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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 and therefore 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), respiratory alkalosis (secondary, to get pH up), hyperammonemia (secondary, b/c OA interfere with UC), ketotic hypoglycemia (vs. FAO), neutropenia, elevated glycine (OA block glycine oxidation) - ketotic hyperglycinemia, liver fxn usually normal conditions: IVA, MMA, PA, MMA with 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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FAO
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defect in beta oxidation of FA of different lengths
presents when energy demands are high and body is trying to use fats lethargy, irritibality, encephalopathy myopathy (muscle weakness, rhabdomyolysis) - esp. older onset and longer chains CM (VLCAD/LCHAD only) hypoketotic hypoglycemia (vs. others) (except SCAD) UOA - dicarboxylic acid +/- ammonia b/c FA block UC +/- low carnitine abnl blood acylcarnitine, abnl 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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UCD
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UC in liver, produces arginine, ammonia -> urea for excretion
glycine and benzoate can be used to form hippurate with ammonia for alternate excretion newborn presentation - intoxication phenotype severe - hours to days after birth mild - even adult onset, protein avoidance lethargy, vomiting, poor feeding, FTT cerebral edema (b/c ammonia builds up) stupor, tremor, seizures coma, death (v.) hyperammonemia low plasma urea respiratory alkalosis (primary, due to tachypnea due to ammonia - vs. secondary in OA, AA) conditions: OTC, carbamyl phosphate synthetase deficiency, arginase deficiency, N-acetylglutamate synthetase deficiency tx: protein restriction, meet arginine requirements, augment alternate pathways for NH4 excretion plasma >150mmol/L, normal anion gap, normal serum glucose, use plasma AA to identify which conditoin |
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LSD
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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 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 |
|
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 of 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?
|
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
|
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.
|
excess substrate or insufficient product interferes with morphogenesis, causing malformations
sterol synthetic defects peroxisomal disorders glutaric acidemia type II pdh deficiency some ETC disorders |
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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 |
|
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
signif locus heterogenetiy - 12 compl'n groups disorders of peroxisome biogenesis spectrum: -Zellweger (most severe, die by 1yo) -neonatal adreno-leukodystrophy, -infantile Refsum disease (least severe) dev'l & met'c FTT, DD, dysmorphic features hypotonia, cerebral atrophy, seizures liver cysts, hepatic dysfxn bony stippling (chondrodysplasia punctata of patella, long bones) childhood cataracts, RP hearing loss hemorrhage, intracranial bleeding hepatic involvement, renal cysts tests: high VLCFA, low RBC plasmalogens, high plasma pipicolic acid molecular screening - "PEX gene screen" tx: symptomatic, avoid phytanic acid (cow's milk) |
|
x-linked adrenoleukodystrophy
ABCD1 |
XL
progressive neurodgenerative disorder ass'd with adrenal involvmenet highly variable clinical phenotype: -childhood cerebral: childhood onset, rapid progression -adrenomyeloneuropathy (AMN): onset 20-30s with spastic paraparesis -adrenal only no geno-pheno corr'n defective met'm of VLCFA dx- high VLCFA, genetic tests tx - BMT in boys w mRI abnormalities - 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 |