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Table 3 Overview of all causal therapies

From: Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app

Name of disorder

Treatment strategy

Treatment

Level of evidence

Effect of treatment

ReferenceS

3-hydroxy-3-methylglutaryl-CoA lyase deficiency

Nutritional therapy

Protein defined diet, avoid fasting, sick day management

5

C

[57]

3-hydroxyisobutyryl-CoA hydrolase deficiency (synonym: beta-hydroxyisobutyryl-CoA deacylase deficiency)

Nutritional therapy

Valine restriction

4

A, E, G

[58]

3-phosphoglycerate dehydrogenase deficiency

Nutritional therapy

L-Serine, glycine

4

D, E, F

[59]

5,10-methenyltetrahydrofolate synthetase deficiency (synonym: 5-formyltetrahydrofolate cycloligase deficiency)

Vitamin & trace element

5-methyltetrahydrofolate, methylcobalamin

5

E

[60]

5,10-methylenetetrahydrofolate reductase deficiency

Nutritional therapy

Carnitine, methionine

4

C, D, G

[61]

Vitamin & trace element

Betaine, folate ± 

4

C, D, G

[61]

6-pyruvoyl-tetrahydropterin synthase deficiency

Nutritional therapy

Phenylalanine-reduced diet ± 

4

D, E

[62]

Vitamin & trace element

Folinic acid ± 

4

A, E, F

[62]

Pharmacological therapy

L-dopa + carbidopa, 5-Hydroxytryptophan, sapropterin dihydrochloride (synthetic BH4) co-factor therapy

4

A, B, E, F, G

[62]

7-dehydrocholesterol reductase deficiency

Nutritional therapy

Cholesterol

4

G

[63, 64]

Pharmacological therapy

Simvastatin

1b

B

[63, 64]

ACAD9 deficiency

Vitamin & trace element

Riboflavin

4

A, E

[65]

Alpha-aminoadipic semialdehyde dehydrogenase deficiency (synonym: pyridoxine-dependent epilepsy)

Nutritional therapy

Lysine restriction, arginine

4

A, D, E, F

[66]

Vitamin & trace element

Pyridoxine

4

A, D, E, F

[66]

Alpha-fucosidase deficiency

Stem cell therapy

(Umbilical cord/bone marrow) hematopoietic stem cell transplantation

4

D, E, G

[67]

Alpha-iduronidase deficiency (synonyms: Hurler syndrome [severe]; Scheie syndrome [attenuated])

Enzyme replacement therapy

Intrathecal iduronidase

2b

A, D, G

[68, 69]

Stem cell therapy

Hematopoietic stem cell transplantation

1c

D, G

[68, 69]

Alpha-mannosidase deficiency

Enzyme replacement therapy

Velmanase alfa

1c

D

[70, 71]

Stem cell therapy

Hematopoietic stem cell transplantation

4 to 5

D, E

[70, 71]

Arginase deficiency (synonym: argininemia)

Nutritional therapy

Protein defined diet, arginine or citrulline

2b, effect on growth 4

B, C, D, E, G

[72]

Pharmacological therapy

Sodium phenylbutyrate, glycerol phenylbutyrate, sodium benzoate

2b

B, C, D, E

[72]

Other

Hemodialysis, peritoneal dialysis

4

D

[72]

Solid organ transplant

Liver transplantation

4

A, B, D, E

[72]

Arginine:glycine amidinotransferase (AGAT) deficiency

Nutritional therapy

Creatine

4

A, D, E

[73]

Argininosuccinate lyase deficiency

Nutritional therapy

Protein defined diet, arginine or citrulline

2b, effect on growth 4

B, C, D, E, G

[72]

Pharmacological therapy

Sodium phenylbutyrate, glycerol phenylbutyrate, sodium benzoate

2b

B, C, D, E

[72]

Other

Hemodialysis, peritoneal dialysis

4

D

[72]

Solid organ transplant

Liver transplantation

4

A, B, D, E, systemic phenotype persists

[72]

Argininosuccinate synthetase deficiency (synonym: citrullinemia type 1)

Nutritional therapy

Protein defined diet, arginine or citrulline

2b, effect on growth 4

B, C, D, E, G

[72]

 

Pharmacological therapy

Sodium phenylbutyrate, glycerol phenylbutyrate, sodium benzoate

2b

B, C, D, E

[72]

 

Other

Hemodialysis, peritoneal dialysis

4

D

[72]

 

Solid organ transplant

Liver transplantation

4

A, B, D, E

[72]

Aromatic L-amino acid decarboxylase deficiency

Pharmacological therapy

Dopamine agonist, monoamine oxidase (MAO) inhibitors, L-dopa + carbidopa (depending on mutation)

4

E, G

[74, 75]

Vitamin & trace element

Pyridoxine, folinic acid ± 

4

E, G

[74, 75]

Gene-based therapy

Gene therapy

4

A, B, E

[74, 75]

Arylsulfatase A deficiency

Gene-based therapy

OTL-200 (stem cell-based gene therapy)

2c

A, E

[76, 77]

Stem cell therapy

Hematopoietic stem cell transplantation

4 to 5

D

[76, 77]

Aspartylglucosaminidase deficiency

Stem cell therapy

Hematopoietic stem cell transplantation

4 to 5

D

[78]

ATP-sensitive potassium channel regulatory/pore-forming subunit superactivity

Pharmacological therapy

Sulfonylurea

4

A, B, E, G

[79, 80]

Autosomal recessive GTP cyclohydrolase 1 deficiency

Nutritional therapy

Phenylalanine-reduced diet ± 

4

D, E

[62]

Vitamin & trace element

Folinic acid ± 

4

A, E, F

[62]

Pharmacological therapy

L-dopa + carbidopa, 5-Hydroxytryptophan, sapropterin dihydrochloride (synthetic BH4) co-factor therapy

4, 4 to 5 for 5-Hydroxytryptophan

A, B, E, F, G

[62]

Beta-glucuronidase deficiency (synonym: Sly syndrome)

Enzyme replacement therapy

Vestronidase

4

A, G

[81]

Stem cell therapy

Hematopoietic stem cell transplantation

4

D, G

 

Biotinidase deficiency

Vitamin & trace element

Biotin

2c

A, E, G

[82]

Branched-chain ketoacid dehydrogenase E1 alpha (BCKDHA)/beta (BCKDHB)/E2 (DBT) deficiency (synonym: maple syrup urine disease type 1a (BCKDHA)/2 (DBT); Dihydrolipoyl transacylase deficiency (DBT))

Nutritional therapy

Restriction of branched chain amino acids, isoleucine, valine, avoid fasting, sick day management

4

A, C, D, G

[83, 84]

Vitamin & trace element

Thiamine ± 

4

C, D, G

[83, 84]

Other

Hemodialysis, peritoneal dialysis

4

D

[83, 84]

Solid organ transplant

Liver transplantation

4

C, D, G

[83, 84]

Branched-chain ketoacid dehydrogenase kinase deficiency

Nutritional therapy

Branched-chain amino acid supplementation

5

A, B, G

[85]

CAD trifunctional protein deficiency

Pharmacological therapy

Uridine

4

A, F

[30]

Carbamoyl phosphate synthetase 1 deficiency

Nutritional therapy

Protein defined diet, arginine or citrulline

2b, effect on growth 4

B, C, D, E, G

[72]

Pharmacological therapy

Sodium phenylbutyrate, glycerol phenylbutyrate, sodium benzoate, N-carbamyl-L-glutamate (carglumic acid)

2b, 4 to 5 for carglumic acid

B, C, D, E, D for carglumic acid

[72]

Other

Hemodialysis, peritoneal dialysis

4

D

[72]

Solid organ transplant

Liver transplantation

4

A, B, D, E

[72]

Carbonic anhydrase VA deficiency

Nutritional therapy

Sick day management

4

C, D

[86]

Pharmacological therapy

N-carbamyl-L-glutamate (carglumic acid)

4

C, D

[86]

Citrin deficiency

Nutritional therapy

High-protein/high-fat/low-carbohydrate diet, avoid fasting, avoid glucose iv, lactose restriction, medium -chain triglycerides

4

B, C, D, E, F, G

[87]

Other

Hemodialysis, peritoneal dialysis

4

D

[87]

Solid organ transplant

Liver Transplantation

4

C

[87]

CLN7 disease

Gene based therapy

(Intrathecal) milasen

4 to 5

F

[36]

Coenzyme Q5 methyltransferase deficiency

Vitamin & trace element

CoQ10

4 to 5

A, B, E

[88]

Coenzyme Q8A (ADCK3) deficiency

Vitamin & trace element

CoQ10

4 to 5

E

[89]

Copper-transporting ATPase subunit alpha deficiency (synonyms: Menkes disease [severe]; occipital horn syndrome [milder])

Pharmacological therapy

Copper histidine

4

D

[90]

Copper-transporting ATPase subunit beta deficiency (synonym: Wilson disease)

Vitamin & trace element

Zinc

4

A, E, G

[91, 92]

Pharmacological therapy

Copper chelators, tetrathiomolybdate

4, 1b for tetrathiomolybdate

A, E, G

[91, 92]

Creatine transporter deficiency

Nutritional therapy

Creatine, glycine, arginine

4

A, F

[93]

Cyclic pyranopterin monophosphate synthase deficiency (synonym: molybdenum cofactor deficiency type A)

Pharmacological therapy

Cyclic pyranopterin monophosphate

2b

A, F

[94]

Cystathionine beta-synthase deficiency (synonym: classic homocystinuria)

Nutritional therapy

Protein defined diet, methionine restriction

2c

C, D, G

[95]

Vitamin & trace element

Pyridoxine, betaine

2c

D, E, G

[95]

Dihydrofolate reductase deficiency

Vitamin & trace element

Folic acid

4

F, G

[96]

Dihydropteridine reductase deficiency

Nutritional therapy

Phenylalanine-reduced diet

4

D, E

[62]

Vitamin & trace element

Folinic acid

4

A, E, F

[62]

Pharmacological therapy

L-dopa + carbidopa, 5-Hydroxytryptophan, sapropterin dihydrochloride (synthetic BH4) co-factor therapy ± 

4

A, B, E, F, G

[62]

DNAJC12 deficiency

Pharmacological therapy

BH4, L-dopa + carbidopa ± , 5-hydroxytryptophan ± 

4

A, D, E

[97]

Electron transfer flavoprotein subunit alpha (ETFA)/subunit beta (ETFB)/dehydrogenase deficiency (ETFDH) (synonym: glutaric acidemia type 2A/2B/2C; multiple acyl-CoA dehydrogenase deficiency type 2A/2B/2C)

Nutritional therapy

Carnitine

5

C, D

[98]

Vitamin & trace element

Riboflavin

5

C, D

[98]

Nutritional therapy

Beta-hydroxybutyrate

2c

E, G

[98]

Epsilon-N-trimethyllysine hydroxylase deficiency

Nutritional therapy

Carnitine

4 to 5

A, B, C

[99]

Folate receptor alpha deficiency (synonym: neurodegeneration due to cerebral folate transport deficiency)

Vitamin & trace element

Folinic acid

4

A, D, E, F

[100]

GLUT1 deficiency

Nutritional therapy

Ketogenic diet

4

F

[101]

Pharmacological therapy

Triheptanoin

2b

A, E

[102]

Glutamine synthetase deficiency

Nutritional therapy

Glutamine

4 to 5

A, E

[103]

Glutaryl-CoA dehydrogenase deficiency (synonym: glutaric aciduria type 1)

Nutritional therapy

Protein defined diet, lysine restriction, carnitine

2c

C, D, E, G

[44]

Glycine encephalopathy due to aminomethyltransferase (AMT) or glycine decarboxylase (GLDC) deficiency (synonym: nonketotic hyperglycinemia)

Pharmacological therapy

Sodium benzoate, N-nitrosodimethylamine receptor antagonists

4

B, D, E, F

[104]

Guanidinoacetate methyltransferase deficiency

Nutritional therapy

Arginine restriction, creatine and ornithine

4

B, D, E, F

[105]

Hereditary ceruloplasmin deficiency

Other

Iron chelation

4

D, E

[106]

Holocarboxylase synthetase deficiency

Vitamin & trace element

Biotin

4

D

[107]

Homocystinuria, cblDv1 type

Vitamin & trace element

Hydroxycobalamin, betaine ± 

4

C, D, G

[61]

Iduronate sulfatase deficiency (synonym: Hunter syndrome)

Stem cell therapy

Hematopoietic stem cell transplantation

4

D, E, G

[108]

Ionotropic glutamate receptor NMDA type subunit 1 dysregulation

Pharmacological therapy

Memantine

4 to 5

A, F

[109]

Ionotropic glutamate receptor NMDA type subunit 2A dysregulation

Pharmacological therapy

Memantine, IVIG

4

F

[110, 111]

Ionotropic glutamate receptor NMDA type subunit 2B dysregulation

Nutritional therapy

L-serine (for loss-of-function mutations)

4 to 5

A

[112]

Ionotropic glutamate receptor NMDA type subunit 2D superactivity

Pharmacological therapy

Memantine, IVIG

4

A, F

[111, 113]

Isoleucyl-tRNA synthetase 1 deficiency

Nutritional therapy

L-isoleucine, natural protein fortification

4 to 5

A, E, G

[114, 115]

Isovaleryl-CoA dehydrogenase deficiency (synonym: isovaleric acidemia)

Nutritional therapy

Protein defined diet, carnitine, avoid fasting, sick day management

2c

C, G

[116]

Pharmacological therapy

N-carbamyl-L-glutamate (carglumic acid)

4

C, G

[116]

Leucyl-tRNA synthetase 1 deficiency

Nutritional therapy

L-leucine, natural protein fortification

4 to 5

A, E, G

[114, 115]

MEDNIK syndrome

Vitamin & trace element

Zinc acetate

4 to 5

A, B, G

[117]

Methionine synthase deficiency (synonym: homocystinuria-megaloblastic anemia, cblG type)

Vitamin & trace element

Hydroxycobalamin, betaine ± 

4, 5 for betaine

C, D, G

[61]

Methionine synthase reductase deficiency (synonym: homocystinuria-megaloblastic anemia, cblE type)

Vitamin & trace element

Hydroxycobalamin, betaine ± 

4, 5 for betaine

C, D, G

[61]

Methionyl-tRNA synthetase 1 deficiency

Nutritional therapy

Methionine, increase protein intake

5

A, G

[118]

Methylmalonic aciduria and homocystinuria, cblC type

Nutritional therapy

Carnitine ± 

5

C, D, G

[61]

Vitamin & trace element

Hydroxycobalamin, betaine

4

C, D, G

[61]

Methylmalonic aciduria and homocystinuria, cblD type

Nutritional therapy

Carnitine ± 

5

A, D, G

[61]

Vitamin & trace element

Hydroxycobalamin, betaine ± 

4 to 5, 5 for betaine

A, D, G

[61]

Methylmalonic aciduria and homocystinuria, cblF type

Vitamin & trace element

Hydroxycobalamin, betaine

4

D, G

[61]

Methylmalonic aciduria and homocystinuria, cblJ type

Vitamin & trace element

Hydroxycobalamin, betaine ± 

4 to 5, 5 for betaine

D, G

[119]

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Nutritional therapy

Protein defined diet, carnitine, avoid fasting, sick day management

2c

C, D, G

[120]

Pharmacological therapy

N-carbamyl-L-glutamate (carglumic acid), sodium benzoate, antibiotics

4

C, D, G

[120]

Other

Hemodialysis, peritoneal dialysis

4

D

[120]

Solid organ transplant

Liver and/or kidney transplantation

4

C, D, G

[120]

Methylmalonic aciduria, cblA type

Nutritional therapy

Protein defined diet, carnitine, avoid fasting, sick day management

4

C, D, G

[120]

Vitamin & trace element

Hydroxycobalamin

4

C, D, G

[120]

Pharmacological therapy

N-carbamyl-L-glutamate (carglumic acid), sodium benzoate, antibiotics

4

D

[120]

Other

Hemodialysis, peritoneal dialysis

4

D

[120]

Solid organ transplant

Liver transplantation and/or kidney transplantation

4

C, D, G

[120]

Methylmalonic aciduria, cblB type

Nutritional therapy

Protein defined diet, carnitine, avoid fasting, sick day management

4

C, D, G

[120]

Vitamin & trace element

Hydroxycobalamin

4

C, D, G

[120]

Pharmacological therapy

N-carbamyl-L-glutamate (carglumic acid), sodium benzoate, antibiotics

4

D

[120]

Other

Hemodialysis, peritoneal dialysis

4

D

[120]

Solid organ transplant

Liver transplantation and/or kidney transplantation

4

C, D, G

[120]

Methylmalonic aciduria, cblDv2 type

Nutritional therapy

Protein defined diet, carnitine, avoid fasting, sick day management

4

C, D, G

[120]

Vitamin & trace element

Hydroxycobalamin

4

C, D, G

[120]

Pharmacological therapy

N-carbamyl-L-glutamate (carglumic acid), sodium benzoate, antibiotics

4

D

[120]

Other

Hemodialysis, peritoneal dialysis

4

D

[120]

Solid organ transplant

Liver transplantation and/or kidney transplantation

4

C, D, G

[120]

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

Nutritional therapy

Avoid Fasting, sick day management, dietary precursor restriction ± 

5

C

[121]

Mitochondrial acetoacetyl-CoA thiolase deficiency

Nutritional therapy

Avoid fasting, sick day management, protein restriction, isoleucine restriction

5

C

[122]

Mitochondrial aspartate aminotransferase deficiency

Nutritional therapy

L-serine

4

A

[123]

Vitamin & trace element

Pyridoxine

4

A, F

[123]

Mitochondrial aspartate-glutamate carrier isoform 1 deficiency (synonym: aralar deficiency)

Nutritional therapy

Ketogenic diet

4

A, E, F

[124]

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MT-ND1/MT-ND4/MT-ND5/MT-ND6/MT-CO1/MT-CPO2/MT-CO3/ MT-TQ/MT-TH/MT-TL1/MT-TF/MT-TS1/MT-TS2/MT-TW)

Nutritional therapy

Arginine, citrulline, taurine

4 to 5, 2b for Taurine

C, D, E, F

[125, 126]

Mitochondrial ornithine transporter deficiency (synonym: hyperornithinemia-hyperammonemia-homocitrullinuria syndrome)

Nutritional therapy

Protein defined diet, arginine or citrulline

2b, effect on growth 4

B, C, D, E, G

[72]

Pharmacological therapy

Sodium phenylbutyrate, glycerol phenylbutyrate, sodium benzoate

2b

B, C, D, E

[72]

Other

Hemodialysis, peritoneal dialysis

4

D

[72]

Solid organ transplant

Liver transplantation

4 to 5

A, B, D, E, systemic phenotype persists

[72]

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency

Nutritional therapy

Valine restriction

4

A, E, G

[58]

Mitochondrial sulfur dioxygenase deficiency (synonym: ethylmalonic encephalopathy)

Pharmacological therapy

N-acetylcysteine, antibiotics

4

E, G

[127]

Solid organ transplant

Liver transplantation

4

A

[127]

Mitochondrial thiamine pyrophosphate transporter deficiency

Vitamin & trace element

Thiamine

4

C, D

[128]

N-acetylglutamate synthase deficiency

Nutritional therapy

Protein defined diet, arginine or citrulline

2b, effect on growth 4

B, C, D, E, G

[72]

Pharmacological therapy

Sodium phenylbutyrate, glycerol phenylbutyrate, sodium benzoate, N-carbamyl-L-glutamate (carglumic acid)

2b, 4 for carglumic acid

B, C, D, E, D for carglumic acid

[72]

Other

Hemodialysis, peritoneal dialysis

4

D

[72]

Solid organ transplant

Liver transplantation

4

A, B, D, E

[72]

NAD(P)HX epimerase deficiency

Vitamin & trace element

Niacin, CoQ10

4 to 5

A, G

[129]

Niemann-Pick disease type C1 (NPC1)/C2 (NPC2)

Pharmacological therapy

Miglustat, intrathecal 2-hydroxypropyl-β-cyclodextrin

1b, 2b for 2-hydroxypropyl-β-cyclodextrin

D, E

[130, 131]

NRF2 superactivity (synonym: immunodeficiency, developmental delay, and hypohomocysteinemia)

Vitamin & trace element

Ascorbic acid

4 to 5

A

[132]

Pharmacological therapy

Luteolin

4 to 5

A

[132]

Ornithine transcarbamylase deficiency

Nutritional therapy

Protein defined diet, arginine or citrulline

2b, effect on growth 4

B, C, D, E, G

[72]

Pharmacological therapy

Sodium phenylbutyrate, glycerol phenylbutyrate, sodium benzoate

2b

B, C, D, E

[72]

Other

Hemodialysis, peritoneal dialysis

4

D

[72]

Solid organ transplant

Liver transplantation

4

A, B, D, E

[72]

Phenylalanine hydroxylase deficiency (synonym: phenylketonuria)

Nutritional therapy

Protein defined diet, phenylalanine-free L-amino acid suppletion/Glycomacropeptide (GMP), large neutral amino acid (LNAA), fatty acids

2a, GMP 4

B, D, E

[43]

Pharmacological therapy

Sapropterin dihydrochloride (synthetic BH4) co-factor therapy

1b

B, D, E

[43]

Enzyme replacement therapy

Pegvaliase

1b

B, D, E

[43]

Phenylalanyl-tRNA synthetase subunit beta deficiency

Nutritional therapy

L-phenylalanine

4 to 5

A, G

[115]

Phosphoribosylpyrophosphate synthetase deficiency

Pharmacological therapy

S-adenosylmethionine

4

D, G

[133]

Phosphoserine aminotransferase deficiency

Nutritional therapy

L-Serine, glycine

4

D, E, F

[59]

Phosphoserine phosphatase deficiency

Nutritional therapy

L-Serine, glycine

4

D, E, F

[59]

PIGA-CDG

Nutritional therapy

Ketogenic diet

4

A, F

[134]

PIGM-CDG

Pharmacological therapy

Sodium phenylbutyrate

4

A, F

[134]

PIGO-CDG

Vitamin & trace element

Pyridoxine

4 to 5

F

[134]

PMM2-CDG

Pharmacological therapy

Acetazolamide

1b

E, G

[135]

Propionic acidemia due to propionyl-CoA carboxylase subunit alpha (PCCA)/beta (PCCB) deficiency

Nutritional therapy

Protein defined diet, carnitine, avoid fasting, sick day management

2c

C, D, G

[120]

Pharmacological therapy

N-carbamyl-L-glutamate (carglumic acid), sodium benzoate, antibiotics

4

C, D, G

[120]

Other

Hemodialysis, peritoneal dialysis

4

D

[120]

Solid organ transplant

Liver and/or kidney transplantation

4

C, D, G

[120]

Proton-coupled folate transporter deficiency (synonym: hereditary folate malabsorption)

Vitamin & trace element

(Levo-)folinic acid

4

A, E, F, G

[136]

Pyridoxamine 5′-phosphate oxidase deficiency

Vitamin & trace element

Pyridoxal phosphate

4

D, E, F

[137]

Pyruvate dehydrogenase E1 alpha (PDHA1)/beta (PDHB)/E2 (DLAT)/E3 (DLD)/E3BP (PDHX) deficiency

Nutritional therapy

Ketogenic diet

4 for PDHA1 and PDHX, 5 for other genes

A, D, E, F

[138, 139]

Vitamin & trace element

Thiamine

4 for some mutations

D, E, F

[138, 139]

Pyruvate dehydrogenase phosphatase deficiency

Nutritional therapy

Ketogenic diet, thiamine ± 

4

A, D, E

[140]

S-adenosylhomocysteine hydrolase deficiency

Nutritional therapy

Methionine restriction, creatinine, phosphatidylcholine

4

A, E, G

[141]

Solid organ transplant

Liver transplantation

4 to 5

A, E, G

[141]

Sepiapterin reductase deficiency

Pharmacological therapy

L-dopa + carbidopa, 5-Hydroxytryptophan

4

A, B, E, F, G

[62]

Vitamin & trace element

Folinic acid ± 

5

A, E, F

[62]

Seryl-tRNA synthetase 1 deficiency

Nutritional therapy

L-serine

4 to 5

A, B, G

[114, 115]

SLC35A2-CDG

Nutritional therapy

Galactose

4

E, F, G

[142]

SLC35C1-CDG

Nutritional therapy

Fucose

4

A, G

[134]

SLC39A8 deficiency

Nutritional therapy

Galactose, manganese, uridine

4

F

[134]

Sodium-dependent multivitamin transporter deficiency

Vitamin & trace element

Biotin, alpha-lipoic acid, pantothenic acid

4

A, D, G

[143]

Sterol 27-hydroxylase deficiency (synonym: cerebrotendinous xanthomatosis)

Pharmacological therapy

Chenodeoxycholic Acid

3a

B, D, E, G

[144]

Succinic semialdehyde dehydrogenase deficiency

Pharmacological therapy

Vigabatrin

4

B, F

[145]

Thiamine pyrophosphokinase deficiency

Vitamin & trace element

Thiamine

4

D

[146]

Thiamine transporter 2 deficiency (synonym: biotin-thiamine-responsive basal ganglia disease)

Vitamin & trace element

Thiamine, biotin

2c for thiamine, 4 for biotin

D

[147]

Transcobalamin II deficiency

Vitamin & trace element

Cyanocobalamin, hydroxycobalamin

4

D, E, G

[148]

Tripeptidyl-peptidase 1 deficiency (synonym: CLN2 disease)

Enzyme replacement therapy

Cerliponase alfa

2b

D

[149]

Tyrosine aminotransferase deficiency (synonyms: tyrosinemia type 2; Richner-Hanhart syndrome)

Nutritional therapy

Protein defined diet, phenylalanine and tyrosine restriction

4 G, 5 for D

D, G

[150]

Tyrosine hydroxylase deficiency

Pharmacological therapy

L-dopa + carbidopa

4

A, E

[151]

Vesicular monoamine transporter 2 deficiency

Pharmacological therapy

Pramipexol (dopamine agonist)

4

A, E

[152]

X-linked adrenoleukodystrophy

Gene-based therapy

Gene therapy

5

D, E

[153]

Stem cell therapy

Hematopoietic stem cell transplantation

1c

D, E

[154]

  1. Level of evidence: Level 1a = systematic review of RCT's, 1b = individual RCT, 1c = ‘All or None’ [= (prolongation of) survival with therapy]; Level 2a = systematic review of cohort studies, 2b = individual cohort study, 2c = ‘Outcomes Research’ [focused on end results of therapy for chronic conditions, including functioning and quality of life]; Level 3 = systematic review of case– control studies; Level 4 = individual case–control study or case-series/report; Level 5 = expert opinion without critical appraisal; based on physiology, bench research or first principles. If only one patient was reported, we assigned level ‘4 to 5′ as a way to nuance the treatment effects
  2. Effect of treatment: A = improves psychomotor/cognitive development/IQ, B = improves behavioural/psychiatric disturbance(s), C = prevents acute metabolic decompensation, D = prevents, halts, or slows clinical deterioration, E = improves neurological manifestations (incl. neuro-imaging), F = improves seizure/epilepsy control, G = improves systemic manifestations