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Supplementary Table 1 Proposed treatments in adult neurometabolic diseases.1

Treatments / Diseases / Recommended dose / Route / Adverse effects
Vitamins
B1 (thiamine) / Pyruvate dehydrogenase deficiency / 500–1000 mg/day / Oral / Not reported
B6 / Cystathionine  synthase deficiency / 250–500 mg/day / Oral / Polyneuropathy with doses >1000 mg/d

B9 (folinic acid)

/ Intracerebral folate deficiency, MTHFR deficiency, dyhydropteridine reductase deficiency / 0.5–1 mg/kg/day (intracerebral folate deficiency), 25 mg/day (MTHFR and dyhydropteridine reductase deficiencies) / Oral / Epilepsy with doses >1mg/kg/day
B12 (cobalamin) / CblC disease, MTHFR deficiency / Oral: 1 mg/day, intramuscular: 1 mg/day initially, then 1 mg/week or 1 mg/month. / Intramuscular (CblC disease) or oral / Not reported
H (biotin) / Biotinidase deficiency, biotin-responsive encephalopathy, biotin responsive basal ganglia disease / 10–20 mg/day (biotinidase deficiency and biotin responsive encephalopathy); 0.5 mg/kg/day (biotin responsive basal ganglia disease) / Oral / Not reported

Vitamin E

/ Tocopherol binding protein deficiency, abetalipoproteinemia, hypobetalipoproteinemia / 10–100 mg/kg/day / Oral / Not reported

Vitamin cocktail

/ Can be tried in an unexplained neurological disease (3-month trial) / Doses per day: biotin 10 mg, thiamine 500 mg, riboflavin 300 mg, vitamin B6500 mg, folinic acid 25 mg / Oral / Not reported
Cofactors

BH4

/ PTP synthase deficiency / 1–3 mg/kg/day / Oral / Not reported

Betaine

/ CblC disease, MTHFR deficiency, cystathionine  synthase deficiency / 6–9 g/day / Oral / Not reported

Carbaglu

/ N-acetylglutamate synthetase deficiency / 50 mg/kg/day in four divided doses / Oral or intravenous / Not reported
Neurotransmitters

Levodopa

/ GTP cyclohydrolase 1 deficiency, tyrosine hydroxylase deficiency, PTP synthase deficiency, sepiapterin reductase deficiency, dyhydropteridine reductase deficiency / 150–600 mg/day in three or four divided doses / Oral / Dyskinesias

5-hydroxytryptophan

/ PTP synthase deficiency, sepiapterin reductase deficiency, dyhydropteridine reductase deficiency / 300–600 mg/day in three divided doses / Oral / Nausea, diarrhoea, tachycardia, anorexia
Amino acids

L-serine

/ Serine deficiency / 200–400 mg/kg/day / Oral / Not reported

L-arginine

/ Urea cycle disorders, Triple H syndrome / 100 mg/kg/day (OTC and CPS deficiencies), up to 700mg/kg/day in ASS deficiency / Oral or intravenous / Not reported

L-citrulline

/ Triple H syndrome, OTC deficiency, CPS deficiency / 3.8 g/m2/day / Oral / Not reported
Specific diets
Low phytanic acid / Refsum disease / Phytanate intake between 10 and 20 mg/day / NA / Not reported
Long chain fatty acids restriction / Trifunctional protein deficiency / NA / Not reported
Ketogenic / Pyruvate dehydrogenase deficiency, Glut1 deficiency / Calories intake subdivided into: lipids 70–80%, glucose 5–10%, proteins 15–20% / NA / Not reported

Protein restriction

/ Phenylketonuria, urea cycle disorders, organic acidurias, triple H syndrome, leucinosis / Proteins <1.5 g/kg/day / NA / Not reported
Chelators
D-penicillamine / Wilson disease / 300–900 mg/day (increase progressively) / Oral / Initial worsening of symptoms, lupus, nephropathy
Triethylene tetramine (trientine) / Wilson disease / 600–2.4 g/day / Oral / Not reported
Zinc sulphate / Wilson disease / 600 mg/day initially, then 300 mg/day (maintenance dose) / Oral / Not reported
Sodium benzoate / Nonketotic hyperglycinemia, urea cycle disorders / 250 mg/kg/day in divided doses / Oral or intravenous / Not reported

Sodium phenylbutyrate

/ Urea cycle disorders / 250 mg/kg/day / Oral or intravenous / Not reported
Bioenergetic molecules
Ubiquinone / Coenzyme Q10 deficiency / 10 mg/kg/day / Oral / Not reported

L-carnitine

/ Organic acidurias / 50 mg/kg/day / Oral / Not reported
Enzymes

Imiglucerase

/ Gaucher disease / Usually 60 U/kg per 2 weeks / Intravenous / Not reported

Agalsidase alpha (Replagal)

/ Fabry disease / 0.2 mg/kg per 2 weeks / Intravenous / Not reported

Agalsidase beta (Fabrazyme)

/ Fabry disease / 1 mg/kg per 2 weeks / Intravenous / Not reported
Inhibitors of synthesis of toxic molecules

Chenodeoxycholic acid

/ Cerebrotendinous xanthomatosis / 750 mg/day in three divided doses / Oral / Not reported

Miglustat

/ Gaucher disease / 300 mg/day in three divided doses / Oral / Diarrhea, weight loss, tremor

Heme arginate

/ Porphyrias / 3 mg/kg/day for 4 days / Intravenous / Not reported
Neuroprotective

Dextrometorphan

/ Nonketotic hyperglycinemia / 5 mg/kg/day / Oral / Not reported

Ketamine

/ Nonketotic hyperglycinemia / 1–30 mg/kg/day in four divided doses / Oral / Not reported

1Adapted from Walter JH and Wraith JE (2006) Treatment: present status and new trends. In Inborn Metabolic Diseases: Diagnosis and Treatment, 81–100 (Eds Saudubray JM et al.) Berlin: Springer-Verlag. Abbreviations: ASS, argininosuccinate synthetase; CBlC, cobalamin C; CPS, carbamoyl phosphate synthase; MTHFR=methylene tetrahydrofolate reductase; NA, not applicable; OTC=ornithine transcarbamylase; PTP, pyruvoyl tetrahydrobiopterin synthase.