Neurometabolic Disorders

Disorders of Carbohydrate Metabolism

• Glycogen Storage Diseases (GSDs):
  • Type I (Von Gierke disease)
  • Type II (Pompe disease)
  • Type III (Cori-Forbes disease)
  • Type IV (Andersen disease)
  • Type V (McArdle disease)
  • Type VI (Hers disease)
  • Type VII (Tarui disease)
  • Type IX (Phosphorylase kinase deficiency)
  • Type 0 (Liver glycogen synthase deficiency)
• Galactose metabolism disorders:
  • Galactosemia (GALT, GALE, and GALK deficiencies)
• Fructose metabolism disorders:
  • Hereditary fructose intolerance
  • Fructose-1,6-bisphosphatase deficiency
• Disorders of gluconeogenesis and glycolysis:
  • Pyruvate kinase deficiency
  • Pyruvate dehydrogenase complex deficiency
• Lactic acidemia syndromes:
  • Pyruvate carboxylase deficiency
  • Disorders of the Cori cycle

Disorders of Amino Acid Metabolism

• Phenylalanine metabolism disorders:
  • Phenylketonuria (PKU)
  • Hyperphenylalaninemia
• Tyrosine metabolism disorders:
  • Tyrosinemia type I (fumarylacetoacetate hydrolase deficiency)
  • Tyrosinemia type II (tyrosine aminotransferase deficiency)
  • Tyrosinemia type III (4-hydroxyphenylpyruvate dioxygenase deficiency)
• Branched-chain amino acid disorders:
  • Maple syrup urine disease (MSUD)
  • Isovaleric acidemia
  • 3-Methylcrotonyl-CoA carboxylase deficiency
• Sulfur amino acid disorders:
  • Homocystinuria (cystathionine beta-synthase deficiency)
  • Cystinuria
  • Cystinosis
• Other amino acid metabolism disorders:
  • Argininosuccinic aciduria
  • Non-ketotic hyperglycinemia (glycine encephalopathy)
  • Histidinemia
  • Hyperprolinemia (types I and II)

Disorders of Organic Acid Metabolism

• Short-chain organic acidemias:
  • Propionic acidemia
  • Methylmalonic acidemia
  • Isovaleric acidemia
• Dicarboxylic acidemias:
  • Glutaric acidemia type I
  • 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMG-CoA lyase deficiency)
  • Malonic acidemia
• Multiple carboxylase deficiency:
  • Biotinidase deficiency
  • Holocarboxylase synthetase deficiency

Disorders of Lipid Metabolism

• Fatty Acid Oxidation Disorders:
  • Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
  • Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency
  • Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
  • Carnitine palmitoyltransferase deficiencies (CPT1 and CPT2)
  • Carnitine transporter defect
• Peroxisomal disorders:
  • Zellweger spectrum disorders
  • Adrenoleukodystrophy
  • Refsum disease
• Lysosomal lipid storage diseases:
  • Gaucher disease
  • Niemann-Pick disease types A, B, and C
  • Farber lipogranulomatosis
  • Wolman disease
  • Cholesteryl ester storage disease
• Sphingolipidoses:
  • Tay-Sachs disease
  • Sandhoff disease
  • Krabbe disease
  • Fabry disease
  • Metachromatic leukodystrophy

Disorders of Energy Metabolism

• Mitochondrial respiratory chain disorders:
  • MELAS (Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes)
  • Leigh syndrome
  • MERRF (Myoclonic epilepsy with ragged red fibers)
  • NARP (Neuropathy, ataxia, and retinitis pigmentosa)
  • Kearns-Sayre syndrome
• Coenzyme Q10 deficiency
• Pyruvate dehydrogenase complex deficiency
• Krebs cycle enzyme deficiencies:
  • Fumarase deficiency
  • Succinate dehydrogenase deficiency

Disorders of Purine and Pyrimidine Metabolism

• Purine metabolism disorders:
  • Lesch-Nyhan syndrome (HGPRT deficiency)
  • Adenine phosphoribosyltransferase deficiency
  • Xanthinuria
  • Adenylosuccinate lyase deficiency
• Pyrimidine metabolism disorders:
  • Dihydropyrimidine dehydrogenase deficiency
  • Orotic aciduria

Disorders of Vitamin and Cofactor Metabolism

Disorders of Thiamine (Vitamin B1) Metabolism

• Thiamine-responsive megaloblastic anemia (TRMA)
• Biotin-thiamine-responsive basal ganglia disease (BTBGD)
• Maple syrup urine disease (MSUD) (thiamine-responsive variant)
• Wernicke-Korsakoff syndrome (acquired thiamine deficiency)
• Beriberi (dry and wet forms—acquired deficiency)

Disorders of Riboflavin (Vitamin B2) Metabolism

• Multiple acyl-CoA dehydrogenase deficiency (MADD, Glutaric Aciduria type II)
• Riboflavin transporter deficiency (formerly Brown-Vialetto-Van Laere syndrome & Fazio-Londe disease)
• Riboflavin-responsive mitochondrial disorders

Disorders of Niacin (Vitamin B3) Metabolism

• Pellagra (acquired niacin deficiency)
• Hartnup disease (impaired tryptophan absorption/conversion)

Disorders of Pyridoxine (Vitamin B6) Metabolism

• Pyridoxine-dependent epilepsy (ALDH7A1 deficiency)
• Pyridoxal phosphate-responsive seizures (PNPO deficiency)
• Hypophosphatasia (alkaline phosphatase deficiency)
• Pyridoxine-responsive sideroblastic anemia

Disorders of Biotin (Vitamin B7) Metabolism

• Biotinidase deficiency
• Holocarboxylase synthetase deficiency
• Biotin transporter deficiency (biotin-responsive basal ganglia disease)

Disorders of Folate (Vitamin B9) Metabolism

• Hereditary folate malabsorption (SLC46A1 mutation)
• Cerebral folate deficiency syndrome (CFD)
• Methylenetetrahydrofolate reductase (MTHFR) deficiency
• Glutamate formiminotransferase-cyclodeaminase deficiency (FTCD)
• Dihydrofolate reductase (DHFR) deficiency

Disorders of Vitamin B12 (Cobalamin) Metabolism

• Intrinsic factor deficiency (congenital pernicious anemia)
• Imerslund-Gräsbeck syndrome (cobalamin absorption defect)
• Transcobalamin deficiency
• Methylmalonic acidemia (MMA) (Cbl A, B, C, D, F disorders)
• Combined methylmalonic acidemia and homocystinuria (CblC, CblD, CblF, CblJ)
• Adenosylcobalamin deficiency
• Methylcobalamin deficiency

Disorders of Ascorbic Acid (Vitamin C) Metabolism

• Scurvy (acquired deficiency)
• Vitamin C transporter deficiency (SLC23A1/SLC23A2 mutations)

Disorders of Vitamin A Metabolism

• Vitamin A deficiency (xerophthalmia, night blindness)
• Hypervitaminosis A
• Congenital disorders of retinoid metabolism

Disorders of Vitamin D Metabolism

• Vitamin D-dependent rickets Type 1A (CYP27B1)
• Vitamin D-dependent rickets Type 1B (CYP2R1)
• Vitamin D-dependent rickets Type 2A (VDR deficiency)
• Vitamin D-dependent rickets Type 2B (hormone response element defect)

Disorders of Vitamin E Metabolism

• Ataxia with vitamin E deficiency (AVED)
• Familial isolated vitamin E deficiency (FIVE)
• Abetalipoproteinemia (malabsorption syndrome)

Disorders of Vitamin K Metabolism

• Vitamin K deficiency bleeding (VKDB)
• Combined deficiency of vitamin K-dependent coagulation factors (VKCFD)
• Gamma-glutamyl carboxylase deficiency (GGCX)
• Vitamin K epoxide reductase deficiency (VKOR)

Disorders of Coenzyme Q10 Metabolism

• Primary Coenzyme Q10 deficiency (COQ2, COQ4, COQ6, COQ8A/ADCK3)
• Secondary CoQ10 deficiency

Disorders of Carnitine Metabolism

• Primary systemic carnitine deficiency (SLC22A5)
• Carnitine palmitoyltransferase I deficiency (CPT1)
• Carnitine palmitoyltransferase II deficiency (CPT2)
• Carnitine-acylcarnitine translocase deficiency (CACT)

Disorders of Creatine Metabolism

• Guanidinoacetate methyltransferase (GAMT) deficiency
• Arginine-glycine amidinotransferase (AGAT) deficiency
• Creatine transporter defect (SLC6A8)

Disorders of Alpha-Lipoic Acid Metabolism

• Lipoic acid synthetase deficiency (LIAS)
• Lipoyltransferase 1 deficiency (LIPT1)
• Lipoyltransferase 2 deficiency (LIPT2)
• Pyruvate dehydrogenase complex defects (lipoic acid metabolism)

Disorders of Tetrahydrobiopterin (BH4) Metabolism

• GTP cyclohydrolase I deficiency (GCH1, dopa-responsive dystonia)
• 6-Pyruvoyl-tetrahydropterin synthase deficiency (PTPS)
• Sepiapterin reductase deficiency (SPR)
• Dihydropteridine reductase deficiency (DHPR)
• Pterin-4-alpha-carbinolamine dehydratase deficiency (PCD)

Disorders of Copper Metabolism

• Wilson’s disease (ATP7B)
• Menkes disease (ATP7A)
• Occipital horn syndrome (ATP7A partial deficiency)

Disorders of Iron Metabolism

• Aceruloplasminemia
• Hereditary hemochromatosis

Disorders of Selenium Metabolism

• SECISBP2 deficiency
• Congenital deficiency of selenoproteins

Disorders of Urea Cycle Metabolism

• Primary urea cycle disorders:
  • Carbamoyl phosphate synthetase I (CPSI) deficiency
  • Ornithine transcarbamylase (OTC) deficiency
  • Argininosuccinate lyase deficiency
  • Argininosuccinate synthetase deficiency (Citrullinemia type I)
  • Arginase deficiency (Argininemia)
• Secondary urea cycle disorders:
  • N-acetylglutamate synthase (NAGS) deficiency

Lysosomal Storage Disorders

• Mucopolysaccharidoses (MPS):
  • Hurler syndrome (MPS I)
  • Hunter syndrome (MPS II)
  • Sanfilippo syndrome (MPS III)
  • Morquio syndrome (MPS IV)
  • Maroteaux-Lamy syndrome (MPS VI)
  • Sly syndrome (MPS VII)
• Oligosaccharidoses:
  • Mannosidosis
  • Fucosidosis
  • Schindler disease
• Neuronal ceroid lipofuscinoses (NCLs):
  • CLN1 (Infantile)
  • CLN2 (Late infantile)
  • CLN3 (Juvenile Batten disease)
• Niemann-Pick disease 

Disorders of Neurotransmitter Metabolism

• Catecholamine and serotonin metabolism disorders:
  • Tyrosine hydroxylase deficiency
  • Aromatic L-amino acid decarboxylase (AADC) deficiency
• GABA metabolism disorders:
  • Succinic semialdehyde dehydrogenase deficiency
• Monoamine oxidase (MAO) deficiency
• Pterin metabolism disorders:
  • Tetrahydrobiopterin (BH4) deficiency

Disorders of Cholesterol and Sterol Metabolism

• Cholesterol synthesis disorders:
  • Smith-Lemli-Opitz syndrome (SLOS)
  • Lathosterolosis
  • Desmosterolosis
• Sterol transport disorders:
  • Niemann-Pick type C
  • Sitosterolemia