Screening Flashcards by Changrui Xiao

NBS: High arginine

Check PAA, orotic acid, ammonia

if abnormal -> Argininemia (Arginase Def)
Can get RBC enzyme levels

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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

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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

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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)

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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)

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NBS: high methionine

Action: PAA, Hcy, MAA

Homocystinruia (high Hcy)

MAT/GNMT/SAHH (n-mildly elevated Hcy)

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NBS: Low Met

Action: PAA, Hcy, MMA

CblE, CblG, MTHFR (High Hcy, normal MMA)

CblC, CblD, CblF (High Hcy, high MMA)

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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)

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NBS: high tyrosinie, normal SUAC

Action: PAA

Tyrosinemia type II (Tyr very high)

Tyrosinemia type III or TPN (Tyr high)

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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

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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

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NBS: High C0/C16+C18

Action: routine labs, ACP, F/T Carnitine

CPT1 (C0 high, long chain AC low)

can get enzyme/CPT1A analysis

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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

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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

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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

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NBS: High C8, C6, or C10

Action: Labs, ACP, UOA

MCAD (C8 high, dicarboxycilic acids high, hexanoylglycine)

Get confirmatory gene testing

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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

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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)

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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)

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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

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NBS: high C3 (isolated)

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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

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Succinyl-CoA Synthetase Deficiency

SUCLA2

Presents as encephalopathy and mtDNA depletion

NBS: high C3DC

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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)

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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

Screening Flashcards

(51 cards)