Screening Flashcards
NBS: High arginine
Check PAA, orotic acid, ammonia
- if abnormal -> Argininemia (Arginase Def)
- Can get RBC enzyme levels
NBS: Elevated Citrulline
Actions: Ammonia, PAA, UAA
- Citrullinemia type 1 - UCD
- Citrin deficiency - cholestasis, fatty liver, FTT, hyperketotic hypoglycemia
- Arginosuccinic aciduria (+ ASA) - UCD
- Pyruvate Carboxylase (+ Lys, Ala, Pro) - lactic acidosis, encephalopathy, hypoglycemia, developmental issues
NBS: high citrulline
PAA: high cit, Ala, Lys, Pro
UOA: 2 oxoglutaic acid
High lactate, decreased ketones
Pyruvate Carboxylase Deficiency
Biochem: High lactate, pyruvate, ketones, ammonia
- high Cit, Ala, Lys, Pro, 2 oxoglutaric acid
Clinical: Acidosis, neurological, FTT
NBS: high Leu
Action: Send urine ketones, PAA, UOA
MSUD (increased Val, Ile, Leu and brached chain oxo/OH acids)
Hydroyprolinemia (high hydroxyproline, BCAA normal)
NBS: Abnormal Methionine
Action: PAA, Plama homocysteine, Plasma MMA
Homocystinuria (Met high, Hcy high)
MAT, GNMT, SAHH (Met high, Hcy normal)
MTHFR/CblE/CblG (Met low, Hcy high, MMA normal)
CblC/CblD/CblF (Met low, Hcy high, MMA high)
NBS: high methionine
Action: PAA, Hcy, MAA
Homocystinruia (high Hcy)
MAT/GNMT/SAHH (n-mildly elevated Hcy)
NBS: Low Met
Action: PAA, Hcy, MMA
CblE, CblG, MTHFR (High Hcy, normal MMA)
CblC, CblD, CblF (High Hcy, high MMA)
NBS: high Phe
Action : PAA -> if Phe high start diet, get urine pterins and RBC DHPR
PKU (pterins normal)
DHPR (pterins, DHPR assay abnormal)
GTPCH, PTPS, SR, PCD (pterins abnormal)
NBS: high tyrosinie, normal SUAC
Action: PAA
Tyrosinemia type II (Tyr very high)
Tyrosinemia type III or TPN (Tyr high)
NBS: SUAC high, normal or mildly elevated Tyr
Action: Routine labs, PAA, UOA, AFP
Tyrosinemia type I (Tyr n-high, AFP high, SUAC high)
- Consider molecular testing regardless
NBS: low C0, Acyl-carnitines low-nl
Action: Routine labs, Total and Free carnitine (plasma and urine)
Carnitine uptake defect (C0 low, total carnitine low-nl) - get OCTN2 gene analysis or tranporster assay
If C0 and total carnitine normal - consider maternal CUD and rule out GA1
NBS: High C0/C16+C18
Action: routine labs, ACP, F/T Carnitine
CPT1 (C0 high, long chain AC low)
- can get enzyme/CPT1A analysis
NBS: high C4, +/- C5
Action: Routine labs, ACP, UOA
GA2
Ethylmalonic encephalopathy (C4 high, Ethylmalonic acid, methylsuccinic acid, isovalerylglycine)
If all normal can still be mild GA2
- Get moleculr testing for GA2 (ETF/ETF-QO) or EE (ETHE1) if suspected
NBS: High C4
Action: Routine labs, UOA, ACP
IBDH deficiency (C4 high, Isobutrylglycine high) - ACAD8 (ABDH) sequencing
SCAD (C4 high, EMA) - SCAD sequencing
Ethylmalonic encephalopathy (C4 high, EMA, Isovaleryl glycine, methylsuccinic acid) - ETHE sequencing
NBS: high C4OH, normal C5OH/C5:1
Action: Routine labs, ACP, UOA, Insulin level, confirm C5OH/C5:1 are normal (if high consider organic acidurias)
SCHAD (C4OH high, OH-dicarboxylic acids, 3hydroxy glutarate) - Can get molecular testing
NBS: High C8, C6, or C10
Action: Labs, ACP, UOA
MCAD (C8 high, dicarboxycilic acids high, hexanoylglycine)
- Get confirmatory gene testing
NBS: high C14:1
Action : Labs, CPK, ACP
VLCAD (elevated C14, C16, C18s OR Gene sequencing)
- If ACP is normal MUST get molecular testing to rule out VLCAD
NBS: high C16 or C18:1
Action: Routine labs, CPK, ACP
CPT2 (high C16 and C18s, VLC/C0 ratio + fibroblast assay or CPT2 sequencing)
CACT (high C16 and C18s, VLC/C0 ratio + fibroblast assay or sequencing)
NBS: High C16OH, C18OH
Action: Routine labs, CPK, ACP, UOA
LCAD/TFP (C14OH, C16OH, C18OH, C18:1OH; C6-C14 dicarboxylic acids on UOA OR fibroblast/molecular analysis)
- If ACP/UOA normal MUST get fibroblast testing to rule out LCHAD/TFP, molecular = confirmatory (E510Q common mutaton)
NBS: Low GAA
Action: Routin e labs, GAA enzyme activity, urine Hex4
Pompe (GAA activity low AND confirmed by GAA genetic testing)
- If GAA activity normal but labs/hex4 abnormal OR genetic testing inconclusive -> Evaluate w/ specialist
NBS: high C3 (isolated)
Action: routine labs, UOA, ACP, Homocysteine
Succinyl-CoA Synthetase (high C3 and C4DC, MMA, Hcy normal)
MMA, CblA, CblB (High C3, MMA, Hcy normal)
CblC, CblD, CblF, TC, B12 deficiency (high C3, MMA, Hcy high)
PA (High C3, PA, Hcy normal)
Matenal B12 deficiency/False Postive (All normal)
- Get molecular testing to confirm
NBS: High C3
ACP: High C3 and C4DC
UOA: MMA
Succinyl-CoA Synthetase Deficiency
SUCLA2
- Presents as encephalopathy and mtDNA depletion
NBS: high C3DC
Action: Labs, ACP, UOA, MMA
Malonic Aciduria (C3-DC = malonyl CoA, MMA high); ID, seizures. MA > MMA
CMAMMA (C3DC, MMA high, MLYCD mutation negative) - MMA > MA
NBS: High C5 (isolated)
Action: Routine labs, UOA, ACP
Isovaleric Aciduria (high C5, IVG)
SBCAD (high C5, methylbutyrlglycine)
Pivalic acid (antibiotic) use (pivalic acid high in urine, C5 high)
- If everything is normal condier getting BCAA fibroblast testing
NBS: C5DC elevation
Action: Labs, ACP, UOA
GA1 (C5DC, 3-hydroxyglutyrate, glutaric acid, glutarylcarnitines OR firboblast GCDH assay OR sequencing)
- Low excreters exist, normal labs require enzyme/molecular followup
NBS: high C3DC
ACP: C3DC
UOA: Malonic acid > MMA
Malonic Aciduria
Malonyl CoA Decarboxylase Def
ID, Seizures
NBS: high C5OH
Action: Labs, Glucose, UOA, ACP
3MCC (C5OH, 3 methylcrotonylclycine, 3OH IVA)
HMG-CoA lyase (3-HMG, 3-methylglutaconic acid)
Beta-Ketothiolase (2M3HBA, 2MAA, tiglylglycine)
MHBD/HSD10 (2M3HBA, tiglylglycine)
3-methylglutaconic aciduria type I (3 methylglutaconic acid - Leu metabolism)
Biotinidase (Lactate, 3OH IVA, Methylcrotonylglycine, methylcitric acid; Enzyme assay)
Holocarboxylase (Enzyme assay, do if biotinidase negative)
Biotin Deficiency (If biotiniase and holocarboxylase enzyme normal)
NBS: biotinidase assay reduced
Action: routine labs, lactate, ammonia, repeat biotinidase assay
Biotinidase Deficiency (profound if <10%, partial if 10-30%)
NBS: low GALT activity
Action: Clinical, LFT, RBC Gal-1-P, urine reducing substances
If GALT low -> get genotype
<1% = severe, unless S135/S135 (variant galactosemia - same newborn presentation, less long term ID/POI)
1-10% = look for variant galactosemia
10%+ = look for Duarte (N314D) and variant
NBS: high Galactose
Action: RBC GALT
GALT (GALT level reduced -> get molecular testing for duerte, variant, vs classic)
GALK (RBC GALT normal, urine reducing substances positive, Galactokinase assay abnormal)
GALE (RBC GALT normal, Urine reducing substance negative, epimerase positive)
What is the equation for sensitivity?
True Positive/Affected
A/(A+C)
How do you calculate specificity from this picture?
True Negative/Unaffected
D/(B+D)
Calculate PPV
True positive/positive result
A/(A+B)
Calculate NPV
True negative/negative results
D/(C+D)
2 ways to calculate false positive rate
False positive/unaffected
B/(B+D)
OR
1-specificity
2 ways to calculate false negative rate
false negatives/all affected
C/(A+C)
OR
1-senstivity
What is the difference between clinical validity and clinical utility?
Validity = how good is the test - sensitivty/specificity/PPV/NPV
Utility = what can you do with result - Tx, outcome change, etc
What are the 3 primary lab quality assurance criteria?
- ensure adequate specimen volume
- elimiate false negatives
- minimize false positives to cost effective range
What is immunoreactie trypsinogen level used to screen for?
Cystic fibrosis
What are the most common reasons (3) of false negative NBS?
- Tested too early (inadequate nutritional intake)
- prematurity
- transfusion
R117H in CFTR
Reflex 5T test - 5T = 10% expression in cis
- If 5T in cis and another CF variant in trans -> variable phenotype
- if 5T in trans -> CBAVD
High AFP, normal hCG, uE3, Inhibin A
NTD
High hCG and inhibinA, low AFP and uE3
Down syndrome
Low AFP, hCG, uE3, and Inhibin A
Trisomy 18
Very low uE3, normal AFP, hCG, and Inhibin A
SLOS
or
steroid sulfatase deficiency (XL ichthyosis)
What is the next step after abnormal NIPS?
Genetic counseling, ultrasound, and disagnostic testing
What are reasons for false positive NIPS?
extra DNA present from:
- Placental mosiacism
- vanishing twin
- maternal mosiacism
- maternal malignancy
What are reasons NIPS might fail? What is the next step?
- low fetal DNA (may be 2/2 aneuploidy)
- High maternal BMI
- Early gestational age
Follow up failed NIPS with diagnostic test, NOT repeat NIPS because failure can be due to aneuoploidy
C3DC, C4DC
malonic aciduria vs cmamma
C3DC, C4OH, C5:1
Short-chain enyl-CoA hydratase def
