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Thursday, 22 September 2016

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).





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.







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
MTTL1MTTQ,MTTHMTTK,MTTCMTTS1,MTND1MTND5,MTND6MTTS2 (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
ETFAETFB,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
MOCS1MOCS2,(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
(X-linked)adrenoleukodystrophy
Stemcell transplantation (Gene therapy)
1c (5)
Individual basis (Individual basis)
D,E (D,E)
AGAT deficiency
Creatine supplements
4
Standard of care
A,D
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)
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)
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
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
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)
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)
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
Cobalamin B deficiency
Hydroxycobalamin, protein restriction
4
Standard of care
C,G
Cobalamin C deficiency
Hydroxycobalamin
4
Standard of care
C,D,G
Cobalamin D deficiency
Hydroxy-/cyanocobalamin
4
Standard of care
C,D,G
Cobalamin E deficiency
Hydroxy-/methylcobalamin, betaine
4
Standard of care
C,D,G
Cobalamin F deficiency
Hydroxycobalamin
4
Standard of care
C,D,G
Cobalamin G deficiency
Hydroxy-/methylcobalamin, betaine
4
Standard of care
C,D,G
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)
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
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
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
Hurler syndrome (MPS I)
Haematopoietic stem cell transplantation
1c
Standard of care
D,G
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
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)
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)
MELAS
Arginine supplements
4–5
Standard of Care
C,D,E,F
[26
Menkes disease occipital horn syndrome
Copper histidine
4
Individual basis
D
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
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
MHBD deficiency
Avoid fasting, sick day management, isoleucine restricted diet
5
Standard of care
C
mHMG-CoA synthase deficiency
Avoid fasting,sick day management, +/−dietary precursor restriction
5
Standard of care
C
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
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)
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)
PHGDH deficiency
L-serine & +/−glycine supplements
4
Standard of care
D,F
PSAT deficiency
L-serine & +/−glycine supplements
4
Standard of care
D,F
l.o. Propionic acidemia
Dietary protein restriction, carnitine supplements, avoid fasting, sick day management
2c
Standard of care
C,G
PSPH deficiency
L-serine & +/−glycine supplements
4
Standard of care
D,F
PTPS deficiency
BH4, diet, amine replacement
4
Standard of care
A,E
[91
Pyridoxine dependent epilepsy
Pyridoxine
4
Standard of care
A,F
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
Sanfilippo syndrome B (MPS IIIb)
Haematopoietic stem cell transplantation
4–5
Individual basis
D
Sanfilippo syndrome C (MPS IIIc)
Haematopoietic Stemcell Transplantation
4–5
Individual Basis
D
Sanfilippo syndrome D (MPS IIId)
Haematopoietic stem cell transplantation
4–5
Individual basis
D
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
Sly syndrome (MPS VII)
Haematopoietic stem cell transplantation
4-5
Individual basis
D
Smith–Lemli–Opitz syndrome
Cholesterol & simvastatin
4–5
Individual basis
B,D
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
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
Wilson disease
Zinc & tetrathiomolybdate
1b
Standard of care
E,G









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
ARG1 (AR)
Plasma amino acids
l.o. Argininosuccinic aciduria
ASL (AR)
Plasma amino acids
l.o. Citrullinemia
ASS1 (AR)
Plasma amino acids
Citrullinemia type II
SLC25A13 (AR)
Plasma amino acids
l.o. CPS deficiency
CPS1 (AR)
Plasma amino acids
HHH syndrome (hyperornithinemia, hyperammonemia, homocitrullinuria)
SLC25A15 (AR)
Plasma amino acids
Maple syrup urine disease (variant)
BCKDHA/BCKDHB/DBT(AR)
Plasma amino acids
l.o. NAGS deficiency
NAGS (AR)
Plasma amino acids (& UOA incl orotic acid)
l.o. OTC deficiency
OTC (X-linked)
Plasma amino acids
Phenylketonuria
PAH (AR)
Plasma amino acids (& UOA)
Tyrosinemia type II
TAT (AR)
Plasma amino acids (tHcy)
l.o. MTHFR deficiency
MTHFR (AR)
Plasma total homocysteine
Cobalamin E deficiency
MTRR (AR)
Plasma total homocysteine
Cobalamin G deficiency
MTR (AR)
Plasma total homocysteine (& UOA)
Cobalamin F deficiency
LMBRD1 (AR)
Plasma total homocysteine (& OUA)
Cobalamin C deficiency
MMACHC (AR)
Plasma total homocysteine (& OUA)
Homocystinuria
CBS (AR)
Plasma total homocysteine (& PAA)
l.o. MTHFR deficiency
MTHFR (AR)
Plasma total homocysteine (& UOA)
Cobalamin D deficiency
MMADHC (AR)
Serum ceruloplasmin & copper (& serum iron & ferritin)
Aceruloplasminemia
CP (AR)
Serum copper & ceruloplasmin (& urine copper)
MEDNIK diseases
AP1S1 (AR)
Serum copper & ceruloplasmin (urine deoxypyridonoline)
Menkes disease/occipital horn syndrome
ATP7A (AR)
Serum copper & ceruloplasmin (& urine copper)
Wilson disease
ATP7B (AR)
Urine tests
Urine creatine metabolites
AGAT deficiency
GATM (AR)
Urine creatine metabolites
Creatine transporter defect
SLC6A8 (X-linked)
Urine creatine metabolites
GAMT deficiency
GAMT (AR)
Urine glycosaminoglycans
Hunter syndrome (MPS II)
IDS (X-linked)
Urine glycosaminoglycans
Hurler syndrome (MPS I)
IDUA (AR)
Urine glycosaminoglycans
Sanfilippo syndrome A (MPS IIIa)
SGSH (AR)
Urine glycosaminoglycans
Sanfilippo syndrome B (MPS IIIb)
NAGLU (AR)
Urine glycosaminoglycans
Sanfilippo syndrome C (MPS IIIc)
HGSNAT (AR)
Urine glycosaminoglycans
Sanfilippo syndrome D (MPS IIId)
GNS (AR)
Urine glycosaminoglycans
Sly syndrome (MPS VII)
GUSB (AR)
Urine oligosaccharides
α-Mannosidosis
MAN2B1 (AR)
Urine oligosaccharides
Aspartylglucosaminuria
AGA (AR)
Urine organic acids
β-Ketothiolase deficiency
ACAT1 (AR)
Urine organic acids
Cobalamin A deficiency
MMAA (AR)
Urine organic acids
Cobalamin B deficiency
MMAB (AR)
Urine organic acids
l.o. Glutaric acidemia I
GCDH (AR)
Urine organic acids
Glutaric acidemia II
ETFA, ETFB, ETFDH(AR)
Urine organic acids
HMG-CoA lyase deficiency
HMGCL (AR)
Urine organic acids
Holocarboxylase synthetase deficiency
HLCS (AR)
Urine organic acids
3-Methylglutaconic aciduria type I
AUH (AR)
Urine organic acids
MHBD deficiency
HSD17B10 (X-linked recessive)
Urine organic acids
mHMG-CoA synthase deficiency
HMGCS2 (AR)
Urine organic acids
SCOT deficiency
OXCT1 (AR)
Urine organic acids
SSADH deficiency
ALDH5A1 (AR)
Urine organic acids (& ACP)
Ethylmalonic encephalopathy
ETHE1 (AR)
Urine organic acids (& ACP)
l.o. Isovaleric acidemia
IVD (AR)
Urine organic acids (& ACP)
3-Methylcrotonylglycinuria
MCC1/MCC2 (AR)
Urine organic acids (& ACP)
l.o. Methylmalonic acidemia
MUT (AR)
Urine organic acids (& tHcy)
Cobalamin C deficiency
MMACHC (AR)
Urine organic acids (& tHcy)
Cobalamin D deficiency
MMADHC (AR)
Urine organic acids (& tHcy)
Homocystinuria
CBS (AR)
Urine organic acids incl orotic acid (& PAA)
l.o. OTC deficiency
OTC (X-linked)
Urine organic acids (& PAA)
Tyrosinemia type II
TAT (AR)
Urine organic acids (& ACP)
l.o. Propionic acidemia
PCCA/PCCB (AR)
Urine organic acids (tHcy)
Cobalamin F deficiency
LMBRD1 (AR)
Urine purines & pyrimidines
Lesch–Nyhan syndrome
HPRT (AR)
Urine purines & pyrimidines
Molybdenum cofactor deficiency type A
MOCS1, MOCS2, (AR)
Urine purines & pyrimidines
Pyrimidine 5-nucleotidase superactivity
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
ABCD1 (X-linked)
Plasma very long chain fatty acids
Biotin responsive basal ganglia disease
SLC19A3 (AR)
Gene analysis
Biotinidase deficiency
BTD (AR)
Biotinidase enzyme activity
Cerebral folate receptor-α deficiency
FOLR1 (AR)
CSF 5′-methyltetrahydrofolate
Cerebrotendinous xanthomatosis
CYP27A1 (AR)
Plasma cholestanol
Co-enzyme Q10 deficiency
COQ2, APTX, PDSS1,PDSS2, CABC1, COQ9(most AR)
Co-enzyme Q (fibroblasts) & gene analysis
Congenital intrinsic factor deficiency
GIF (AR)
Plasma vitamin B12 & folate
Dihydrofolate reductase deficiency
DHFR (AR)
CSF 5′-methyltetrahydrofolate
DHPR deficiency (biopterin deficiency)
QDPR (AR)
CSF neurotransmitters & biopterin loading test
Gaucher disease type III
GBA (AR)
Glucocerebrosidase enzyme activity (lymphocytes)
GLUT1 deficiency syndrome
SLC2A1 (AR)
CSF: plasma glucose ratio
GTPCH1 deficiency
GCH1 (AR)
CSF neurotransmitters & biopterin loading test
Hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC)
SLC30A10
Whole blood manganese
Hyperinsulinism hyperammonemia syndrome
GLUD1 (AR)
Gene analysis (& ammonia, glucose, insulin)
Imerslund Gräsbeck syndrome
CUBN & AMN (AR)
Plasma vitamin B12 & folate
MELAS
MTTL1, MTTQ, MTTH,MTTK, MTTC, MTTS1,MTND1, MTND5, MTND6,MTTS2 (Mt)
Mitochondrial DNA mutation testing
l.o. Metachromatic leukodystrophy
ARSA (AR)
Arylsulfatase-α enzyme activity
Niemann–Pick disease type C
NPC1 NPC2 (AR)
Filipin staining test (fibroblasts) & gene analyses
l.o. Non-ketotic hyperglycinemia
AMT/GLDC/GCSH (AR)
CSF amino acids (& PAA)
PCBD deficiency (biopterin deficiency)
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)
PHGDH (AR)
CSF amino acids (& PAA)
PSAT deficiency (serine deficiency)
PSAT1 (AR)
CSF amino acids (& PAA)
PSPH deficiency (serine deficiency)
PSPH (AR)
CSF amino acids (& PAA)
PTS deficiency (biopterin deficiency)
PTS (AR)
CSF neurotransmitters & biopterin loading test
Pyridoxine dependent epilepsy
ALDH7A1 (AR)
Urine α-aminoadipic semialdehyde & plasma pipecolic acid
Sjögren Larsson syndrome
ALDH3A2 (AR)
Fatty aldehyde dehydrogenase enzyme activity
Smith Lemli Opitz syndrome
DHCR7 (AR)
Plasma 7-dehydrocholesterol:cholesterol ratio
SPR deficiency (biopterin deficiency)
SPR (AR)
CSF neurotransmitters, biopterin & Phe loading test (enzyme activity, gene analysis)
Thiamine responsive encephalopathy
SLC19A3 (AR)
Gene analysis
Tyrosine hydroxylase deficiency
TH (AR)
CSF neurotransmitters, gene analysis
VMAT2 deficiency
SLC18A2 (AR)
Urine mono-amine metabolites









17 comments:

  1. This information has been out there on the web,in a similar form,for a few years.Particularly on this site out of Canada. http://www.treatable-id.org/

    This may be where you got the list from.

    The site appears,at least in part,to be a project of the Treatable Intellectual Disability Endeavor at British Columbia Children's Hospital.

    http://www.tidebc.org/

    As they say on the TIDE-BC site,the easiest way to find out if one of these diseases is the root cause is whole exome or whole genome sequencing.This saves endless rounds of guesswork testing for one inborn error of metabolism after another.

    ReplyDelete
    Replies
    1. At BC Children's hospital with an autism diagnosis you get a "microarray" test - which I don't think is the whole genome sequencing, but maybe I am wrong? My daughters microarray came back as normal (from BC Children's). I am not sure how I would find out if they tested for all of the above.

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    2. Microarray is just one kind of genetic test. Whole genome sequencing costs about $1,000 at UBC and it is for research purposes in theory. All the tests for those 81 disorders are available, but I doubt you get them, without asking/paying. Many syndromes have physical signs that should alert the physician and then they should investigate.

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    3. Thank you Peter this is good to know and I will contact BC Children's to confirm is I can get it done - in Canada things are tricky as they won't let you order certain tests even if you are willing to pay privately. I contacted GeneDX as they do whole genome and they have a new Autism ID Panel in which they also test parents. Here is more info directly from them:
      "We have a relatively new test called the Autism/ID Xpanded Panel. This is focused more on sequence variants rather than copy number variants. It uses exome sequencing to look at 2000 genes that have been associated with autism and/or intellectual disability. We run this on samples from the proband and the parents at the same time. Including the parents in the analysis means we can look directly at the inheritance of a variant to try to determine its significance. This is currently $5000 USD"

      Delete
  2. I have been reading the same papers wondering if UBC approach is suitable in autism. It has been developed for ID, but there’s a story of a boy with autism as his main diagnosis and severe SIBs, enrolled into TIDE-BC and diagnosed with neurometabolic condition at the age of 16(!), who improved on proper treatment:
    http://www.tidebc.org/pa/Jake/

    Detailed testing for inborn errors of metabolism is not something for ‘do it yourself’ way and if you don’t live in Vancouver, Arkansas or Thessaloniki you are perhaps in a neurometabolic desert re autism. It is the tertiary reference center for IEMs in my country where I was told to ‘lower my expectations and accept disability’. So: is it possible to develop a list of screening tests for IEMs in autism available for parents who do not want to lower their expectations or wait 16 years?

    Fig. 1 in the second paper presents the “two-tiered algorithm for diagnosis of treatable IEMs in IDD. The first tier testing comprises group metabolic tests in urine and blood which should be performed in every patient with IDD of unknown cause.” Maybe the first tier should be considered in autism as well? At time of first symptoms suggesting ID, in non-responders, severe end of spectrum or even for all at time of ASD diagnosis if early established?

    These screening tests are:
    Blood: ammonia, lactate, plasma amino acids, total homocysteine, acylcarnitine profile, copper, ceruloplasmin.
    Urine: organic acids, purines and pyrimidines, creatine metabolites, oligosaccharides, glycosaminoglycans.

    Most can be done in my local lab or elsewhere sending the samples.
    In case of abnormal results one can insist on further evaluation.

    Also there is a relevant case report by the team of Prof. Evangeliou:
    https://www.ncbi.nlm.nih.gov/pubmed/26806207
    “Succinic Semialdehyde Dehydrogenase Deficiency Presenting as Autism Spectrum Disorder”
    Table 1 lists: “Inborn errors of metabolism with autism phenotype as the main or only symptom”.

    Or is just WES enough?

    What do you think?

    ReplyDelete
    Replies
    1. Genetic testing is not a mature science. You definitely need the Whole genome not just the exome and even then there are lots of false negatives. When they know where to look they find dysfunctions, but when looking at the entire genome they miss things. This means you can pay lots of money and think you have covered all possible errors when you have not.

      So measuring specific biological markers in the lab still has great merit. The problem is that sometimes there are no reliable markers.

      Delete
    2. Hi Peter and all,
      Please bear with me for the long post.

      We consulted Dr.Rossignol and he recommended Creon, Oxytocin nasal spray, Sulforaphane, L thianine, L taurine and leucovorin immediately after consultation.
      Also we did the following tests and got results.
      24 hour EEG with video monitoring
      Comprehensive stool analysis/parasitology X3 (Doctors data lab)
      Urine microbial organic acid test (Great plains lab)
      Blood test:
      Amino acids plasma
      Comprehensive metabolic panel
      IGE total
      CRP
      ANA
      ASO titer
      Anti DNAse-B
      CBC with automated Diff
      TSH, FT3, FT4
      Total cholesterol
      Carnitine and Acyl Carnitine profile
      Ferritin, Lead, 25 Hydroxy vitamin D, Zinc, Magnesium
      AM Cortisol, DHEA Sulphate, testosterone
      Homocysteine
      Uric acid serum
      IGF-1
      MMR, DPT and Polio titer
      Fragile X (AWAITING RESULT)

      Except Ferritin, vitamin D, Zinc and total cholesterol (for which we will start supplements) all are normal. Few negligible red marks in plasma amino acid. Dr.Rossignol said that CSF can give conclusive ideas but patient is very young and so let us proceed slowly. Let us do the supplements for the next 3 months, give MB12 shots daily (now alternative days) reach optimum level of leucovorin and then we will review.

      We asked whether Whole genome sequencing or Chromosomal microarray will give ideas, he was non-committal saying that not only these tests are expensive but without good interpretation they are of no use. What about SPECT or MRI? He said EEG is normal and we would treat based on that. However it is optional. We asked any other tests that will give conclusive ideas he said that ‘Laboratoire Philppe Auguste’ does some tests. That might help.

      http://labbio.sectolink.org/index.php?page=contact

      Any idea about this lab and the tests?

      Will TH1 and TH2 profile give any ideas? Immunologist and/or endocrinologist may help? They will come to India for the Christmas holidays. Lab tests and Doctor fees will be cost-effective here.

      Oxytocin, L-theanine, L-taurine and sulforaphane show no response. His anxiety (mixed with fear and panic, more like separation anxiety) and irritability remain the same. No improvement in awareness and communication. 5mg X2 bumetanide for 40 days had no effect. However we have now got 1mg tablets we will try in the near future. As we have started with leucovorin we have to reach 20mg level. By the by leucovorin makes him more irritable and unmanagable so we tried GABA supplement and it makes him calmer. Does it mean bumetanide will not be effective?
      Once again, sorry for the long post. Thank you.


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    3. That is a lot of tests. I am not sure of their value or the ones from the lab in France.

      It appears that a negative reaction to leucoverin is quite common, that might suggest it is unwise to continue.

      Bumetanide will either help within a few weeks or be of no value. If he does not respond then it is not for him.

      Delete
  3. WES is enough for some patients.It was for me,to find one of my two genetic diagnoses.It is not uncommon to have both an inborn error of metabolism,and another genetic disorder besides,as I do.I have MTHFR Deficiency that was diagnosed several years ago by dumb luck,and another genetic disorder,diagnosed last year by WES,the nature of which is still being determined.As with a lot of tests,the costs of a WES has come down.Here in the USA,there is a lab called GeneDx,that can do the test very affordably on a sliding scale according to one's income.

    ReplyDelete
    Replies
    1. Roger,
      When they did WES for you, they were looking specifically for something based on your biomarkers or they looked generally for each and every mutation? What is the normal procedure? Thank you.

      Delete
  4. Thank you Roger and Peter for reply.

    There’s another paper by TIDE-BC team on WES and management of neurometabolic disorders:
    https://www.ncbi.nlm.nih.gov/pubmed/27276562

    "We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%)."

    I think this is great result and it’s important that they combined WES with detailed clinical analysis and metabolic biomarkers.

    There were children with autism among them:
    “An example from this study was an 8-year-old boy with intellectual developmental disorder, autism, movement disorder, intractable epileptic encephalopathy, and persistently abnormal neurotransmitter profiles [...] in whom we identified a de novo pathogenic splice-site variant. This mutation resulted in the deletion of exon 14 in SCN2A, encoding voltage gated sodium channel type II. [...] We hypothesized that this channelopathy causes abnormal synaptic secretion and uptake of monoamine metabolites through impaired vesicular release and imbalance in electrochemical ion gradients, which in turn aggravate the seizures.Treatment with oral 5-hydroxytryptophan, levodopa, carbidopa, and a dopa agonist normalized the child’s levels of neurotransmitters in the cerebrospinal fluid and was associated with improvements in attention, communication, and seizure control."

    My question was about screening for neurometabolic conditions in autism that parents could do on their own and in case of positive result look for further evaluation (as simple, cheap and sensitive as possible).

    ReplyDelete
  5. I don't know if this topic has been discussed before...
    my almost 12 year old son has I think reached puberty. and is engaged is mastabatory behaviour a lot!!! Is there anything I can give him to reduce this compulsion? while I know that it's very common age wise,I think I need to address this. He is very high functioning and completely verbal. thoughts? ideas? thanks!

    ReplyDelete
    Replies
    1. Debbie, you might want to talk to a behavioral specialist. Being so high functioning, your son likely never had one.

      One such person is Peter Gerhardt, who writes a lot about this subject, but any experienced ABA consultant can advise you.

      http://search.naric.com/research/rehab/documents/O19258%20-%20Power%20Point.pdf

      It is not a medical or biological problem. it is a behavioral issue.

      Delete
    2. Thanks for your prompt reply.
      Do you really think this is purely behavioural?
      B/c I think if he didn't feel the urge to seek out this pleasurable sensation, then he wouldn't be feeling the need to masterbate; does that make any sense? Thanks

      Delete
    3. Debbie, find an older ABA behavioral consultant who will have seen hundreds of boys passing puberty. He/she will tell you about all the various issues that can arise and how to deal with them. Having had that discussion you will feel better about your son's behavior and how to guide it. Our own ABA consultant gave us advice a while back even without us asking for it, so it must be a regular issue that comes up.

      Delete
  6. Hi Peter,
    Have you heard or read about the MSSNG study through Sick Kids hospital in Toronto, Canada? They are completing Whole Genome Sequencing on 10,000 families worldwide, and on the Sick Kids Hospital website there is a few pages about how this test should be offered instead of the microarray to every diagnosed child as it picks up more info then the standard microarray. Here is the info: https://www.mss.ng/about

    ReplyDelete
    Replies
    1. It is interesting and the more high quality data available the better.

      Delete

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