12 compl'n groups disorders of peroxisome biogenesis spectrum: -Zellweger (most severe, die by 1y) -neonatal adreno-leukodystrophy, -infantile Refsum disease (least severe) dev'l & met'c FTT, DD, dysmorphic, hypotonia, cerebral atrophy, sz, liver cysts, hepatic dysfxn bony stippling (chondrodysplasia punctata of patella, long bones), childhd cataracts, RP, hearing loss hemorrhage, intracranial bleed, hepatic involvement, renal cysts tests: ↑VLCFA, low RBC plasmalogens, ↑plasma pipicolic acid molecular screen - "PEX gene screen" tx: symptomatic, avoid phytanic acid (cow's milk) |
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x-linked adrenoleukodystrophy
ABCD1 |
XL
progress neurodgenerative disorder ass'd w/ adrenal involvmentt highly variable clinical phenotype: -childhood cerebral: childhood onset, rapid progressn -adrenomyeloneuropathy (AMN): onset 20-30s w/ spastic paraparesis -adrenal only no geno-pheno corr'n defective met'm of VLCFA dx- ↑VLCFA, gx tests tx - BMT in boys w MRI abN- lorenzo's oil (?) |
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refsum disease
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AR deficiency of phytanoyl-CoA hydroxylase
crebellar ataxia polyneuropathy, RP, elevated CSF dx - high phytanic acid, molecular testing tx - phytanic acid-restricted diet |
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NBS criteria
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-serious & reasonable frequency
-difficult to dx clinically & requires test -irreversible damage w/o treatment -test is rapid, sensitive & specific -feasible intervention improves outcome -NBS program is cost effective |
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What happens when there's a truly abnormal result on NBS?
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truly abnl = single or multiple analytes >> cut off
-lab notifies MD ASAP, gives contact for metabolic specialists -ACT sheet specific to disorder -FACT sheet for families |
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disorders on MS/MS:
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by acylcarnitines
-9 OA (IVA, GA-1, HMG, MCD, MUT, Cbl A,B, 3MCC, PROP, BKT) -5 FAO (MCAD, VLCAD, LCHAD, TFP, CUD) by AA - 6 AA disorders (PKU, MSUD, HCY, TYR I , ASA, CIT) hematology -Hb SS -Hb S/beta thal -Hb S/C Others -CH -biotinidase -CAH -GALT -HEAR -CF |
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hemoglobin disorders
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by HPLC
FS (Hb SS) -> CBC and/or DNA -> refer to specialist FSC (Hb SC) -> refer to specialist FSA (Hb Sbeta thal) -> refer to specialist FAS (Hb AS) -> no further testing |
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NBS - AA disorders and their metabolities
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-PKU - high phe
-HCY - high met -MSUD - high leucine -argininemia - high arginine -arginosuccinic aciduria (ASA); -citrullinemia I (CIT) & II - citrulline -TYR I, II & III - tyrosine |
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NBS - FAOD analytes
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-carnitine uptake deficiency - C0
-CPT 1 deficiency - C0; C0/C16+C18 -CPT2/CACT - C16 &/or C18:1 -glutaric acid 2/ethylmalonic encephalopathy - C4;C5 -LCHAD, TFP - C16-OH +/- C18:1-OH -MCAD - C8; C6, C10 -SCAD/ethyl malonic enceph/isobutyryl CoA Dehydro D - C4 -VLCAD - C14:1 +/- |
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NBS - OAD and analytes
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-biotinidase, HMC - C5-OH
-glutaric acidemia 1 - C5-DC -IVA, short/branched chain acylCoA dehy d - C5 -MMA, PA - C3 |
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NBS by other methods (not NBS) - how done?
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biotinidase deficiency - enzyme assay
CF - immnoreactive trypsinogen and/or DNA (sensitivity increased with DNA testing) hearing - auditory brainstem response (ABR)/evoked otoacoustic emissions (OAE) |
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galactosemia NBS outcomes
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classical GALT - high galactose, low GALT
galactokinase (GALK) - high galactose, low GALK epimerase (GALE) - high galactose, low GALE |
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cystinuria
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AAD
AR defect in absorption of cystine & dibasic AA (lysine, arginine, ornithine) - increased excretion cystine stone formation in childhood, recurrent if untreated tx - preventive hydration, penicillamine or n-acetylcysteine, alkalinization of urine to increase cystine solubility |
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Galactosemia mutations
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>160 mutations
-classic - Q188R - 70% of Caucasian alleles, 1/128 carrier rate -duarte - N314D - common 1/27 - activity: D/N (75%), D/D (50%), D/G (25%) -LA (N314D+L218L) - 140% activity |
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endocrine disorders on NBS and their abnl results
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primary congenital hypothyroidism (CH)- high TSH or low T4 +/- high TSH
congenital adrenal hyperplasia (CAH, 21-hydrox.) - high 17OHP TSH >24hr of age confirm with T4, TSH, TRH |
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PHE levels
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-classical PKU: >1200uM or >20mg%
-non PKU HPA: 120uM(nl)-1000uM (?treat? controversial) -aim w tx for 120-360uM or 2-6mg% -maternal PKU aim for 120-350uM or <6mg% for several months prior to conception |
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lab results in OTC
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high
-v. high ammonia (>2000), -high glutamine (with ammonia), -high orotic acid** (only UCD with this) (b/c CAP (OTC substrate) builds up and gets converted to orotic acid) low - citrulline (product of OTC), arginine (2 steps after OTC); normal UOA (vs. UOA disorders) |
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AS (arginosuccinate synthase) deficiency
aka citrullinemia |
-AS is step after OTC, citrulline -> ASA
high -Paa -- citrulline vs. high (>1000) - b/c citrulline is the substrate -v. high ammonia (1000-3000 µmol/L) low -Paa - v. low argininosuccinic acid |
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CPSD -
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-step before OTC, product is CAP
high -ammonia low -orotic acid (vs. OTC) (b/c no CAP made to go to orotic acid) -citruline (like OTC) (b/c no CAP --> citrullne, i.e. downstream of enzyme defect) |
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how to differentiate between OAD and UCD in hyperammonemia?
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acidosis
-present - UOAD -absent - UCD |
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approach to investigation of lactic acidosis
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lactate/pyruvate ratio
-increased --> mitochnodrial disease -normal --> glycemia? ----hypoglycemic --> GSD, gluconeogenesis disorders ----normoglycemic --> PDH deficiency, PC def, type A abnl uOA -dicarboxylic acids --> FAOD -characteristic organic acids --> OAD |
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most common symptoms in Gaucher type 1 (nonneuronopathic)?
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-splenomegaly
-hepatomegaly -bone disease -thrombocytopenia -anemia -growth retardation -brusing, bleeding -fatigue -bone pain/crisis -abdominal pain |