More on Treatable ID Masquerading as Autism

I did write a post a while back highlighting an excellent on line resource that gives clinicians data on 81 treatable forms of Intellectual Disability, ID (formerly known as mental retardation, MR).

Treatable ID/MR

There is a big overlap between the causes of some ID and causes of some autism.

If you have a case of autism, it is worth reviewing the 81 treatable forms of ID, just in case you have one, even a mild version causing minimal ID.  Partial dysfunctions certainly are possible, as we saw with biotin. 

It is also very interesting to look through the therapies used and see how they overlap with those used by people in their n=1 case of autism.

For example the therapy for SLOS (Smith–Lemli–Opitz syndrome) which is related to very low cholesterol is to give cholesterol and Simvastatin.  Simvastatin is widely used in older people to LOWER cholesterol.  Statins have several other known modes of action. We use Atorvastatin.

Note all the vitamin related syndromes etc.

The data is all on the online resource that is highlighted at the top of every page in this blog, but as one regular reader from Hong Kong pointed out, it is better to actually read it in table form.  

He recommended the two papers below.  I reproduced some of the tables, but I suggest you click the link to read the papers. 

The formatting is not so good, since I have cut and paste from the papers.

You have the syndromes, their therapies and their diagnostic tests.

Complicated questions should be addressed to the authors of the papers or your doctor.

Treatable inborn errors of metabolism causing intellectual disability: A systematic literature review

Table 2Overview of all 81 treatable IDs.In this table, the IEMs are grouped according to the biochemical phenotype as presented in standard textbooks, and alphabetically. Of note, primary CoQ deficiency was considered as one single IEM even though more though 6 genes have been described; this is true as well for MELAS and Pyruvate Dehydrogenase Complex deficiency.
Biochemical category	Disease name	OMIM#	Biochemical deficiency	Gene(s)
Amino acids	HHH syndrome (hyperornithinemia, hyperammonemia, homocitrullinemia)	238970	Ornithine translocase	SLC25A15 (AR)
	l.o. Non-ketotic hyperglycinemia	605899	Aminomethyltransferase/glycine decarboxylase/glycine cleavage system H protein	AMT/GLDC/GCSH (AR)
	Phenylketonuria	261600	Phenylalanine hydroxylase	PAH (AR)
	PHGDH deficiency(Serine deficiency)	601815	Phosphoglycerate dehydrogenase	PHGDH (AR)
	PSAT deficiency(Serine deficiency)	610992	Phosphoserine aminotransferase	PSAT1 (AR)
	PSPH deficiency(Serine deficiency)	614023	Phosphoserine phosphatase	PSPH (AR)
	Tyrosinemia type II	276600	Cytosolic tyrosine aminotransferase	TAT (AR)
Cholesterol & bile acids	Cerebrotendinous xanthomatosis	213700	Sterol-27-hydroxylase	CYP27A1 (AR)
	Smith–Lemli–Opitz Syndrome	270400	7-Dehydroxycholesterol reductase	DHCR7 (AR)
Creatine	AGAT deficiency	612718	Arginine: glycine amidinotransferase	GATM (AR)
	Creatine transporter Defect	300352	Creatine transporter	SLC6A8 (X-linked)
	GAMT deficiency	612736	Guanidino-acetate-N-methyltransferase	GAMT (AR)
Fatty aldehydes	Sjögren–Larsson syndrome	270200	Fatty aldehyde dehydrogenase	ALDH3A2 (AR)
Glucose transport & regulation	GLUT1 deficiency syndrome	606777	Glucose transporter blood–brain barrier	SLC2A1 (AR)
	Hyperinsulinism hyperammonemia syndrome	606762	Glutamate dehydrogenase superactivity	GLUD1 (AR)
Hyperhomocysteinemia	Cobalamin C deficiency	277400	Methylmalonyl-CoA mutase and homocysteine : methyltetrahydrofolate methyltransferase	MMACHC (AR)
	Cobalamin D deficiency	277410	C2ORF25 protein	MMADHC (AR)
	Cobalamin E deficiency	236270	Methionine synthase reductase	MTRR (AR)
	Cobalamin F deficiency	277380	Lysosomal cobalamin exporter	LMBRD1 (AR)
	Cobalamin G deficiency	250940	5-Methyltetrahydrofolate-homocysteine S-methyltransferase	MTR (AR)
	Homocystinuria	236200	Cystathatione β-synthase	CBS (AR)
	l.o. MTHFR deficiency	236250	Methylenetetrahydrofolate reductase deficiency	MTHFR (AR)
Lysosomes	α-Mannosidosis	248500	α-Mannosidase	MAN2B1 (AR)
	Aspartylglucosaminuria	208400	Aspartylglucosaminidase	AGA (AR)
	Gaucher disease type III	231000	ß-Glucosidase	GBA (AR)
	Hunter syndrome (MPS II)	309900	Iduronate-2-sulfatase	IDS (X-linked)
	Hurler syndrome (MPS I)	607014	α-L-iduronidase	IDUA (AR)
	l.o. Metachromatic leukodystrophy	250100	Arylsulfatase A	ARSA (AR)
	Niemann–Pick disease type C	257220	Intracellular transport cholesterol & sphingosines	NPC1 NPC2 (AR)
	Sanfilippo syndrome A (MPS IIIa)	252900	Heparan-N-sulfatase	SGSH (AR)
	Sanfilippo syndrome B (MPS IIIb)	252920	N-acetyl-glucosaminidase	NAGLU (AR)
	Sanfilippo syndrome C (MPS IIIc)	252930	Acetyl-CoA glucosamine-N-acetyl transferase	HGSNAT (AR)
	Sanfilippo syndrome D (MPS IIId)	252940	N-acetyl-glucosamine-6-Sulfatase	GNS (AR)
	Sly syndrome (MPS VII)	253220	β-glucuronidase	GUSB (AR)
Metals	Aceruloplasminemia	604290	Ceruloplasmin (iron homeostasis)	CP (AR)
	Menkes disease/Occipital horn syndrome	304150	Copper transport protein (efflux from cell)	ATP7A (AR)
	Wilson disease	277900	Copper transport protein (liver to bile)	ATP7B (AR)
Mitochondria	Co enzyme Q10 deficiency	607426	Coenzyme Q2 or mitochondrial parahydroxybenzoate-polyprenyltransferase; aprataxin; prenyl diphosphate synthase subunit 1; prenyl diphosphate synthase subunit 2; coenzyme Q8; coenzyme Q9	COQ2, APTX, PDSS1, PDSS2, CABC1, COQ9 (most AR)
	MELAS	540000	Mitochondrial energy deficiency	MTTL1, MTTQ,MTTH, MTTK,MTTC, MTTS1,MTND1, MTND5,MTND6, MTTS2 (Mt)
	PDH complex deficiency	OMIM# according to each enzyme subunit deficiency: 312170; 245348; 245349	Pyruvate dehydrogenase complex (E1α, E2, E3)	PDHA1 (X-linked), DLAT (AR), PDHX (AR)
Neurotransmission	DHPR deficiency (biopterin deficiency)	261630	Dihydropteridine reductase	QDPR (AR)
	GTPCH1 deficiency (biopterin deficiency)	233910	GTP cyclohydrolase	GCH1 (AR)
	PCD deficiency (biopterin deficiency)	264070	Pterin-4α-carbinolamine dehydratase	PCBD1 (AR)
	PTPS deficiency (biopterin deficiency)	261640	6-Pyruvoyltetrahydropterin synthase	PTS (AR)
	SPR deficiency (biopterin deficiency)	612716	Sepiapterin reductase	SPR (AR)
	SSADH deficiency	271980	Succinic semialdehyde dehydrogenase	ALDH5A1 (AR)
	Tyrosine Hydroxylase Deficiency	605407	Tyrosine Hydroxylase	TH (AR)
Organic acids	3-Methylcrotonyl glycinuria	GENE OMIM # 210200; 210210	3-Methylcrotonyl CoA carboxylase (3-MCC)	MCC1/MCC2 (AR)
	3-Methylglutaconic aciduria type I	250950	3-Methylglutaconyl-CoA hydratase	AUH (AR)
	β-Ketothiolase deficiency	203750	Mitochondrial acetoacetyl-CoA thiolase	ACAT1 (AR)
	Cobalamin A deficiency	251100	MMAA protein	MMAA (AR)
	Cobalamin B deficiency	251110	Cob(I)alamin adenosyltransferase	MMAB (AR)
	Ethylmalonic encephalopathy	602473	Mitochondrial sulfur dioxygenase	ETHE1 (AR)
	l.o. Glutaric acidemia I	231670	Glutaryl-CoA dehydrogenase	GCDH (AR)
	Glutaric acidemia II	231680	Multiple acyl-CoA dehydrogenase	ETFA, ETFB,ETFDH (AR)
	HMG-CoA lyase deficiency	246450	3-Hydroxy-3-methylglutaryl-CoA lyase	HMGCL (AR)
	l.o. Isovaleric acidemia	243500	Isovaleryl-CoA dehydrogenase	IVD (AR)
	Maple syrup urine disease (variant)	248600	Branched-chain 2-ketoacid complex	BCKDHA/BCKDHB/ DBT (AR)
	l.o. Methylmalonic acidemia	251000	Methylmalonyl-CoA mutase	MUT (AR)
	MHBD deficiency	300438	2-Methyl-3-hydroxybutyryl-CoA dehydrogenase	HSD17B10 (X-linked recessive)
	mHMG-CoA synthase deficiency	605911	Mitochondrial 3-hydroxy-3-Methylglutaryl-CoA synthase	HMGCS2 (AR)
	l.o. Propionic acidemia	606054	Propionyl-CoA carboxylase	PCCA/PCCB (AR)
	SCOT deficiency	245050	Succinyl-CoA 3-oxoacid CoA transferase	OXCT1 (AR)
Peroxisomes	X-linked adrenoleukodystrophy	300100	Peroxisomal transport membrane protein ALDP	ABCD1 (X-linked)
Pyrimidines	Pyrimidine 5-nucleotidase superactivity	GENE OMIM # 606224	Pyrimidine-5-nucleotidase Superactivity	NT5C3 (AR)
Urea cycle	l.o. Argininemia	207800	Arginase	ARG1 (AR)
	l.o. Argininosuccinic aciduria	207900	Argininosuccinate lyase	ASL (AR)
	l.o. Citrullinemia	215700	Argininosuccinate Synthetase	ASS1 (AR)
	Citrullinemia type II	605814	Citrin (aspartate–glutamate carrier)	SLC25A13
	l.o. CPS deficiency	237300	Carbamoyl phosphate synthetase	CPS1 (AR)
	l.o. NAGS deficiency	237310	N-acetylglutamate synthetase	NAGS (AR)
	l.o. OTC Deficiency	311250	Ornithine transcarbamoylase	OTC (X-linked)
Vitamins/co-factors	Biotinidase deficiency	253260	Biotinidase	BTD (AR)
	Biotin responsive basal ganglia disease	607483	Biotin transport	SLC19A3(AR)
	Cerebral folate receptor-α deficiency	613068	a.o. Cerebral folate transporter	FOLR1 (AR)
	Congenital intrinsic factor deficiency	261000	Intrinsic factor deficiency	GIF (AR)
	Holocarboxylase synthetase deficiency	253270	Holocarboxylase synthetase	HLCS (AR)
	Imerslund Gräsbeck syndrome	261100	IF-Cbl receptor defects (cubulin/amnionless)	CUBN & AMN (AR)
	Molybdenum co-factor deficiency type A	252150	Sulfite oxidase & xanthine dehydrogenase & aldehyde oxidase	MOCS1, MOCS2,(AR)
	Pyridoxine dependent epilepsy	266100	Pyridoxine phosphate oxidase	ALDH7A1 (AR),
	Thiamine responsive encephalopathy	606152	Thiamine transport	SLC19A3 (AR)

Table 5Overview of all causal therapies (n=91).This Table provides an overview of the specific therapy/-ies available for each IEM with relevant level(s) of evidence, therapeutic effect(s) on primary and/or secondary outcomes and use in clinical practice. For 10 IEMs, two therapies are available; these are listed separately (in brackets).
Disease name	Therapeutic modality (−ies)	Level of evidence	Clinical practice	Treatment effect	Literature references
Aceruloplasminemia	Iron chelation	4	Standard of care	D,E	[[45], [46],[47]]
(X-linked)adrenoleukodystrophy	Stemcell transplantation (Gene therapy)	1c (5)	Individual basis (Individual basis)	D,E (D,E)	[[48], [49],[50]]
AGAT deficiency	Creatine supplements	4	Standard of care	A,D	[[51], [52],[53]]
α-Mannosidosis	Haematopoietic stem cell transplantation	4-5	Individual basis	D	[54
l.o. Argininemia	Dietary protein restriction, arginine supplement, sodium benzoate, phenylbutyrate (Liver transplantation)	2b (4)	Standard of care (Individual basis)	B,C,D,E,F,G (C)	[[55], [56],[57], [58],[59], [60],[61]]
l.o. Argininosuccinic aciduria	Dietary protein restriction, arginine supplement, sodium benzoate, phenylbutyrate (liver transplantation)	2b (4)	Standard of care (individual basis)	B,C,D,E,F,G (C)	[[55], [56],[57], [58],[60], [61]]
Aspartylglucosaminuria	Haematopoietic stem cell transplantation	4-5	Individual basis	D	[62
β-Ketothiolase deficiency	Avoid fasting, sickday management, protein restriction	5	Standard of care	C	[[63], [64],[65]]
Biotin responsive basal ganglia disease	Biotin supplement	4	Standard of care	A,E	[66
Biotinidase deficiency	Biotin supplement	2c	Standard of care	A,E,G	[67
Cerebral folate receptor-α deficiency	Folinic acid	4	Standard of care	A,D,E,F	[[68], [69]]
Cerebrotendinous xanthomatosis	Chenodesoxycholic acid, HMG reductase inhibitor	4	Standard of care	B,D,E,G	[[70], [71],[72]]
l.o. Citrullinemia	Dietary protein restriction, arginine supplement, sodium benzoate, phenylbutyrate (Liver transplantation)	2b (4)	Standard of care (Individual basis)	B,C,D,E,F,G (C)	[[55], [56],[57], [60],[61]]
Citrullinemia type II	Dietary protein restriction, arginine supplement, sodium benzoate, phenylbutyrate (Liver transplantation)	2b (4)	Standard of care (Individual basis)	B,C,D,E,F,G (C)	[[50], [51],[52], [73],[55], [56]]
Co enzyme Q10 deficiency	CoQ supplements	4	Standard of care	E,F	[[74], [75]]
Cobalamin A deficiency	Hydroxycobalamin, protein restriction	4	Standard of care	C,G	[[76], [77],[78], [79]]
Cobalamin B deficiency	Hydroxycobalamin, protein restriction	4	Standard of care	C,G	[[76], [77],[78], [79]]
Cobalamin C deficiency	Hydroxycobalamin	4	Standard of care	C,D,G	[[76], [77],[78], [79]]
Cobalamin D deficiency	Hydroxy-/cyanocobalamin	4	Standard of care	C,D,G	[[76], [77],[78], [79]]
Cobalamin E deficiency	Hydroxy-/methylcobalamin, betaine	4	Standard of care	C,D,G	[[76], [77],[78], [79]]
Cobalamin F deficiency	Hydroxycobalamin	4	Standard of care	C,D,G	[[76], [77],[78], [79]]
Cobalamin G deficiency	Hydroxy-/methylcobalamin, betaine	4	Standard of care	C,D,G	[[76], [78],[79]]
Congenital intrinsic factor deficiency	Hydroxycobalamin	4	Standard of care	A,E,G	[80
l.o. CPS deficiency	Dietary protein restriction, arginine supplement, sodium benzoate, phenylbutyrate (Liver transplantation)	2b & 4	Standard of care (Individual basis)	B,C,D,E,F,G (C)	[[55], [56],[57], [60],[61]]
Creatine transporter defect	Creatine, glycine, arginine supplements	4-5	Individual basis	F	[29
DHPR deficiency	BH4,diet, amine replacement, folinic acid	4	Standard of care	A,E	[52
Ethylmalonic encephalopathy	N-acetylcysteine, oral metronidazol	4	Standard of care	E,G	[81
GAMT deficiency	Arginine restriction, creatine & ornithine supplements	4	Standard of care	B,D,E,F	[[48], [52],[82], [83]]
Gaucher disease type III	Haematopoietic stem cell transplantation	4–5	Individual basis	D,G	[[84], [85]]
GLUT1 deficiency syndrome	Ketogenic diet	4	Standard of Care	F	[[19], [86]]
l.o. Glutaric acidemia I	Lysine restriction, carnitine supplements	2c	Standard of care	C,D,E,G	[[87], [88]]
Glutaric acidemia II	Carnitine, riboflavin, β-hydroxybutyrate supplements; sick day management	5	Standard of care	C,G	[[89], [90]]
GTPCH1 deficiency	BH4, amine replacement	4	Standard of care	A,E	[91
HHH syndrome	Dietary protein restriction, ornithine supplement, sodium benzoate, phenylacetate	4	Standard of care	B,C,D,E,F,G	[92
HMG-CoA lyase deficiency	Protein restriction, avoid fasting, sick day management,	5	Standard of care	C	[[58], [59],[60], [93]]
Holocarboxylase synthetase deficiency	Biotin supplement	4	Standard of care	A,E,G	[[94], [95]]
Homocystinuria	Methionine restriction, +/−pyridoxine, +/−betaine	2c	Standard of care	C,D,G	[[96], [76]]
Hunter syndrome (MPS II)	Haematopoietic stem cell transplantation	4–5	Individual basis	D,G	[[24], [85],[97]]
Hurler syndrome (MPS I)	Haematopoietic stem cell transplantation	1c	Standard of care	D,G	[[24], [85],[97]]
Hyperammonemia–Hyperinsulinism syndrome	Diazoxide	4–5	Standard of care	D	[[98], [99]]
Imerslund Gräsbeck syndrome	Hydroxycobalamin	4	Standard of Care	A,E,G	[100
l.o. Isovaleric acidemia	Dietary protein restriction, carnitine supplements, avoid fasting, sick day management	2c	Standard of care	C,G	[[101], [102],[103], [104],[93]]
l.o. NAGS deficiency	Dietary protein restriction, arginine supplement, sodium benzoate, phenylbutyrate (Liver transplantation)	2b & 4	Standard of care (Individual basis)	B,C,D,E,F,G (C)	[[55], [56],[57], [105],[60], [61]]
l.o. Non-ketotic hyperglycinemia	Glycine restriction; +/−sodium benzoate, NMDA receptor antagonists, other neuromodulating agents	4-5	Standard of Care	B,D,E,F	[106
Maple syrup urine disease (variant)	Dietary restriction branched amino-acids, avoid fasting, (Liver transplantation)	4 & 4	Standard of care (Individual basis)	B,C,D (A,C)	[[107], [108],[109], [110]]
MELAS	Arginine supplements	4–5	Standard of Care	C,D,E,F	[26
Menkes disease occipital horn syndrome	Copper histidine	4	Individual basis	D	[[111], [112],[113]]
l.o. Metachromatic leukodystrophy	Haematopoietic stem cell transplantation	4-5	Individual basis	D	[[114], [85]]
3-Methylcrotonyl glycinuria	Dietary protein restriction; carnitine, glycine, biotin supplements; avoid fasting; sick day management	5	Standard of care	C	[[115], [116]]
3-Methylglutaconic aciduria type I	Carnitine Supplements, Avoid Fasting, Sick Day Management	5	Standard of care	C	[117
l.o. Methylmalonic acidemia	Dietary protein restriction, carnitine supplements, avoid fasting, sick day management	2c	Standard of care	C,G	[[101], [102],[103], [104],[93]]
MHBD deficiency	Avoid fasting, sick day management, isoleucine restricted diet	5	Standard of care	C	[[63], [64],[65], [93]]
mHMG-CoA synthase deficiency	Avoid fasting,sick day management, +/−dietary precursor restriction	5	Standard of care	C	[[63], [64],[65], [93]]
Molybdenum co-factor deficiency type A	Precursor Z/cPMP	4	Individual basis	A,F	[25
l.o. MTHFR deficiency	Betaine supplements, +/−folate, carnitine, methionine supplements	4	Standard of care	C,D,G	[[76], [79]]
Niemann–Pick disease type C	Miglustat	1b	Standard of care	D,E	[[118], [119],[120], [121]]
l.o. OTC deficiency	Dietary protein restriction, citrulline supplements, Sodium benzoate/phenylbutyrate (Liver transplantation)	2b & 4	Standard of care (Individual basis)	B,C,D,E,F,G (C)	[[55], [56],[57], [60],[61]]
PCD deficiency	BH4	4	Standard of care	A,E	[91
PDH complex deficiency	Ketogenic diet & thiamine	4	Individual basis	D,E,F	[122
Phenylketonuria	Dietary phenylalanine restriction +/−amino-acid supplements (BH(4) supplement)	2a (4)	Standard of care (Individual basis)	B, D, E (C)	[[123], [23],[124], [143]]
PHGDH deficiency	L-serine & +/−glycine supplements	4	Standard of care	D,F	[[125], [126]]
PSAT deficiency	L-serine & +/−glycine supplements	4	Standard of care	D,F	[[125], [126]]
l.o. Propionic acidemia	Dietary protein restriction, carnitine supplements, avoid fasting, sick day management	2c	Standard of care	C,G	[[101], [102],[103], [104],[93]]
PSPH deficiency	L-serine & +/−glycine supplements	4	Standard of care	D,F	[[125], [126]]
PTPS deficiency	BH4, diet, amine replacement	4	Standard of care	A,E	[91
Pyridoxine dependent epilepsy	Pyridoxine	4	Standard of care	A,F	[[127], [128]]
Pyrimidine 5-nucleotidase superactivity	Uridine supplements	1b	Standard of care	A,B,F,G	[129
Sanfilippo syndrome A (MPS IIIa)	Haematopoietic stem cell transplantation	4–5	Individual basis	D	[[24], [85],[97]]
Sanfilippo syndrome B (MPS IIIb)	Haematopoietic stem cell transplantation	4–5	Individual basis	D	[[24], [85],[97]]
Sanfilippo syndrome C (MPS IIIc)	Haematopoietic Stemcell Transplantation	4–5	Individual Basis	D	[[24], [85],[97]]
Sanfilippo syndrome D (MPS IIId)	Haematopoietic stem cell transplantation	4–5	Individual basis	D	[[24], [85],[97]]
SCOT deficiency	Avoid fasting, protein restriction, sick day management	5	Standard of care	C	[65
Sjögren–Larsson syndrome	Diet: low fat, medium chain & essential fatty acid supplements & Zileuton	5	Individual basis	D,G	[[130], [131]]
Sly syndrome (MPS VII)	Haematopoietic stem cell transplantation	4-5	Individual basis	D	[[24], [85],[97]]
Smith–Lemli–Opitz syndrome	Cholesterol & simvastatin	4–5	Individual basis	B,D	[[27], [132],[133]]
SPR deficiency	Amine replacement	4	Standard of care	A,E	[134
SSADH deficiency	Vigabatrin	4	Individual basis	B,F	[135
Thiamine-responsive encephalopathy	Thiamin supplement	4-5	Standard of care	E	[[136], [137]]
Tyrosine hydroxylase deficiency	L-dopa substitution	4	Standard of care	A,E	[138
Tyrosinemia type II	Dietary phenylalanine & tyrosine restriction	4-5	Standard of care	D,G	[[34], [139],[140]]
Wilson disease	Zinc & tetrathiomolybdate	1b	Standard of care	E,G	[[113], [141],[142]]

The metabolic evaluation of the child with an intellectual 

developmental disorder: Diagnostic algorithm for identification of treatable causes and new digital resource

Table 2aOverview of the first tier metabolic screening tests denoting all diseases (with OMIM# and gene(s)) potentially identified per individual test.
Diagnostic test	Disease	OMIM#	Gene
Blood tests
Plasma amino acids	l.o. Argininemia	207800	ARG1 (AR)
Plasma amino acids	l.o. Argininosuccinic aciduria	207900	ASL (AR)
Plasma amino acids	l.o. Citrullinemia	215700	ASS1 (AR)
Plasma amino acids	Citrullinemia type II	605814	SLC25A13 (AR)
Plasma amino acids	l.o. CPS deficiency	237300	CPS1 (AR)
Plasma amino acids	HHH syndrome (hyperornithinemia, hyperammonemia, homocitrullinuria)	238970	SLC25A15 (AR)
Plasma amino acids	Maple syrup urine disease (variant)	248600	BCKDHA/BCKDHB/DBT(AR)
Plasma amino acids	l.o. NAGS deficiency	237310	NAGS (AR)
Plasma amino acids (& UOA incl orotic acid)	l.o. OTC deficiency	311250	OTC (X-linked)
Plasma amino acids	Phenylketonuria	261600	PAH (AR)
Plasma amino acids (& UOA)	Tyrosinemia type II	276600	TAT (AR)
Plasma amino acids (tHcy)	l.o. MTHFR deficiency	236250	MTHFR (AR)
Plasma total homocysteine	Cobalamin E deficiency	236270	MTRR (AR)
Plasma total homocysteine	Cobalamin G deficiency	250940	MTR (AR)
Plasma total homocysteine (& UOA)	Cobalamin F deficiency	277380	LMBRD1 (AR)
Plasma total homocysteine (& OUA)	Cobalamin C deficiency	277400	MMACHC (AR)
Plasma total homocysteine (& OUA)	Homocystinuria	236200	CBS (AR)
Plasma total homocysteine (& PAA)	l.o. MTHFR deficiency	236250	MTHFR (AR)
Plasma total homocysteine (& UOA)	Cobalamin D deficiency	277410	MMADHC (AR)
Serum ceruloplasmin & copper (& serum iron & ferritin)	Aceruloplasminemia	604290	CP (AR)
Serum copper & ceruloplasmin (& urine copper)	MEDNIK diseases	609313	AP1S1 (AR)
Serum copper & ceruloplasmin (urine deoxypyridonoline)	Menkes disease/occipital horn syndrome	304150	ATP7A (AR)
Serum copper & ceruloplasmin (& urine copper)	Wilson disease	277900	ATP7B (AR)
Urine tests
Urine creatine metabolites	AGAT deficiency	612718	GATM (AR)
Urine creatine metabolites	Creatine transporter defect	300352	SLC6A8 (X-linked)
Urine creatine metabolites	GAMT deficiency	612736	GAMT (AR)
Urine glycosaminoglycans	Hunter syndrome (MPS II)	309900	IDS (X-linked)
Urine glycosaminoglycans	Hurler syndrome (MPS I)	607014	IDUA (AR)
Urine glycosaminoglycans	Sanfilippo syndrome A (MPS IIIa)	252900	SGSH (AR)
Urine glycosaminoglycans	Sanfilippo syndrome B (MPS IIIb)	252920	NAGLU (AR)
Urine glycosaminoglycans	Sanfilippo syndrome C (MPS IIIc)	252930	HGSNAT (AR)
Urine glycosaminoglycans	Sanfilippo syndrome D (MPS IIId)	252940	GNS (AR)
Urine glycosaminoglycans	Sly syndrome (MPS VII)	253220	GUSB (AR)
Urine oligosaccharides	α-Mannosidosis	248500	MAN2B1 (AR)
Urine oligosaccharides	Aspartylglucosaminuria	208400	AGA (AR)
Urine organic acids	β-Ketothiolase deficiency	203750	ACAT1 (AR)
Urine organic acids	Cobalamin A deficiency	251100	MMAA (AR)
Urine organic acids	Cobalamin B deficiency	251110	MMAB (AR)
Urine organic acids	l.o. Glutaric acidemia I	231670	GCDH (AR)
Urine organic acids	Glutaric acidemia II	231680	ETFA, ETFB, ETFDH(AR)
Urine organic acids	HMG-CoA lyase deficiency	246450	HMGCL (AR)
Urine organic acids	Holocarboxylase synthetase deficiency	253270	HLCS (AR)
Urine organic acids	3-Methylglutaconic aciduria type I	250950	AUH (AR)
Urine organic acids	MHBD deficiency	300438	HSD17B10 (X-linked recessive)
Urine organic acids	mHMG-CoA synthase deficiency	605911	HMGCS2 (AR)
Urine organic acids	SCOT deficiency	245050	OXCT1 (AR)
Urine organic acids	SSADH deficiency	271980	ALDH5A1 (AR)
Urine organic acids (& ACP)	Ethylmalonic encephalopathy	602473	ETHE1 (AR)
Urine organic acids (& ACP)	l.o. Isovaleric acidemia	243500	IVD (AR)
Urine organic acids (& ACP)	3-Methylcrotonylglycinuria	210200	MCC1/MCC2 (AR)
Urine organic acids (& ACP)	l.o. Methylmalonic acidemia	251000	MUT (AR)
Urine organic acids (& tHcy)	Cobalamin C deficiency	277400	MMACHC (AR)
Urine organic acids (& tHcy)	Cobalamin D deficiency	277410	MMADHC (AR)
Urine organic acids (& tHcy)	Homocystinuria	236200	CBS (AR)
Urine organic acids incl orotic acid (& PAA)	l.o. OTC deficiency	311250	OTC (X-linked)
Urine organic acids (& PAA)	Tyrosinemia type II	276600	TAT (AR)
Urine organic acids (& ACP)	l.o. Propionic acidemia	606054	PCCA/PCCB (AR)
Urine organic acids (tHcy)	Cobalamin F deficiency	277380	LMBRD1 (AR)
Urine purines & pyrimidines	Lesch–Nyhan syndrome	300322	HPRT (AR)
Urine purines & pyrimidines	Molybdenum cofactor deficiency type A	252150	MOCS1, MOCS2, (AR)
Urine purines & pyrimidines	Pyrimidine 5-nucleotidase superactivity	606224	NT5C3 (AR)

Table 2bOverview of all diseases (in alphabetical order) requiring second tier biochemical testing, i.e. a specific test per disease approach; for each disease the OMIM# and gene(s) are listed.
Disease	OMIM#	Gene(s)	Diagnostic test
(X-linked) Adrenoleukodystrophy	300100	ABCD1 (X-linked)	Plasma very long chain fatty acids
Biotin responsive basal ganglia disease	607483	SLC19A3 (AR)	Gene analysis
Biotinidase deficiency	253260	BTD (AR)	Biotinidase enzyme activity
Cerebral folate receptor-α deficiency	613068	FOLR1 (AR)	CSF 5′-methyltetrahydrofolate
Cerebrotendinous xanthomatosis	213700	CYP27A1 (AR)	Plasma cholestanol
Co-enzyme Q10 deficiency	607426	COQ2, APTX, PDSS1,PDSS2, CABC1, COQ9(most AR)	Co-enzyme Q (fibroblasts) & gene analysis
Congenital intrinsic factor deficiency	261000	GIF (AR)	Plasma vitamin B12 & folate
Dihydrofolate reductase deficiency	613893	DHFR (AR)	CSF 5′-methyltetrahydrofolate
DHPR deficiency (biopterin deficiency)	261630	QDPR (AR)	CSF neurotransmitters & biopterin loading test
Gaucher disease type III	231000	GBA (AR)	Glucocerebrosidase enzyme activity (lymphocytes)
GLUT1 deficiency syndrome	606777	SLC2A1 (AR)	CSF: plasma glucose ratio
GTPCH1 deficiency	233910	GCH1 (AR)	CSF neurotransmitters & biopterin loading test
Hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC)	613280	SLC30A10	Whole blood manganese
Hyperinsulinism hyperammonemia syndrome	606762	GLUD1 (AR)	Gene analysis (& ammonia, glucose, insulin)
Imerslund Gräsbeck syndrome	261100	CUBN & AMN (AR)	Plasma vitamin B12 & folate
MELAS	540000	MTTL1, MTTQ, MTTH,MTTK, MTTC, MTTS1,MTND1, MTND5, MTND6,MTTS2 (Mt)	Mitochondrial DNA mutation testing
l.o. Metachromatic leukodystrophy	250100	ARSA (AR)	Arylsulfatase-α enzyme activity
Niemann–Pick disease type C	257220	NPC1 NPC2 (AR)	Filipin staining test (fibroblasts) & gene analyses
l.o. Non-ketotic hyperglycinemia	605899	AMT/GLDC/GCSH (AR)	CSF amino acids (& PAA)
PCBD deficiency (biopterin deficiency)	264070	PCBD1 (AR)	CSF neurotransmitters & biopterin loading test
PDH complex deficiency	OMIM# according to each enzyme subunit deficiency: 312170;245348; 245349	PDHA1 (X-linked), DLAT(AR), PDHX (AR)	Serum & CSF lactate:pyruvate ratio enzyme activity, gene analysis
PHGDH deficiency (serine deficiency)	601815	PHGDH (AR)	CSF amino acids (& PAA)
PSAT deficiency (serine deficiency)	610992	PSAT1 (AR)	CSF amino acids (& PAA)
PSPH deficiency (serine deficiency)	614023	PSPH (AR)	CSF amino acids (& PAA)
PTS deficiency (biopterin deficiency)	261640	PTS (AR)	CSF neurotransmitters & biopterin loading test
Pyridoxine dependent epilepsy	266100	ALDH7A1 (AR)	Urine α-aminoadipic semialdehyde & plasma pipecolic acid
Sjögren Larsson syndrome	270200	ALDH3A2 (AR)	Fatty aldehyde dehydrogenase enzyme activity
Smith Lemli Opitz syndrome	270400	DHCR7 (AR)	Plasma 7-dehydrocholesterol:cholesterol ratio
SPR deficiency (biopterin deficiency)	612716	SPR (AR)	CSF neurotransmitters, biopterin & Phe loading test (enzyme activity, gene analysis)
Thiamine responsive encephalopathy	606152	SLC19A3 (AR)	Gene analysis
Tyrosine hydroxylase deficiency	605407	TH (AR)	CSF neurotransmitters, gene analysis
VMAT2 deficiency	193001	SLC18A2 (AR)	Urine mono-amine metabolites