To facilitate a practical guide for biochemical and genetic diagnosis, we assessed which tests are necessary to diagnose each of the conditions. Accordingly we grouped the diseases into diseases diagnosed via ‘metabolic screening tests’ versus those diagnosed via a ‘single test per single disease’ approach.
As Screening Tests we defined those tests in blood and urine, which are readily available in biochemical laboratories in most developed countries, and with a yield of at least 2 IEM per test. Overall, these screening tests reliably provide clues for diagnosis for 65% (53/81) of all treatable IDs.
For the remaining 28 treatable conditions (35%) a specific ‘one test per one disease’ approach is required. These diseases are listed accordingly under Specific Tests.
For most diseases further confirmatory (biochemical / genetic) testing is needed.
As Screening Tests we defined those tests in blood and urine, which are readily available in biochemical laboratories in most developed countries, and with a yield of at least 2 IEM per test. Overall, these screening tests reliably provide clues for diagnosis for 65% (53/81) of all treatable IDs.
For the remaining 28 treatable conditions (35%) a specific ‘one test per one disease’ approach is required. These diseases are listed accordingly under Specific Tests.
For most diseases further confirmatory (biochemical / genetic) testing is needed.
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Plasma Amino Acids
Molecular testing
CSF Other
Urine Organic Acids
Plasma Total Homocysteine
Metals
CSF Neurotransmitters
Urine Glycosaminoglycans
Specific Tests
Miscellaneous
Please note: Routine metabolic screening tests comprise the following: plasma amino-acids, total homocysteine & urine organic acids, creatine metabolites, purines/pyrimidines. These tests are all accessible and affordable with the potential to identify 2 or more IEMs (max 21).
As mucopolysaccharidoses and oligosaccharidoses can often be recognized based on clinical features, urine glycosaminoglycans and oligosaccharides are listed as specific tests here.
CSF Amino Acids
Urine Purine & Pyrimidines
Urine Creatine Metabolites
Enzyme Activity
Screening Tests
Urine Oligosaccharides
Plasma Amino Acids
SLC25A15 (AR)
Plasma Amino Acids
Tyrosinemia type II
ASL (AR)
l.o. Argininemia
l.o. NAGS Deficiency
Plasma Amino Acids
TAT (AR)
CPS1 (AR)
Phenylketonuria
PDHA1 (Xlinked), DLAT (AR), PDHX (AR)
Plasma Amino Acids
l.o. OTC Deficiency
MTHFR (AR)
l.o. CPS deficiency
Plasma Amino Acids
Plasma Amino Acids,
Serum & CSF Lactate:Pyruvate Ratio
(Enzyme Activity, Gene(s) Analysis)
BCKDHA / BCKDHB/ DBT (AR)
OTC (X-linked)
ARG1 (AR)
Plasma Amino Acids,
Plasma Total Homocysteine
l.o. Citrullinemia
PAH (AR)
Plasma Amino Acids, Urine Organic Acids
Maple Syrup Urine Disease (Variant)
Plasma Amino Acids
Plasma Amino Acids
HHH syndrome
SLC25A13
NAGS (AR)
l.o. MTHFR Deficiency
l.o. Citrullinemia type II
Plasma Amino Acids
Plasma Amino Acids
PDH Complex Deficiency
ASS1 (AR)
l.o. Argininosuccinic Aciduria
Plasma Amino Acids
Plasma Amino Acids
MTR (AR)
MMADHC (AR)
Cobalamin F deficiency
l.o. MTHFR Deficiency
CBS (AR)
Plasma Total Homocysteine,
Urine Organic Acids
Plasma Total Homocysteine
Homocystinuria
Cobalamin G deficiency
LMBRD1 (AR)
Cobalamin D deficiency
Plasma Total Homocysteine,
Urine Organic Acids
MTHFR (AR)
Plasma Amino Acids,
Plasma Total Homocysteine
Plasma Total Homocysteine,
Urine Organic Acids
MTRR (AR)
Plasma Total Homocysteine
MMACHC (AR)
Cobalamin E deficiency
Plasma Total Homocysteine
Plasma Total Homocysteine,
Urine Organic Acids
Cobalamin C deficiency
GAMT (AR)
Urine Creatine Metabolites
Urine Creatine Metabolities
Creatine Transporter Defect
Urine Creatine Metabolites
Urine Creatine Metabolites
SLC6A8 (X-linked)
AGAT Deficiency
GAMT Deficiency
GATM (AR)
Urine Glycosaminoglycans,
N-Acetyl-glucosamine-6-sulfatase activity
IDS (X-linked)
Urine Glycosaminoglycans,
N-acetyl-glucosaminidase activity
Urine Glycosaminoglycans,
β-Glucuronidase activity
GNS (AR)
Hunter Syndrome (MPS II)
Sanfilippo Syndrome D (MPS IIId)
Sanfilippo Syndrome A (MPS IIIa)
Sanfilippo Syndrome C (MPS IIIc)
Sanfilippo Syndrome B (MPS IIIb)
Urine Glycosaminoglycans
Urine Glycosaminoglycans,
Iduronate-2-sulphatase activity
GUSB (AR)
Hurler Syndrome (MPS I)
Urine Glycosaminoglycans,
Heparan-N-sulfatase activity
NAGLU (AR)
SGSH (AR)
HGSNAT (AR)
Sly Syndrome (MPS VII)
IDUA (AR)
Urine Glycosaminoglycans, Acetyl CoA glucosamine N-acetyl transferase activity
Urine Glycosaminoglycans,
Iduronidase activity
MAN2B1 (AR)
Urine Oligosaccharides
Urine Oligosaccharides
α-Mannosidosis
Urine Oligosaccharides
Aspartylglycosaminuria
AGA (AR)
TAT (AR)
Urine Organic Acids
Urine Organic Acids
HMG-CoA Lyase Deficiency
3-Methylcrotonylglycinuria
Urine Organic Acids, Acylcarnitine Profile
β-Ketothiolase Deficiency
HLCS (AR)
Urine Organic Acids
l.o. Isovaleric Acidemia
ETFA, ETFB, ETFDH (AR)
MHBD Deficiency
Cobalamin C deficiency
Urine Organic Acids
mHMG-CoA Synthase Deficiency
Homocystinuria
Plasma Amino Acids, Urine Organic Acids
SCOT deficiency
MUT (AR)
Cobalamin F deficiency
GCDH (AR)
MMAA (AR)
l.o. Propionic Acidemia
Tyrosinemia Type II
MMAB (AR)
HMGCL (AR)
CBS (AR)
Cobalamin B deficiency
Urine Organic Acids
l.o. Methylmalonic Acidemia
Plasma Total Homocysteine, Urine Organic Acids
ALDH5A1 (AR)
Glutaric Acidemia II
Urine Organic Acids
Cobalamin D deficiency
HMGCS2 (AR)
PCCA / PCCB (AR)
Plasma Total Homocysteine, Urine Organic Acids
MCC1 / MCC2 (AR)
Urine Organic Acids
l.o. Glutaric Acidemia I
MMADHC (AR)
MMACHC (AR)
ACAT1 (AR)
Urine Organic Acids
HMGCL (AR)
Cobalamin A deficiency
Urine Organic Acids, Acylcarnitine Profile
Urine Organic Acids
Urine Organic Acids
Holocarboxylase Synthetase Deficiency
Urine Organic Acids, Acylcarnitine Profile
Urine Organic Acids
Urine Organic Acids
LMBRD1 (AR)
Plasma Total Homocysteine, Urine Organic Acids
Plasma Total Homocysteine, Urine Organic Acids
HSD17B10 (X-linked recessive)
OXCT1 (AR)
SSADH Deficiency
Urine Organic Acids, Acylcarnitine Profile
Urine Purines & Pyrimidines
Pyrimidine 5-Nucleotidase Superactivity
Urine Purines & Pyrimidines
Molybdenum Cofactor Deficiency Type A
Urine Purines & Pyrimidines
MOCS1, MOCS2, (AR
NT5C3 (AR)
CSF Amino Acids, Plasma Amino Acids
AMT /GLDC / GCSH (AR)
PSPH (AR)
PSAT Deficiency
CSF Amino Acids, Plasma Amino Acids
CSF Amino Acids, Plasma Amino Acids
CSF Amino-Acids
PSPH Deficiency
PSAT1 (AR)
PHGDH (AR)
CSF Amino Acids, Plasma Amino Acids
l.o. Non-Ketotic Hyperglycinemia
PHGDH Deficiency
CSF Neurotransmitters,
Gene Analysis, TH gene test
PSAT1 (AR)
SPR Deficiency
Tyrosine Hydroxylase Deficiency
DHPR Deficiency
CSF Neurotransmitters
GTPCH1 Deficiency
CSF Neurotransmitters,
Biopterin & Phe Loading Test,
Enzyme Activity, Gene Analysis
CSF Neurotransmitters &
Biopterin Loading Test
CSF Neurotransmitters &
Biopterin Loading Test
PTS (AR)
PCBD Deficiency
QDPR (AR)
GCH1 (AR)
CSF Neurotransmitters &
Biopterin Loading Test
CSF Neurotransmitters &
Biopterin Loading Test
TH (AR)
SPR (AR)
PTS Deficiency
CSF: Plasma glucose ratio
GLUT1 Deficiency Syndrome
SLC2A1 (AR)
Cerebral Folate Receptor-α Deficiency
CSF: Tetrahydrofolate
CSF Other
FOLR1 (AR)
GBA (AR)
Gaucher Disease Type III
Sjögren-Larsson syndrome
BTD (AR)
Glucocerebrosidase Enzyme Activity (lymphocytes)
ALDH3A2 (AR)
Fatty Aldehyde Dehydrogenase Enzyme Activity
Arylsulfatase-A enzyme activity
Biotinidase enzyme activity
Biotinidase Deficiency
Enzyme activity
ARSA (AR)
l.o. Metachromatic Leukodystrophy
Serum Copper & Ceruloplasmin;
Urine Deoxypyridonoline
Metals
Aceruloplasminaemia
Serum Copper & Ceruloplasmin, Urine Copper
Wilson disease
CP (AR)
ATP7A (AR)
Serum Ceruloplasmin, Copper, Iron, Ferritin
ATP7B (AR)
Menkes Disease Occipital Horn Syndrome
NPC1 NPC2 (AR)
Biotin Responsive Basal
Ganglia Disease
Gene Analysis
GLUD1 (AR)
Molecular testing
MTTL1, MTTQ, MTTH, MTTK, MTTC, MTTS1, MTND1, MTND5, MTND6, MTTS2 (Mt)
Filipin staining test (fibroblasts) &
Gene(s) Analysis
Mitochondrial DNA Mutation Testing
MELAS
Hyperinsulinism Hyperammonemia Syndrome
SLC19A3(AR)
Niemann-Pick Disease Type C
Gene Analysis (& ammonia, glucose, insulin)
Urine α-Aminoadipic Semialdehyde &
Plasma Pipecolic Acid
Plasma Vitamin B12 & Folate
Plasma 7-Dehydrocholesterol: Cholesterol ratio
Congenital Intrinsic Factor Deficiency
ALDH7A1 (AR)
CYP27A1 (AR)
Plasma Very Long Chain Fatty Acids
Pyridoxine Dependent Epilepsy
Co-Enzyme Q deficiency
Cerebrotendinous Xanthomatosis
CUBN & AMN (AR)
Imerslund-Gräsbeck Syndrome
Co-Enzyme Q (fibroblasts) & gene(s) analysis
X-linked Adrenoleukodystrophy
Plasma Vitamin B12 & Folate
Plasma Cholestanol
Miscellaneous
DHCR7 (AR)
GIF (AR)
ABCD1 (X-linked)
Smith Lemli Opitz Syndrome
COQ2, APTX, PDSS1, PDSS2, CABC1, COQ9 (most AR)