Newborn screening for inborn errors of metabolism

Analyte	Analytical platforms	Differential diagnosis			Available second-tier test	Initial confirmatory testing^Δ	Urgency of clinical follow-up^◊	ACT Sheet and ACMG algorithm links
Analyte	Analytical platforms	Core conditions*	Secondary conditions*	Other conditions^¶	Available second-tier test	Initial confirmatory testing^Δ	Urgency of clinical follow-up^◊	ACT Sheet and ACMG algorithm links
Amino acids
Arginine (Arg)	MS/MS	N/A	Arginase deficiency	N/A	N/A	Plasma amino acids Urine organic acids Urine orotic acid	Next business day	ACT Sheet for increased arginine (argininemia) ACMG algorithm for elevated arginine
Argininosuccinic acid (ASA)	MS/MS	Argininosuccinate lyase deficiency^§	N/A	N/A	N/A	Plasma amino acids Urine organic acids Urine orotic acid	Immediately	ACT Sheet for elevated citrulline (amino acidemia/urea cycle disorder) ACMG algorithm for elevated citrulline (amino acidemia)
Citrulline (Cit), elevated	MS/MS	Citrullinemia type I (argininosuccinate synthetase deficiency)^§ Argininosuccinate lyase deficiency^§	Citrullinemia type II (citrin deficiency)^§	Pyruvate carboxylase deficiency	N/A	Plasma amino acids Urine organic acids Urine orotic acid	Immediately	ACT Sheet for elevated citrulline (amino acidemia/urea cycle disorder) ACMG algorithm for elevated citrulline (amino acidemia)
Citrulline (Cit), reduced	MS/MS	N/A	N/A	Ornithine transcarbamylase deficiency Carbamoyl phosphate synthetase type I deficiency N-acetylglutamate synthetase deficiency MT-ATP6 related mitochondrial disease	N/A	Plasma amino acids Urine organic acids Urine orotic acid Plasma acylcarnitines	Immediately	ACT Sheet for decreased citrulline ACMG algorithm for decreased citrulline
Glutamine/pyroglutamic acid (Gln/Pyrog)	MS/MS	N/A	Citrullinemia type II (citrin deficiency)^§	5-oxoprolinase or glutathione synthetase deficiency Ornithine transcarbamylase deficiency Carbamoyl phosphate synthetase type I deficiency	N/A	Plasma amino acids Urine organic acids Urine orotic acid	Next business day	ACT Sheet for elevated citrulline (amino acidemia/urea cycle disorder) ACMG algorithm for elevated citrulline (amino acidemia)
Glycine (Gly)	MS/MS	N/A	N/A	Nonketotic hyperglycinemia	N/A	Plasma amino acids Glycine in cerebrospinal fluid	Next business day	N/A
Leucine/isoleucine/OH proline (Xle), elevated	MS/MS	Maple syrup urine disease^§^¥	N/A	Pyruvate dehydrogenase component E3 deficiency (dihydrolipoamide dehydrogenase deficiency) Hydroxyprolinemia (hydroxy-L-proline oxidase deficiency)	Allo-isoleucine	Plasma amino acids Urine organic acids	Immediately	ACT Sheet for increased leucine (maple syrup urine disease) ACMG algorithm for elevated leucine
Leucine/isoleucine/OH proline (Xle), reduced	MS/MS	N/A	N/A	Branched-chain ketoacid dehydrogenase kinase deficiency^¥	N/A	Plasma amino acids	Next business day	N/A
Lysine (Lys)	MS/MS	N/A	2;4-dienoyl-CoA reductase deficiency	Alpha-aminoadipic semialdehyde synthase deficiency	N/A	Plasma amino acids Plasma acylcarnitines	Next business day	N/A
Methionine (Met)	MS/MS	Cystathionine beta-synthase deficiency	Methionine adenosyltransferase I/III, S-adenosylhomocysteine hydrolase, and glycine N-methyltransferase deficiencies Cobalamin metabolism defect complementation types C/D^§^‡	Methylenetetrahydrofolate reductase deficiency Cobalamin metabolism defect complementation type D combined^† Cobalamin metabolism defect complementation types E/F/G/J/X^‡	Total homocysteine	Plasma amino acids Total homocysteine	Next business day	ACT Sheet for elevated methionine +/– elevated homocysteine (homocystinuria [cystathionine beta-synthase deficiency (CBS deficiency)]) ACMG algorithm for elevated methionine +/– elevated homocysteine
Ornithine/asparagine (Orn/Asn)	MS/MS	N/A	N/A	Ornithine aminotransferase deficiency Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome	N/A	Plasma amino acids Urine amino acids	Immediately	N/A
Phenylalanine (Phe)	MS/MS	Phenylketonuria (phenylalanine hydroxylase deficiency)	Mild phenylalanine hydroxylase deficiency GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase deficiencies Dihydropteridine reductase and pterin-4 alpha-carbinolamine dehydratase deficiencies	Untreated maternal phenylketonuria**		Plasma amino acids Urine pterins	Immediately	ACT Sheet for elevated phenylalanine (phenylalanine hydroxylase deficiency [PAH]) ACMG algorithm for PAH deficiency (elevated phenylalanine)
Succinylacetone (SUAC)	MS/MS	Tyrosinemia type I (fumarylacetoacetase deficiency)	N/A	N/A	N/A	Plasma amino acids Urine organic acids Alpha fetoprotein	Next business day	ACT Sheet for increased tyrosine (tyrosinemia) ACMG algorithm for normal/elevated tyrosine, elevated succinylacetone
Tyrosine (Tyr)	MS/MS	Tyrosinemia type I (fumarylacetoacetase deficiency)	Tyrosinemia type II (tyrosine aminotransferase deficiency) Tyrosinemia type III (4-hydroxyphenylpyruvate dioxygenase deficiency)	N/A	Succinylacetone	Plasma amino acids Urine organic acids	Next business day	ACT Sheet for increased tyrosine (tyrosinemia) ACMG algorithm for elevated tyrosine, normal succinylacetone
Acylcarnitines
Carnitine (C0), reduced	MS/MS	Carnitine uptake defect (organic cation transporter 2 [OCTN2] deficiency)	N/A	Untreated maternal cases of carnitine uptake defect, glutaric acidemia type [glutaryl-CoA dehydrogenase deficiency], 3-methylcrotonyl-CoA carboxylase deficiency^¶¶	N/A	Plasma total and free carnitine Plasma acylcarnitines	Next business day	ACT Sheet for decreased C0 (carnitine uptake defect [CUD; primary carnitine deficiency]) ACMG algorithm for carnitine uptake defect (decreased C0 [free carnitine])
Carnitine (C0), elevated	MS/MS	N/A	Carnitine palmitoyltransferase type I deficiency^§	N/A	N/A	Plasma total and free carnitine Plasma acylcarnitines	Immediately	ACT Sheet for elevated C0/C16+C18 acylcarnitine (carnitine palmitoyltransferase I deficiency [CPT I]) ACMG algorithm for CPT1 (elevated C0 +/– C0/[C16+C18])
Propionylcarnitine (C3)	MS/MS	Propionic acidemia (propionyl-CoA carboxylase deficiency)^§ Multiple carboxylase deficiency (holocarboxylase deficiency)^§ Methylmalonyl-CoA mutase deficiency^§ Cobalamin metabolism defect complementation types A/B	Cobalamin metabolism defect complementation types C/D^§	Cobalamin metabolism defect complementation type F Transcobalamin receptor defect Untreated maternal vitamin B12 defect	Methylmalonic acid Methylcitric acid Total homocysteine	Plasma total and free carnitine Plasma acylcarnitines Urine organic acids	Immediately	ACT Sheet for elevated C3 acylcarnitine (propionic acidemia and methylmalonic acidemia) ACMG algorithm for elevated C3 (isolated)
Formiminoglutamic acid (FIGLU)	MS/MS	N/A	Short-chain acyl-CoA dehydrogenase deficiency Isobutyryl-CoA dehydrogenase deficiency	Glutamate formiminotransferase deficiency (FIGLUuria)	N/A	Plasma acylcarnitines Urine organic acids	Next business day	ACT Sheet for elevated C4 acylcarnitine (short-chain acyl-CoA dehydrogenase [SCAD] deficiency) ACMG algorithm for SCAD deficiency (elevated C4)
Butyryl-/isobutyrylcarnitine (C4)	MS/MS	N/A	Short-chain acyl-CoA dehydrogenase deficiency Isobutyryl-CoA dehydrogenase deficiency Glutaric acidemia type II^§	Ethylmalonic encephalopathy Glutamate formiminotransferase deficiency (FIGLUuria)	Ethylmalonic acid	Urine acylglycines Urine organic acids Plasma acylcarnitines Urine acylcarnitines	Next business day	ACT Sheet for elevated C4 acylcarnitine (short-chain acyl-CoA dehydrogenase [SCAD] deficiency) ACMG algorithm for SCAD deficiency (elevated C4)
Tiglylcarnitine (C5:1)	MS/MS	Beta-ketothiolase deficiency^§	2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (HSD10 disease)	N/A	N/A	Urine organic acids Plasma acylcarnitines Urine acylcarnitines	Immediately	ACT Sheet for elevated C5-OH acylcarnitine (organic acidemias) ACMG algorithm for Organic acidemias (elevated C5-OH)
Isovaleryl-/2-methylbutyrylcarnitine (C5)	MS/MS	Isovaleric acidemia^§	2-methylbutyrylglycinuria Glutaric acidemia type II^§	Ethylmalonic encephalopathy	N/A	Urine acylglycines Urine organic acids Plasma acylcarnitines	Immediately	ACT Sheet for elevated C5 acylcarnitine (isovaleric acidemia) ACMG algorithm for isovaleric acidemia (increased C5 [isolated])
OH butyrylcarnitine (C4-OH)	MS/MS	N/A	Short-/medium-chain acyl-CoA dehydrogenase deficiency	N/A	N/A	Urine organic acids Plasma acylcarnitines	Next business day	ACT Sheet for elevated C4-OH acylcarnitine (short-chain hydroxyacyl-Co-A dehydrogenase [SCHAD] deficiency) ACMG algorithm for elevated C4-OH (SCHAD deficiency)
Hexanoylcarnitine (C6)	MS/MS	Medium-chain acyl-CoA dehydrogenase deficiency^§	Glutaric acidemia type II^§	N/A	N/A	Urine acylglycines Urine organic acids Plasma acylcarnitines	Immediately	N/A
OH isovalerylcarnitine (C5-OH)	MS/MS	3-methylcrotonyl-CoA carboxylase deficiency 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency^§ Beta-ketothiolase deficiency^§ Multiple carboxylase deficiency (holocarboxylase deficiency)^§	2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (HSD10 disease) 3-methylglutaconic aciduria type I	MT-ATP6-related mitochondrial disease Biotinidase deficiency (partial)	N/A	Urine organic acids Plasma acylcarnitines Urine acylcarnitines	Immediately	ACT Sheet for elevated C5-OH acylcarnitine (organic acidemias) ACMG algorithm for organic acidemias (elevated C5-OH)
Octanoylcarnitine (C8)	MS/MS	Medium-chain acyl-CoA dehydrogenase deficiency^§	Glutaric acidemia type II^§ Medium-chain 3-ketoacyl-CoA thiolase deficiency	N/A	N/A	Urine acylglycines Urine organic acids Plasma acylcarnitines	Immediately	ACT Sheet for elevated C8 with lesser elevations of C6 and C10 acylcarnitine (medium-chain acyl-CoA dehydrogenase [MCAD] deficiency) ACMG algorithm for elevated C8 and lesser elevations of C6 and C10
Malonyl-/OH octanoylcarnitine (C3DC)	MS/MS	N/A	Malonyl-CoA decarboxylase deficiency Medium-chain 3-ketoacyl-CoA thiolase deficiency	N/A	N/A	Urine organic acids Plasma acylcarnitines	Immediately	ACT Sheet for elevated C3-DC acylcarnitine (malonic acidemia) ACMG algorithm for malonic acidemia (elevated C3-DC)
Decadienoylcarnitine (C10:2)	MS/MS	N/A	2;4-Dienoyl-CoA reductase deficiency	N/A	N/A	Plasma acylcarnitines Plasma amino acids	Next business day	N/A
Decenoylcarnitine (C10:1)	MS/MS	Medium-chain acyl-CoA dehydrogenase deficiency^§	Glutaric acidemia type II^§	N/A	N/A	Urine acylglycines Urine organic acids Plasma acylcarnitines	Immediately	N/A
Decanoylcarnitine (C10)	MS/MS	Medium-chain acyl-CoA dehydrogenase deficiency^§	Glutaric acidemia type II^§	N/A	N/A	Urine acylglycines Urine organic acids Plasma acylcarnitines	Immediately	N/A
Succinyl-/methylmalonylcarnitine (C4DC)	MS/MS	Methylmalonyl-CoA mutase deficiency^§ Cobalamin metabolism defect complementation types A/B	N/A	Succinyl-CoA synthase deficiency	Methylmalonic acid Total homocysteine	Urine organic acids Plasma acylcarnitines	Next business day	N/A
Glutaryl-/OH decanoylcarnitine (C5DC)	MS/MS	Glutaric acidemia type I (glutaryl-CoA dehydrogenase deficiency)^§	Glutaric acidemia type II^§	N/A	Glutaric 3-hydroxyglutaric acid 2-hydroxyglutaric acid	Urine organic acids Plasma acylcarnitines Urine acylcarnitines	Immediately	ACT Sheet for elevated C5-DC acylcarnitine (glutaric acidemia type I [GA I]) ACMG algorithm for glutaric acidemia type I (GA I; elevated C5-DC)
Dodecanoylcarnitine (C12)	MS/MS	Very-long-chain acyl-CoA dehydrogenase deficiency^§	Glutaric acidemia type II^§	N/A	N/A	Plasma acylcarnitines Urine organic acids Molecular genetic analysis	Immediately	N/A
Methylglutarylcarnitine (C6DC)	MS/MS	3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency^§	N/A	N/A	N/A	Urine organic acids Plasma acylcarnitines Urine acylcarnitines	Immediately	N/A
Tetradecanedioylcarnitine (C14:2)	MS/MS	Very-long-chain acyl-CoA dehydrogenase deficiency^§ Long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency/trifunctional protein deficiency^§	Glutaric acidemia type II^§	N/A	N/A	Plasma acylcarnitines Urine organic acids Molecular genetic analysis	Immediately	N/A
Tetradecenoylcarnitine (C14:1)	MS/MS	Very-long-chain acyl-CoA dehydrogenase deficiency^§ Long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency/trifunctional protein deficiency^§	Glutaric acidemia type II^§	N/A	N/A	Plasma acylcarnitines Urine organic acids Molecular genetic analysis	Immediately	N/A
Tetradecanoylcarnitine (C14)	MS/MS	Very-long-chain acyl-CoA dehydrogenase deficiency^§ Long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency/trifunctional protein deficiency^§	Glutaric acidemia type II^§ Carnitine-acylcarnitine translocase deficiency^§ Carnitine palmitoyltransferase type II deficiency^§	N/A	N/A	Plasma acylcarnitines Urine organic acids Molecular genetic analysis	Immediately	N/A
OH tetradecanoylcarnitine (C14-OH)	MS/MS	Long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency/trifunctional protein deficiency^§	Glutaric acidemia type II^§	N/A	N/A	Plasma total and free carnitine Plasma acylcarnitines Urine organic acids	Immediately	N/A
Palmitoleylcarnitine (C16:1)	MS/MS	Very-long-chain acyl-CoA dehydrogenase deficiency^§ Long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency/trifunctional protein deficiency^§	Glutaric acidemia type II^§ Carnitine-acylcarnitine translocase deficiency^§ Carnitine palmitoyltransferase type II deficiency^§	N/A	N/A	Plasma acylcarnitines Urine organic acids Molecular genetic analysis	Immediately	N/A
Palmitoylcarnitine (C16)	MS/MS	Very-long-chain acyl-CoA dehydrogenase deficiency^§	Glutaric acidemia type II^§ Carnitine-acylcarnitine translocase deficiency I^§ Carnitine palmitoyltransferase type II deficiency^§	N/A	N/A	Plasma total and free carnitine Plasma acylcarnitines Urine organic acids	Immediately	N/A
OH hexadecenoylcarnitine (C16:1-OH)	MS/MS	Long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency/trifunctional protein deficiency^§	N/A	N/A	N/A	Plasma total and free carnitine Plasma acylcarnitines Urine organic acids	Immediately	N/A
OH palmitoylcarnitine (C16-OH)	MS/MS	Long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency/trifunctional protein deficiency^§	Glutaric acidemia type II^§	N/A	N/A	Plasma total and free carnitine Plasma acylcarnitines Urine organic acids	Immediately	N/A
Oleylcarnitine (C18:1)	MS/MS	N/A	Carnitine-acylcarnitine translocase deficiency^§ Carnitine palmitoyltransferase type II deficiency^§	N/A	N/A	Plasma total and free carnitine Plasma acylcarnitines Urine organic acids	Immediately	ACT Sheet for increased C16 and/or C18:1 acylcarnitine (carnitine palmitoyltransferase II [CPT II] deficiency and carnitine acylcarnitine translocated [CACT] deficiency) ACMG algorithm for elevated C16 +/– C18:1 (CPT II or CACT)
Stearylcarnitine (C18)	MS/MS	N/A	Glutaric acidemia type II^§ Carnitine-acylcarnitine translocase deficiency^§ Carnitine palmitoyltransferase type II deficiency^§	N/A	N/A	Plasma total and free carnitine Plasma acylcarnitines Urine organic acids	Immediately	N/A
OH oleylcarnitine (C18:1-OH)	MS/MS	Long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency/trifunctional protein deficiency^§	N/A	N/A	N/A	Plasma total and free carnitine Plasma acylcarnitines Urine organic acids	Immediately	N/A
OH stearylcarnitine (C18-OH)	MS/MS	Long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency/trifunctional protein deficiency^§	N/A	N/A	N/A	Plasma total and free carnitine Plasma acylcarnitines Urine organic acids	Immediately	N/A
Enzymes
Biotinidase	Fluorometry	Biotinidase deficiency	N/A	N/A	N/A	Biotinidase in serum	Next business day	ACT Sheet for absent/reduced biotinidase activity (biotinidase deficiency) ACMG algorithm for biotinidase deficiency
Galactose-1-phoshate uridyltransferase (GALT)	Fluorometry	Galactose-1-phosphate uridyltransferase deficiency^§	N/A	N/A	N/A	GALT in RBCs	Immediately	ACT Sheet for absent/reduced galactose-1-phosphate uridyltransferase (GALT; classic galactosemia) ACMG algorithm for galactosemia (GALT deficiency)
Acid alpha-glucosidase (GAA)	MS/MS or fluorometry	Pompe disease	N/A	N/A	Creatine Creatinine	GAA in WBCs Glucotetrasaccharides in urine Molecular genetic analysis	Immediately	ACT Sheet for Pompe disease (glycogen storage disease type III) ACMG algorithm for Pompe disease (acid alpha-glucosidase deficiency)
Galactocerebrosidase (GALC)	MS/MS or fluorometry	N/A	N/A	Krabbe disease	Psychosine (galactosylsphingosine)	GALC in WBCs Psychosine in RBCs Molecular genetic analysis	Immediately^ΔΔ	ACT Sheet for decreased galactocerebrosidase, elevated psychosine (Krabbe disease [infantile form]) ACT Sheet for decreased galactocerebrosidase, mildly elevated psychosine (Krabbe disease [late-onset form]) ACMG algorithm for Krabbe disease (galactocerebrosidase deficiency)
Alpha-iduronidase (IDUA)	MS/MS or fluorometry	Mucopolysaccharidosis I	N/A	N/A	Dermatan sulfate Heparan sulfate	IDUA in WBCs Glycosaminoglycans in blood or urine Molecular genetic analysis	Next business day	ACT Sheet for alpha-L-iduronidase deficiency/with or without glycosaminoglycans (GAG; mucopolysaccharidosis type 1 [MPS I])
Iduronate-2-sulfatase (IDS)	MS/MS or fluorometry	Mucopolysaccharidosis II	N/A	Multiple sulfatase deficiency	Dermatan sulfate Heparan sulfate	IDS in WBCs Glycosaminoglycans in blood or urine Molecular genetic analysis	Next business day	ACT Sheet for iduronate 2-sulfatase deficiency (mucopolysaccharidoses type II) ACMG algorithm for mucopolysaccharidosis type II (MPS II; decreased iduronate 2-sulfatase [I2S] activity)
Alpha-galactosidase A (GLA)	MS/MS or fluorometry	N/A	N/A	Fabry disease	N/A	GLA in WBCs Molecular genetic analysis	Next business day	ACT Sheet for decreased alpha-galactosidase A (Fabry disease) ACMG algorithm for alpha-galactosidase A (alpha-gal A) deficiency
Acid beta-glucosidase (GBA)	MS/MS or fluorometry	N/A	N/A	Gaucher disease	Glucopsychosine (glucosylsphingosine)	GBA in WBCs Glucopsychosine in blood Molecular genetic analysis	Next business day	ACT Sheet for decreased beta-glucocerebrosidase (Gaucher disease) ACMG algorithm for Gaucher disease (decreased beta-glucocerebrosidase activity)
Acid sphingomyelinase (ASM)	MS/MS	N/A	N/A	Niemann-Pick disease A, B	Lysosphingomyelin	ASM in WBCs Lysosphingomyelin in blood Molecular genetic analysis	Next business day	ACT Sheet for decreased acid sphingomyelinase (acid sphingomyelinase deficiency [ASMD]) ACMG algorithm for acid sphingomyelinase deficiency (ASMD; decreased acid sphingomyelinase [ASM])
Glucose-6-phosphate dehydrogenase (G6PD)	Fluorometry	N/A	N/A	Glucose-6 phosphate dehydrogenase deficiency	N/A	G6PD in RBCs Molecular genetic analysis	Immediately	N/A
Other analytes
Total galactose	Fluorometry	Galactose-1-phosphate uridyltransferase deficiency^§	Galactokinase (GALK) deficiency UDP-galactose-4-epimerase (GALE) deficiency Galactose mutarotase (GALM) deficiency	N/A	N/A	GALT in RBCs Galactose-1-phosphate in RBCs GALK/GALE in RBCs	Immediately	ACT Sheet for elevated total galactose with normal GALT enzyme activity (primary or secondary hypergalactosemia) ACMG algorithm for primary or secondary hypergalactosemia (elevated galactose)
Lysophosphatidylcholines (LPC)	MS/MS	X-linked adrenoleukodystrophy	N/A	Zellweger spectrum disease Peroxisomal bifunctional protein Peroxisomal acyl-CoA oxidase (ACOX1) deficiency	LPC	Plasma very-long-chain fatty acids	Next business day	ACT Sheet for elevated lysophosphatidylcholines (X-linked adrenoleukodystrophy [X-ALD])
Guanidinoacetate (GUAC), creatine (Cr), creatinine (Crea)	MS/MS	N/A	N/A	Guanidinoacetate methyltransferase deficiency Arginine:glycine amidinotransferase deficiency Cerebral creatine deficiency syndrome 1	N/A	GUAC Creatine Creatinine in plasma or urine	Immediately	ACT Sheet for increased guanidinoacetate (guanidinoacetate methyltransferase deficiency) ACMG algorithm for GAMT deficiency (elevated guanidinoacetate)

Newborn screening markers for inborn errors of metabolism and their differential diagnoses. Conditions are categorized as much as possible based on the Recommended Uniform Screening Panel (RUSP), but also included are conditions not yet widely screened for. Second-tier tests are performed on the original newborn screening sample, are employed to clarify abnormal results for primary screening markers with poor specificity (overlapping reference and disease ranges), and determine if a screening result is reported as positive or negative. However, only few programs make use of these tests. Urgency of clinical follow-up is dependent on the likelihood that a condition can present shortly after birth and benefit of screening requires treatment initiation as early as possible.

ACMG: American College of Medical Genetics and Genomics; MS/MS: tandem mass spectrometry; ATP: adenosine triphosphate; GTP: guanosine triphosphate; RBC: red blood cell; WBC: white blood cell.

* Core and secondary conditions based on recommendations by the US Secretary of Health and Human Services.

¶ Conditions that are also identifiable by newborn screening using the respective markers but have not been recognized by Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) as core or secondary conditions.

Δ Tests performed in other than dried blood spot samples; requires additional routine tests (refer to ACMG ACT sheets and algorithms).

◊ Further information on follow-up requirements can be found from the ACMG ACT sheets and algorithms.

§ Conditions recognized, as of 2014, by the Society of Inherited Metabolic Disorders (SIMD) as time critical.^[1]

¥ Valine also typically elevated in maple syrup urine disease and reduced in branched-chain ketoacid dehydrogenase kinase deficiency.

‡ Methionine concentration in condition is low.

† Methionine concentration in condition may be low or normal.

** Newborns of mothers with poorly controlled or untreated phenylketonuria during pregnancy are not affected with phenylketonuria but may have suffered from the teratogenic effect of high phenylalanine concentrations in utero, resulting in maternal phenylketonuria syndrome.^[2] Refer to UpToDate topic on phenylketonuria for further details.

¶¶ Detection is possible because of secondary carnitine deficiency of the newborn.

ΔΔ If psychosine is markedly elevated; mild psychosine can be followed up on the next business day (refer to relevant ACT Sheets: immediate and next day).^[3,4]

References:

Society of Inherited Metabolic Disorders (SIMD) position statement: Identifying abnormal newborn screens requiring immediate notification of the health care provider. Available at: https://www.simd.org/Issues/SIMD%20NBS%20Critical%20Conditions%20policy%20statement.pdf (Accessed on September 18, 2022).
Grohmann-Held K, Burard P, Baerwald CGO, et al. Impact of pregnancy planning and preconceptual dietary training on metabolic control and offspring's outcome in phenylketonuria. J Inherit Med Dis 2022; 45:1070.
Guenzel AJ, Turgeon CT, Nickander KK, et al. The critical role of psychosine in screening, diagnosis, and monitoring of Krabbe disease. Genet Med 2020; 22:1108.
Thompson-Stone R, Ream MA, Gelb M, et al. Consensus recommendations for the classification and long-term follow up of infants who screen positive for Krabbe Disease. Mol Genet Metab 2021; 134:53.

Adapted from:

Matern D, Wilcken B, Rinaldo P. Newborn screening for inborn errors of metabolism. In: Inborn Metabolic Diseases: Diagnosis and Treatment, 5th ed, Saudubray J-M, van den Berghe G, Walter JH (Eds), Springer-Verlag 2012.
Greene C, Matern D. Newborn screening for inborn errors of metabolism. In: Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, Blau N, Duran M, Gibson KM (Eds), Springer-Verlag 2014.

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Newborn screening for inborn errors of metabolism