IMDs

1. Disorders of intermediary metabolism

1.1 Disorders of amino acid metabolism

a. Urea cycle disorders and inherited hyper ammonemias

  • N-acetylglutamate synthase deficiency
  • Carbamoyl phosphate synthetase 1 deficiency
  • Ornithine transcarbamylase deficiency
  • Argininosuccinate synthetase deficiency (Citrullinemia type 1)
  • Argininosuccinate lyase deficiency (Argininosuccinase deficiency; argininosuccinic aciduria)
  • Arginase deficiency (Argininemia)
  • Mitochondrial ornithine transporter deficiency (Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome; ornithine translocase deficiency)
  • Citrin deficiency
  • Carbonic anhydrase VA deficiency
  • Glutamate dehydrogenase superactivity (Hyperinsulinism-hyperammonemia syndrome; familial hyperinsulinemic hypoglycemia type 6)

b. Organic acidurias

  • Isovaleryl-CoA dehydrogenase deficiency (Isovaleric acidemia)
  • Isobutyryl-CoA dehydrogenase deficiency
  • 2-Methylbutyryl-CoA dehydrogenase deficiency (Short/branched-chain acyl-CoA dehydrogenase deficiency; 2-methylbutyrylglycinuria)
  • 3-Methylcrotonyl-CoA carboxylase 1 deficiency (3-methylcrotonylglycinuria type 1)
  • 3-Methylcrotonyl-CoA carboxylase 2 deficiency (3-methylcrotonylglycinuria type 2)
  • 3-methylglutaconyl-CoA hydratase deficiency (3-methylglutaconic aciduria type 1)
  • Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (Crotonase deficiency)
  • 3-hydroxyisobutyryl-CoA hydrolase deficiency (β-hydroxyisobutyryl-CoA deacylase deficiency)
  • 3-hydroxyisobutyrate dehydrogenase deficiency
  • Methylmalonate semialdehyde dehydrogenase deficiency
  • Propionic acidemia due to propionyl-CoA carboxylase subunit alpha deficiency
  • Propionic acidemia due to propionyl-CoA carboxylase subunit beta deficiency
  • Methylmalonic aciduria due to methylmalonyl-CoA epimerase deficiency
  • Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
  • Glutaryl-CoA dehydrogenase deficiency (Glutaric acidemia type 1)
  • Succinate-hydroxymethylglutarate-CoA transferase deficiency (Glutaric acidemia type 3)
  • Malonyl-CoA decarboxylase deficiency(Malonic aciduria)

c. Disorders of branched-chain amino acid metabolism

  • Branched-chain aminotransferase 2 deficiency (Hypervalinemia and hyperleucine- isoleucinemia)
  • Branched-chain ketoacid dehydrogenase E1 alpha deficiency (Maple syrup urine disease type 1a)
  • Branched-chain ketoacid dehydrogenase E1 beta deficiency (Maple syrup urine disease type 1b)
  • Dihydrolipoyl transacylase deficiency (Maple syrup urine disease type 2; branched-chain ketoacid dehydrogenase E2 deficiency)
  • Branched-chain ketoacid dehydrogenase kinase deficiency
  • Branched-chain ketoacid dehydrogenase phosphatase deficiency

d. Disorders of phenylalanine and tyrosine metabolism

  • Phenylalanine hydroxylase deficiency (Phenylketonuria)
  • Tyrosinase deficiency (Oculocutaneous albinism type 1)
  • Tyrosine aminotransferase deficiency (Tyrosinemia type 2; Richner-Hanhart syndrome)
  • 4-hydroxyphenylpyruvate dioxygenase deficiency (Tyrosinemia type 3)
  • Hawkinsinuria (Tyrosinemia type 3)
  • Homogentisic acid oxidase deficiency (Alkaptonuria)
  • Maleylacetoacetate isomerase deficiency (Benign hypersuccinylacetonemia)
  • Fumarylacetoacetase deficiency (Tyrosinemia type 1)

e. Disorders of the metabolism of sulfur-containing amino acids and hydrogen sulfide

  • Methionine adenosyltransferase I/III deficiency (Mudd’s disease)
  • Methionine adenosyltransferase II deficiency
  • Methanethiol oxidase deficiency (Extraoral halitosis)
  • Glycine N-methyltransferase deficiency
  • S-adenosylhomocysteine hydrolase deficiency
  • Adenosine kinase deficiency
  • Methionine synthase deficiency (Homocystinuria-megaloblastic anemia, cblG type)
  • Cystathionine beta-synthase deficiency (Classical homocystinuria)
  • Cystathionine gamma-lyase deficiency(Cystathioninuria)
  • Mercaptopyruvate sulfurtransferase deficiency (Mercaptolactate-cysteine disulfiduria)
  • Mitochondrial sulfide:quinone oxidoreductase deficiency
  • Mitochondrial sulfur dioxygenase deficiency (Ethylmalonic encephalopathy)
  • Isolated sulfite oxidase deficiency (Sulfocysteinuria)

f. Disorders of glycine and serine metabolism

  • Nonketotic hyperglycinemia due to glycine decarboxylase deficiency (Glycine encephalopathy)
  • Nonketotic hyperglycinemia due to aminomethyltransferase deficiency (Glycine encephalopathy)
  • 3-phosphoglycerate dehydrogenase deficiency
  • Phosphoserine aminotransferase deficiency
  • Phosphoserine phosphatase deficiency
  • ASCT1 transporter deficiency (Spastic tetraplegia, thin corpus callosum, and progressive microcephaly)
  • Mitochondrial serine hydroxymethyltransferase deficiency

g. Disorders of ornithine, proline and hydroxyproline metabolism

  • Ornithine aminotransferase deficiency (Gyrate atrophy of choroid and retin)
  • Delta-1-pyrroline-5-carboxylate synthase deficiency, cutis laxa phenotype (Autosomal recessive cutis laxa type 3A; autosomal dominant cutis laxa type 3)
  • Delta-1-pyrroline-5-carboxylate synthase deficiency, spastic paraplegia phenotype (Spastic paraplegia type 9)
  • Pyrroline-5-carboxylate reductase 1 deficiency (Autosomal recessive cutis laxa type 2B; autosomal recessive cutis laxa type 3B)
  • Pyrroline-5-carboxylate reductase 2 deficiency (Hypomyelinating leukodystrophy type 1)
  • Proline dehydrogenase deficiency (Proline oxidase deficiency; hyperprolinemia type 1)
  • Pyrroline-5-carboxylate dehydrogenase deficiency (Hyperprolinemia type 2)
  • Hydroxyproline dehydrogenase deficiency (Hydroxyprolinemia)
  • 4-hydroxy-2-oxoglutarate aldolase 1 deficiency (Primary hyperoxaluria type 3)

h. Disorders of lysine, hydroxylysine, and tryptophan metabolism

  • Alpha-aminoadipic semialdehyde synthase deficiency (Familial hyperlysinemia; saccharopinuria)
  • DHTKD1 deficiency (2-aminoadipic 2-oxoadipic aciduria; Charcot-Marie-Tooth disease type 2Q)
  • 5-phosphohydroxylysine phospholyase deficiency (Phosphohydroxylysinuria)
  • Hydroxylysinuria
  • Tryptophan 2,3-dioxygenase deficiency (Hypertryptophanemia)
  • Kynureninase deficiency (Xanthurenic aciduria; hydroxykynureninuria; vertebral, cardiac, renal, and limb defects syndrome type 2)
  • 3-hydroxyanthranilic acid 3,4-dioxygenase deficiency (Vertebral, cardiac, renal, and limb \ defects \syndrome type 1)
  • Kynurenine-3-hydroxylase deficiency

i. Disorders of glutamate/glutamine and aspartate/asparagine metabolism

  • Glutamate pyruvate transaminase 2 deficiency
  • Glutamate decarboxylase 1 deficiency (Spastic cerebral palsy type 1)
  • Glutamine synthetase deficiency
  • Glutaminase superactivity
  • Glutaminase deficiency
  • Asparagine synthetase deficiency
  • Aspartate N-acetyltransferase deficiency (Hypoacetylaspartia; N-acetylaspartate deficiency)
  • Aspartoacylase deficiency (Canavan disease; aminoacylase 2 deficiency)

j. Disorders of histidine metabolism

  • Histidine ammonia-lyase deficiency (Histidase deficiency; histidinemia)
  • Urocanase deficiency (Urocanic aciduria)

k. Disorders of amino acid transport

  • Hartnup disorder
  • Iminoglycinuria
  • Hyperglycinuria
  • Cystinuria type A
  • Cystinuria type B
  • Lysinuric protein intolerance (Dibasic aminoaciduria type 2)
  • Glutamate aspartate transporter deficiency (EAAT1 deficiency; episodic ataxia type 6)
  • Astroglial glutamate aspartate transporter deficiency (EAAT2 deficiency; early infantile \ epileptic encephalopathy type 41)
  • Dicarboxylic aminoaciduria
  • Large neutral amino acid transporter deficiency
  • Neuronal system A amino acid transporter deficiency (Foveal hypoplasia type 2 with or without optic nerve misrouting and/or anterior segment dysgenesis)
  • Vesicular neutral amino acid transporter 3 deficiency (Autosomal recessive intellectual disability type 48)
  • Cystinosis
  • Lysosomal cationic amino acid transporter deficiency (Retinitis pigmentosa type 68)
  • Cationic amino acid transporter 2 deficiency
  • Cationic amino acid transporter 3 deficiency
  • GABA transporter deficiency (Myoclonic-atonic epilepsy)
  • Taurine transporter deficiency
  • Dibasic aminoaciduria type 1
  • Blue diaper syndrome (Drummond syndrome)
  • Lysine malabsorption syndrome
  • Histidinuria
  • Methionine malabsorption syndrome (Oasthouse disease; Smith-Strang disease; methioninuria)

l. Other disorders of amino acid metabolism

  • Aminoacylase 1 deficiency

1.2 Disorders of peptide and amine metabolism

a. Disorders of glutathione metabolism

  • Gamma-glutamylcysteine synthetase deficiency (Glutamate-cysteine ligase deficiency)
  • Glutathione synthetase deficiency
  • Gamma-glutamyl transpeptidase deficiency (Glutathioninuria; γ-glutamyl transferase deficiency)
  • Dipeptidase deficiency (Cysteinylglycinuria)
  • 5-Oxoprolinase deficiency
  • Glutathione reductase deficiency
  • Glutathione peroxidase 4 deficiency (Spondylometaphyseal dysplasia, Sedaghatian type)
  • NRF2 superactivity (Immunodeficiency, developmental delay, and hypohomocysteinemia – IEMDHH)

b. Other disorders of peptide metabolism

  • Prolidase deficiency
  • X-prolyl aminopeptidase 3 deficiency (Nephronophthisis-like nephropathy type 1)
  • Serum carnosinase deficiency (Carnosinemia; homocarnosinosis)
  • Homocarnosinosis

c. Disorders of methylamine metabolism

  • Dimethylglycine dehydrogenase deficiency (Dimethylglycinuria)
  • Sarcosine dehydrogenase deficiency (Sarcosinemia)
  • Flavin monooxygenase 3 deficiency (Primary trimethylaminuria)

d. Disorders of polyamine metabolism

  • Ornithine decarboxylase superactivity (Bachmann-Bupp syndrome)
  • Spermine synthase deficiency (Snyder-Robinson syndrome)
  • Spermidine/spermine N(1)-acetyltransferase superactivity
  • Methylthioadenosine phosphorylase deficiency (Diaphyseal medullary stenosis with malignant fibrous histiocytoma)
  • Diaminopentanuria (Cystine-lysinuria)

1.3 Disorders of carbohydrate metabolism

a. Disorders of galactose and fructose metabolism

  • Galactose-1-phosphate uridylyltransferase deficiency (Classic galactosemia; galactosemia type 1)
  • Galactose epimerase deficiency (Galactosemia type 3)
  • Galactokinase deficiency (Galactosemia type 2)
  • Galactose mutarotase deficiency (Galactosemia type 4)
  • Hepatic fructokinase deficiency (Essential fructosuria)
  • Aldolase B deficiency (Hereditary fructose intolerance)
  • Triokinase/FMN cyclase deficiency
  • D-glycerate kinase deficiency (D-glyceric aciduria)
  • Sorbitol dehydrogenase deficiency

b. Disorders of gluconeogenesis

  • Fructose-1,6-bisphosphatase deficiency
  • Pyruvate carboxylase deficiency
  • Cytosolic phosphoenolpyruvate carboxykinase deficiency
  • Mitochondrial phosphoenolpyruvate carboxykinase deficiency
  • Glycerol kinase deficiency

c. Disorders of glycolysis

  • Hemolytic anemia due to hexokinase deficiency
  • Hereditary motor and sensory neuropathy, Russe type (Charcot-Marie-Tooth disease type 4G)
  • Retinitis pigmentosa type 79
  • Glucokinase deficiency (Permanent neonatal diabetes mellitus; MODY type 2)
  • Glucokinase superactivity (Permanent neonatal diabetes mellitus; MODY type 2)
  • Glucose-6-phosphate isomerase deficiency
  • Muscle phosphofructokinase deficiency (Glycogen storage disease type 7; Tarui disease)
  • Aldolase A deficiency (Glycogen storage disease type 12)
  • Triose phosphate isomerase deficiency
  • Phosphoglycerate kinase deficiency
  • Muscle phosphoglycerate mutase deficiency (Glycogen storage disease type 1; DiMauro disease)
  • Enolase beta deficiency (Glycogen storage disease type 13)
  • Pyruvate kinase deficiency
  • Lactate dehydrogenase A deficiency (Glycogen storage disease type 11)
  • Lactate dehydrogenase B deficiency
  • D-lactate dehydrogenase deficiency (Hereditary D-lactic aciduria)

d. Disorders of glycogen metabolism

  • Muscle glycogenin 1 deficiency (Glycogen storage disease type 15; polyglucosan body myopathy type 2)
  • Liver glycogenin 2 deficiency
  • Muscle glycogen synthase deficiency (Glycogen storage disease type 0b)
  • Hepatic glycogen synthase deficiency (Glycogen storage disease type 0a)
  • Glucose-6-phosphatase deficiency (Glycogen storage disease type 1a)
  • Glucose-6-phosphate transporter deficiency (Glycogen storage disease type 1b)
  • Glycogen debranching enzyme deficiency (Glycogen storage disease type 3; Cori Forbes disease; limit dextrinosis)
  • Glycogen branching enzyme deficiency (Glycogen storage disease type 4; Andersen disease; adult polyglucosan body disease)
  • Muscle glycogen phosphorylase deficiency (Glycogen storage disease type 5; McArdle disease)
  • Liver glycogen phosphorylase deficiency (Glycogen storage disease type 6; Hers disease)
  • Hepatic phosphorylase kinase subunit alpha 2 deficiency (Glycogen storage disease type 9a)
  • Phosphorylase kinase subunit beta deficiency (Glycogen storage disease type 9b)
  • Hepatic phosphorylase kinase subunit gamma 2 deficiency (Glycogen storage disease type 9c)
  • Muscle phosphorylase kinase subunit alpha 1 deficiency (Glycogen storage disease type 9d)
  • Cardiac phosphorylase kinase deficiency
  • HOIL1 deficiency (Polyglucosan body myopathy type 1)
  • HOIL1 interacting protein deficiency
  • Laforin deficiency (Progressive myoclonic epilepsy type 2A)
  • Malin deficiency (Progressive myoclonic epilepsy type 2B)

e. Disorders of pentose metabolism

  • Glucose-6-phosphate dehydrogenase deficiency
  • Ribose 5-phosphate isomerase deficiency
  • Transaldolase deficiency
  • Transketolase deficiency (Short stature, developmental delay, and congenital heart defects)
  • Sedoheptulose kinase deficiency
  • L-xylulose reductase deficiency (Pentosuria; xylitol dehydrogenase deficiency)
  • L-arabinosuria

f. Disorders of carbohydrate transmembrane transport and absorption

  • GLUT1 deficiency (GLUT1 deficiency)
  • Neuronal glucose transporter deficiency (Intellectual developmental disorder with neuropsychiatric features)
  • Glucose transporter 2 deficiency (Fanconi-Bickel syndrome)
  • Intestinal sodium-glucose cotransporter 1 deficiency (Glucose-galactose malabsorption)
  • Sodium-glucose cotransporter 2 deficiency (Familial renal glucosuria type 1)
  • MAP17 deficiency (Familial renal glucosuria type 2)
  • Congenital sucrase-isomaltase deficiency
  • Trehalase deficiency
  • Congenital lactase deficiency (Congenital alactasia)
  • Sialin deficiency (Infantile sialic acid storage disease, severe; Salla disease, milder)

1.4 Disorders of fatty acid and ketone body metabolism

a. Disorders of carnitine metabolism

  • Primary carnitine deficiency
  • Carnitine palmitoyltransferase 1A deficiency
  • Carnitine palmitoyltransferase 1C deficiency (Autosomal dominant spastic paraplegia type 73)
  • Carnitine palmitoyltransferase 2 deficiency
  • Carnitine-acylcarnitine translocase deficiency
  • Epsilon-N-trimethyllysine hydroxylase deficiency
  • Gamma-butyrobetaine hydroxylase deficiency
  • Carnitine acetyltransferase deficiency

b. Disorders of mitochondrial fatty acid oxidation

  • Short-chain acyl-CoA dehydrogenase deficiency
  • Medium-chain acyl-CoA dehydrogenase deficiency
  • Very long-chain acyl-CoA dehydrogenase deficiency
  • Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Familial hyperinsulinemic hypoglycemia type 4)
  • Trifunctional protein subunit alpha deficiency (Long-chain hydroxyacyl-CoA dehydrogenase or complete mitochondrial trifunctional protein deficiency)
  • Trifunctional protein subunit beta deficiency (Complete mitochondrial trifunctional protein deficiency)
  • Isolated mitochondrial long-chain ketoacyl-CoA thiolase deficiency (Complete mitochondrial trifunctional protein deficiency)
  • Medium-chain 3-ketoacyl-CoA thiolase (MCKAT) deficiency
  • Electron transfer flavoprotein subunit alpha deficiency (Glutaric acidemia type 2A; multiple acyl-CoA dehydrogenase deficiency type 2A)
  • Electron transfer flavoprotein subunit beta deficiency (Glutaric acidemia type 2B; multiple acyl-CoA dehydrogenase deficiency type 2B)
  • Electron transfer flavoprotein dehydrogenase deficiency (Glutaric acidemia type 2C; multiple acyl-CoA dehydrogenase deficiency type 2C)
  • Long-chain fatty acid plasma membrane transporter deficiency

c. Disorders of ketone body metabolism

  • Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
  • Succinyl-CoA:3-oxoacid-CoA transferase deficiency
  • Mitochondrial acetoacetyl-CoA thiolase deficiency (β-ketothiolase deficiency; α-methylacetoacetic aciduria)
  • Cytosolic acetoacetyl-CoA thiolase deficiency
  • 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (Hydroxymethylglutaric aciduria)
  • Monocarboxylate transporter 1 deficiency
  • Monocarboxylate transporter 1 superactivity

1.5 Disorders of energy substrate metabolism

a. Disorders of pyruvate metabolism

  • Pyruvate dehydrogenase E1 alpha deficiency
  • Pyruvate dehydrogenase E1 beta deficiency
  • Dihydrolipoamide acetyltransferase deficiency (Pyruvate dehydrogenase E2 deficiency)
  • Dihydrolipoamide dehydrogenase deficiency (E3 deficiency)
  • Pyruvate dehydrogenase E3-binding protein deficiency (Pyruvate dehydrogenase component X deficiency)
  • Pyruvate dehydrogenase phosphatase deficiency
  • Pyruvate dehydrogenase phosphatase regulatory subunit deficiency
  • Pyruvate dehydrogenase kinase isoenzyme 3 superactivity (X-linked Charcot-Marie-Tooth type 6)
  • Mitochondrial pyruvate carrier deficiency

b. Disorders of the Krebs cycle

  • Mitochondrial aconitase deficiency (Infantile cerebellar-retinal degeneration)
  • Cytosolic NADP+-dependent isocitrate dehydrogenase 1 superactivity (Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria; Ollier disease and Mafucci syndrome)
  • Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 superactivity (D-2-hydroxyglutaric aciduria type 2, dominant; Ollier disease and Maffuci syndrome, somatic)
  • Mitochondrial NAD+-dependent isocitrate dehydrogenase 3 subunit alpha deficiency
  • Mitochondrial NAD+-dependent isocitrate dehydrogenase 3 subunit beta deficiency
  • Dihydrolipoamide succinyltransferase deficiency
  • Alpha-ketoglutarate dehydrogenase deficiency (Oxoglutaric aciduria)
  • ATP-specific succinyl-CoA synthetase subunit beta deficiency (Mitochondrial DNA depletion syndrome type 5)
  • GTP-specific succinyl-CoA synthetase subunit alpha deficiency (Mitochondrial DNA depletion syndrome type 9)
  • Fumarate hydratase deficiency (Fumarase deficiency; fumaric aciduria)
  • Fumarate hydratase deficiency, tumoral phenotype (Hereditary leiomyomatosis and renal cell cancer; Reed syndrome)
  • Mitochondrial malate dehydrogenase deficiency (Early infantile epileptic encephalopathy type 51)
  • Mitochondrial malate dehydrogenase deficiency, tumoral phenotype
  • Plasma membrane citrate transporter deficiency (Early infantile epileptic encephalopathy type 25)
  • Sodium dicarboxylate cotransporter 3 deficiency

c. Disorders of creatine metabolism

  • Arginine:glycine amidinotransferase (AGAT) deficiency (Cerebral creatine deficiency syndrome type 3)
  • Arginine:glycine amidinotransferase aggregation syndrome (Fanconi renotubular syndrome type 1; Luder-Sheldon syndrome)
  • Guanidinoacetate methyltransferase deficiency (Cerebral creatine deficiency syndrome type 2)
  • Creatine transporter deficiency (Cerebral creatine deficiency syndrome type 1)

1.6 Mitochondrial DNA-related disorders

a. Disorders of mtDNA-encoded oxidative phosphorylation proteins

  • NADH dehydrogenase core subunit 1 deficiency
  • NADH dehydrogenase core subunit 2 deficiency
  • NADH dehydrogenase core subunit 3 deficiency
  • NADH dehydrogenase core subunit 4 deficiency
  • NADH dehydrogenase core subunit 4L deficiency
  • NADH dehydrogenase core subunit 5 deficiency
  • NADH dehydrogenase core subunit 6 deficiency
  • Mitochondrial cytochrome b deficiency
  • Cytochrome c oxidase subunit 1 deficiency
  • Cytochrome c oxidase subunit 2 deficiency
  • Cytochrome c oxidase subunit 3 deficiency
  • Mitochondrial ATP synthase F0 subunit 6 deficiency
  • Mitochondrial ATP synthase F0 subunit 8 deficiency

b. Disorders of mtDNA-encoded tRNA and rRNA

  • Mitochondrial tRNA-Ala deficiency
  • Mitochondrial tRNA-Arg deficiency
  • Mitochondrial tRNA-Asn deficiency
  • Mitochondrial tRNA-Asp deficiency
  • Mitochondrial tRNA-Cys deficiency
  • Mitochondrial tRNA-Glu deficiency
  • Mitochondrial tRNA-Gln deficiency
  • Mitochondrial tRNA-Gly deficiency
  • Mitochondrial tRNA-His deficiency
  • Mitochondrial tRNA-Ile deficiency
  • Mitochondrial tRNA-Leu 1 deficiency
  • Mitochondrial tRNA-Leu 2 deficiency
  • Mitochondrial tRNA-Lys deficiency
  • Mitochondrial tRNA-Met deficiency
  • Mitochondrial tRNA-Phe deficiency
  • Mitochondrial tRNA-Pro deficiency
  • Mitochondrial tRNA-Ser 1 deficiency
  • Mitochondrial tRNA-Ser 2 deficiency
  • Mitochondrial tRNA-Thr deficiency
  • Mitochondrial tRNA-Trp deficiency
  • Mitochondrial tRNA-Tyr deficiency
  • Mitochondrial tRNA-Val deficiency
  • Mitochondrial ribosomal RNA 12S deficiency
  • Mitochondrial ribosomal RNA 16S deficiency

c. Disorders associated with single large-scale mtDNA deletions

  • Pearson syndrome
  • Kearns-Sayre syndrome
  • mtDNA related-progressive external ophthalmoplegia

1.7 Nuclear-encoded disorders of oxidative phosphorylation

a. Disorders of complex I subunits and assembly factors

  • NADH dehydrogenase flavoprotein 1 deficiency
  • NADH dehydrogenase flavoprotein 2 deficiency
  • NADH dehydrogenase iron-sulfur protein 1 deficiency
  • NADH dehydrogenase iron-sulfur protein 2 deficiency
  • NADH dehydrogenase iron-sulfur protein 3 deficiency
  • NADH dehydrogenase iron-sulfur protein 4 deficiency
  • NADH dehydrogenase iron-sulfur protein 6 deficiency
  • NADH dehydrogenase iron-sulfur protein 7 deficiency
  • NADH dehydrogenase iron-sulfur protein 8 deficiency
  • NADH dehydrogenase alpha subcomplex subunit 1 deficiency
  • NADH dehydrogenase alpha subcomplex subunit 2 deficiency
  • NADH dehydrogenase alpha subcomplex subunit 6 deficiency
  • NADH dehydrogenase alpha subcomplex subunit 8 deficiency
  • NADH dehydrogenase alpha subcomplex subunit 9 deficiency
  • NADH dehydrogenase alpha subcomplex subunit 10 deficiency
  • NADH dehydrogenase alpha subcomplex subunit 11 deficiency
  • NADH dehydrogenase alpha subcomplex subunit 12 deficiency
  • NADH dehydrogenase alpha subcomplex subunit 13 deficiency
  • NADH dehydrogenase beta subcomplex subunit 3 deficiency
  • NADH dehydrogenase beta subcomplex subunit 8 deficiency
  • NADH dehydrogenase beta subcomplex subunit 9 deficiency
  • NADH dehydrogenase beta subcomplex subunit 10 deficiency
  • NADH dehydrogenase beta subcomplex subunit 11 deficiency (Linear skin defects with multiple congenital anomalies type 3)
  • NADH dehydrogenase subunit C2 deficiency
  • Complex I assembly factor 1 deficiency
  • Complex I assembly factor 2 deficiency
  • Complex I assembly factor 3 deficiency
  • Complex I assembly factor 4 deficiency
  • Complex I assembly factor 5 deficiency
  • Complex I assembly factor 6 deficiency
  • Complex I assembly factor 7 deficiency
  • Complex I assembly factor 8 deficiency
  • FOXRED1 deficiency
  • NUBPL deficiency
  • ACAD9 deficiency
  • Transmembrane protein 126A deficiency (Optic atrophy type 7)
  • Transmembrane protein 126B deficiency
  • TIMMDC1 deficiency (Mitochondrial complex I deficiency, nuclear type 31)

b. Disorders of complex II subunits and assembly factors

  • Succinate dehydrogenase subunit A deficiency
  • Succinate dehydrogenase subunit A deficiency, tumoral phenotype (Hereditary paraganglioma syndrome type 5)
  • Succinate dehydrogenase subunit B deficiency
  • Succinate dehydrogenase subunit B deficiency, tumoral phenotype (Hereditary paraganglioma syndrome type 4; Cowden syndrome type 2)
  • Succinate dehydrogenase subunit C deficiency, tumoral phenotype (Hereditary paraganglioma syndrome type 3)
  • Succinate dehydrogenase subunit D deficiency
  • Succinate dehydrogenase subunit D deficiency, tumoral phenotype (Hereditary paraganglioma syndrome type 1; Cowden syndrome type 3)
  • Succinate dehydrogenase complex assembly factor 1 deficiency
  • Succinate dehydrogenase complex assembly factor 2 deficiency, tumoral phenotype (Hereditary paraganglioma syndrome type 2)

c. Disorders of complex III subunits and assembly factors

  • UQCRFS1 deficiency
  • UQCRB deficiency
  • UQCRC2 deficiency
  • UQCRQ deficiency
  • UQCC2 deficiency (Mitochondrial complex III deficiency, nuclear type 7)
  • UQCC3 deficiency
  • Mitochondrial cytochrome c1 deficiency
  • Holocytochrome c synthase deficiency (Linear skin defects with multiple congenital anomalies type 1)
  • BCS1L deficiency (GRACILE syndrome; Björnstad syndrome)
  • TTC19 deficiency
  • LYRM7 deficiency

d. Disorders of complex IV subunits and assembly factors

  • Cytochrome c oxidase subunit 4I1 deficiency
  • Cytochrome c oxidase subunit 4I2 deficiency (Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis)
  • Cytochrome c oxidase subunit 5A deficiency
  • Cytochrome c oxidase subunit 6A1 deficiency (Recessive intermediate Charcot-Marie-Tooth disease type D)
  • Cytochrome c oxidase subunit 6A2 deficiency
  • Cytochrome c oxidase subunit 6B1 deficiency
  • Cytochrome c oxidase subunit 7B deficiency (Linear skin defects with multiple congenital anomalies type 2)
  • Cytochrome c oxidase subunit 8A deficiency
  • Cytochrome c oxidase subunit NDUFA4 (COXFA4) deficiency
  • Cytochrome c oxidase assembly factor 3 deficiency
  • Cytochrome c oxidase assembly factor 5 deficiency
  • Cytochrome c oxidase assembly factor 6 deficiency
  • Cytochrome c oxidase assembly factor 7 deficiency
  • Cytochrome c oxidase assembly factor 10 deficiency
  • Cytochrome c oxidase assembly factor 14 deficiency
  • Cytochrome c oxidase assembly factor 15 deficiency
  • Cytochrome c oxidase assembly factor 20 deficiency
  • SCO1 deficiency
  • SCO2 deficiency
  • SURF1 deficiency
  • LRPPRC deficiency
  • TACO1 deficiency
  • PET100 deficiency
  • PET117 deficiency
  • FASTKD2 deficiency
  • APOPT1 deficiency
  • CEP89 deficiency

e. Disorders of complex V subunits and assembly factors

  • Mitochondrial ATP synthase F1 subunit alpha deficiency
  • Mitochondrial ATP synthase F1 subunit delta deficiency
  • Mitochondrial ATP synthase F1 subunit epsilon deficiency
  • DAPIT deficiency (USMG5 deficiency)
  • Mitochondrial ATP synthase F1 subunit O deficiency
  • Mitochondrial ATP synthase F1 assembly factor 2 deficiency
  • Transmembrane protein 70 deficiency

1.8 Disorders of mitochondrial cofactor biosynthesis

a. Disorders of coenzyme Q10 biosynthesis

  • Prenyl diphosphate synthase subunit 1 deficiency (Primary coenzyme Q10 deficiency type 2)
  • Prenyl diphosphate synthase subunit 2 deficiency (Primary coenzyme Q10 deficiency type 3)
  • Coenzyme Q2 polyprenyltranferase deficiency (Primary coenzyme Q10 deficiency type 1)
  • Coenzyme Q4 deficiency (Primary coenzyme Q10 deficiency type 7)
  • Coenzyme Q5 methyltransferase deficiency (Primary coenzyme Q10 deficiency type 9)
  • Coenzyme Q6 monooxygenase deficiency (Primary coenzyme Q10 deficiency type 6)
  • Coenzyme Q7 hydroxylase deficiency (Primary coenzyme Q1 deficiency type 8)
  • ADCK2 deficiency
  • Coenzyme Q8A (ADCK3) deficiency (Primary coenzyme Q1 deficiency type 4; ADCK3 deficiency)
  • Coenzyme Q8B (ADCK4) deficiency (Nephrotic syndrome type 9; ADCK4 deficiency)
  • Coenzyme 9 deficiency (Primary coenzyme Q1 deficiency type 5)

b. Disorders of lipoic acid and iron-sulfur metabolism

  • Lipoyltransferase 2 deficiency (Neonatal severe encephalopathy with lactic acidosis and brain abnormalities – NELABA)
  • Lipoic acid synthase deficiency (Hyperglycinemia, lactic acidosis, and seizures)
  • Lipoyltransferase 1 deficiency
  • NFU1 deficiency (Multiple mitochondrial dysfunctions syndrome type 1)
  • BOLA3 deficiency (Multiple mitochondrial dysfunctions syndrome type 2 with hyperglycinemia)
  • Glutaredoxin 5 deficiency
  • IBA57 deficiency
  • ISCA1 deficiency (Multiple mitochondrial dysfunctions syndrome type 5)
  • ISCA2 deficiency (Multiple mitochondrial dysfunctions syndrome type 4)
  • ISCU deficiency (Hereditary myopathy with lactic acidosis, Swedish type myopathy with exercise intolerance)
  • ABCB7 deficiency (Sideroblastic anemia and spinocerebellar ataxia)
  • Ferredoxin reductase deficiency (Auditory neuropathy and optic atrophy)
  • Ferredoxin 2 deficiency
  • ISD11 deficiency (Combined oxidative phosphorylation deficiency 19)
  • NFS1 deficiency (Infantile mitochondrial complex II/III deficiency – IMC23D)
  • Frataxin deficiency (Friedreich ataxia)

c. Disorders of mitochondrial cytochrome c biosynthesis

  • Mitochondrial cytochrome c deficiency (Thrombocytopenia type 4)

1.9 Disorders of mitochondrial DNA maintenance and replication

a. Disorders of mitochondrial nucleotide pool maintenance

  • Mitochondrial deoxyguanosine kinase deficiency (Mitochondrial DNA depletion syndrome type 3; arPEO with mitochondrial DNA deletions type 4; noncirrhotic portal hypertension)
  • Mitochondrial thymidine kinase deficiency (Mitochondrial DNA depletion syndrome type 2)
  • Mitochondrial UMP-CMP kinase 2 deficiency
  • MPV17 deficiency (Mitochondrial DNA depletion syndrome type 6)
  • Mitochondrial ribonucleotide reductase small subunit deficiency (Mitochondrial DNA depletion syndrome type 8; adPEO with mitochondrial DNA deletions type 5)
  • Thymidine phosphorylase deficiency (Mitochondrial neurogastrointestinal encephalopathy syndrome)
  • SAMHD1 deficiency (Aicardi-Goutières syndrome type 5; stenosis, aneurysm, moyamoya and stroke – SAMS association)

b. Disorders of mtDNA replication and maintenance

  • Mitochondrial DNA polymerase gamma catalytic subunit deficiency (Mitochondrial DNA depletion syndrome type 1; Alpers-Huttenlocher syndrome; mitochondrial recessive ataxia syndrome – MIRAS; arPEO type 1; adPEO type 1)
  • Mitochondrial DNA polymerase gamma accessory subunit deficiency (adPEO with mitochondrial DNA deletions type 4)
  • TWINKLE mitochondrial DNA helicase deficiency (Mitochondrial DNA depletion syndrome type 7; Perrault syndrome type 5; arPEO with mitochondrial DNA deletions type 5)
  • Single-stranded DNA-binding protein 1 deficiency (Optic atrophy type 13 with retinal and foveal abnormalities)
  • DNA2 helicase deficiency (adPEO with mitochondrial DNA deletions type 6)
  • Mitochondrial genome maintenance exonuclease 1 deficiency (Mitochondrial DNA depletion syndrome type 11)
  • Mitochondrial ribonuclease H1 deficiency (arPEO with mitochondrial DNA deletions type 2)
  • Topoisomerase 3 alpha deficiency (arPEO with mitochondrial DNA deletions type 5)

1.10 Disorders of mitochondrial gene expression

a. Disorders of mitochondrial transcript processing and modification

  • Mitochondrial RNA polymerase deficiency
  • Mitochondrial RNA import protein deficiency (Combined oxidative phosphorylation deficiency type 13)
  • Mitochondrial transcription factor A deficiency
  • Ribonuclease P 5′ tRNA processing enzyme deficiency (Combined oxidative phosphorylation deficiency 3)
  • HSD10 disease (2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency)
  • RNase P catalytic subunit deficiency
  • Ribonuclease Z 3′ tRNA processing enzyme deficiency (Combined oxidative phosphorylation deficiency 17)
  • Mitochondrial poly(A) polymerase deficiency
  • Mitochondrial poly(A) exoribonuclease deficiency
  • CCA-adding tRNA-nucleotidyltransferase deficiency (Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay, severe; retinitis pigmentosa and erythrocytic microcytosis, milder)
  • Mitochondrial methionyl-tRNA formyltransferase deficiency (Combined oxidative phosphorylation deficiency type 15)
  • Mitochondrial methionyl-tRNA methyltransferase deficiency
  • tRNA 5-taurinomethyluridine modifier deficiency (Combined oxidative phosphorylation deficiency type 23)
  • tRNA 5-carboxymethylaminomethyl transferase deficiency (Combined oxidative phosphorylation deficiency type 1)
  • Pseudouridine synthase 1 deficiency (Myopathy, lactic acidosis, and sideroblastic anemia type 1)
  • tRNA isopentenyl transferase deficiency
  • tRNA methyltransferase 5 deficiency (Combined oxidative phosphorylation deficiency type 26)
  • tRNA 5-methylaminomethyl-2-thiouridylate-methyltransferase deficiency (Transient infantile liver failure)
  • tRNA-His guanylyltransferase 1 like deficiency

b. Disorders of mitochondrial aminoacyl-tRNA synthetases

  • Mitochondrial alanyl-tRNA synthetase deficiency (Combined oxidative phosphorylation deficiency type 8; progressive leukoencephalopathy with ovarian failure)
  • Mitochondrial arginyl-tRNA synthetase deficiency (Pontocerebellar hypoplasia type 6)
  • Mitochondrial asparaginyl-tRNA synthetase deficiency (Combined oxidative phosphorylation deficiency type 24)
  • Mitochondrial aspartyl-tRNA synthetase deficiency (Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation)
  • Mitochondrial cysteinyl-tRNA synthetase deficiency (Combined oxidative phosphorylation deficiency type 27)
  • Mitochondrial glutamyl-tRNA synthetase deficiency (Combined oxidative phosphorylation deficiency type 12)
  • Mitochondrial histidyl-tRNA synthetase deficiency (Perrault syndrome type 2)
  • Mitochondrial isoleucyl-tRNA synthetase deficiency (Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia – CAGSSS)
  • Mitochondrial leucyl-tRNA synthetase deficiency (Perrault syndrome type 4)
  • Mitochondrial methionyl-tRNA synthetase deficiency (Autosomal recessive spastic ataxia type 3)
  • Mitochondrial phenylalanyl-tRNA synthetase deficiency (Combined oxidative phosphorylation deficiency type 14)
  • Mitochondrial prolyl-tRNA synthetase deficiency
  • Mitochondrial seryl-tRNA synthetase deficiency (Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis – HUPRA)
  • Mitochondrial threonyl-tRNA synthetase deficiency (Combined oxidative phosphorylation deficiency type 21)
  • Mitochondrial tyrosyl-tRNA synthetase deficiency (Myopathy, lactic acidosis, and sideroblastic anemia type 2)
  • Mitochondrial valyl-tRNA synthetase deficiency (Combined oxidative phosphorylation deficiency type 2)
  • Mitochondrial tryptophanyl-tRNA synthetase deficiency (Mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis, with or without seizures)
  • Mitochondrial and cytoplasmic glycyl-tRNA synthetase deficiency (Charcot-Marie-Tooth disease type 2D; distal hereditary motor neuropathy type 5A; infantile spinal muscular atrophy, James type)
  • Mitochondrial and cytoplasmic lysyl-tRNA synthetase deficiency (Recessive intermediate Charcot-Marie-Tooth type B; autosomal recessive deafness type 89)
  • Mitochondrial glutamyl-tRNA(Gln) amidotransferase subunit A deficiency
  • Mitochondrial glutamyl-tRNA(Gln) amidotransferase subunit B deficiency
  • Mitochondrial glutamyl-tRNA(Gln) amidotransferase subunit C deficiency

c. Disorders of the mitoribosome

  • Mitochondrial ribosomal large subunit 3 deficiency (Combined oxidative phosphorylation deficiency type 9)
  • Mitochondrial ribosomal large subunit 12 deficiency
  • Mitochondrial ribosomal large subunit 24 deficiency
  • Mitochondrial ribosomal large subunit 44 deficiency (Combined oxidative phosphorylation deficiency type 16)
  • Mitochondrial ribosomal small subunit 2 deficiency
  • Mitochondrial ribosomal small subunit 7 deficiency
  • Mitochondrial ribosomal small subunit 14 deficiency
  • Mitochondrial ribosomal small subunit 16 deficiency (Combined oxidative phosphorylation deficiency type 2)
  • Mitochondrial ribosomal small subunit 22 deficiency (Combined oxidative phosphorylation deficiency type 5)
  • Mitochondrial ribosomal small subunit 23 deficiency
  • Mitochondrial ribosomal small subunit 25 deficiency (Combined oxidative phosphorylation deficiency type 50)
  • Mitochondrial ribosomal small subunit 28 deficiency
  • Mitochondrial ribosomal small subunit 34 deficiency (Combined oxidative phosphorylation deficiency type 32)
  • Mitochondrial ribosomal small subunit 39 deficiency
  • ERAL1 deficiency (Perrault syndrome type 6)
  • Mitochondrial rRNA methyltransferase 2 deficiency
  • RMND1 deficiency (Combined oxidative phosphorylation deficiency type 11)
  • Mitochondrial elongation factor G1 deficiency (Combined oxidative phosphorylation deficiency type 1)
  • Mitochondrial elongation factor G2 deficiency
  • Mitochondrial elongation factor Ts deficiency (Combined oxidative phosphorylation deficiency type 3)
  • Mitochondrial elongation factor Tu deficiency (Combined oxidative phosphorylation deficiency type 4)
  • C12orf65 release factor deficiency (Combined oxidative phosphorylation deficiency type 7; autosomal recessive spastic paraplegia type 55)
  • GUF1 deficiency (Early infantile epileptic encephalopathy 4)

1.11 Other disorders of mitochondrial function

a. Disorders of mitochondrial shuttles and carriers

  • Mitochondrial citrate carrier deficiency (Combined D-2- and L-2-hydroxyglutaric aciduria)
  • Mitochondrial phosphate carrier deficiency
  • Adenine nucleotide translocator deficiency (Mitochondrial DNA depletion syndrome type 12 (cardiomyopathic type); adPEO with mitochondrial DNA deletions type 2)
  • Mitochondrial dicarboxylate transporter deficiency
  • Mitochondrial oxoglutarate/malate carrier deficiency (Hereditary paraganglioma syndrome type 6)
  • Mitochondrial aspartate-glutamate carrier isoform 1 deficiency (Early infantile epileptic encephalopathy type 39; aralar deficiency)
  • Mitochondrial aspartate aminotransferase deficiency
  • Cytosolic malate dehydrogenase deficiency
  • Cytosolic glycerol-3-phosphate dehydrogenase deficiency (Transient infantile hypertriglyceridemia)
  • Mitochondrial oxodicarboxylate carrier deficiency
  • Mitochondrial glutamate transporter deficiency (Early infantile epileptic encephalopathy type 3)
  • Mitochondrial ATP-Mg/phosphate transporter deficiency (Gorlin-Chaudhry-Moss syndrome; Fontaine syndrome)
  • S-adenosylmethionine carrier deficiency (Combined oxidative phosphorylation deficiency type 28)
  • Mitochondrial glycine transporter deficiency (Congenital sideroblastic anemia type 2)
  • Mitochondrial calcium uniporter deficiency (Myopathy with extrapyramidal signs)
  • Mitochondrial calcium uniporter 2 deficiency

b. Disorders of mitochondrial protein import

  • TOMM70 deficiency
  • TIMM8A deficiency (Mohr-Tranebjaerg syndrome)
  • TIMM14 deficiency (Dilated cardiomyopathy with ataxia – DCMA syndrome; 3-methylglutaconic aciduria type 5)
  • TIMM22 deficiency
  • Acylglycerol kinase deficiency (Sengers syndrome)
  • TIMM50 deficiency (3-methylglutaconic aciduria type 9)
  • MAGMAS deficiency (Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type)

c. Disorders of mitochondrial protein quality control

  • Mitochondrial-processing peptidase alpha deficiency (Autosomal recessive spinocerebellar ataxia type 2)
  • Mitochondrial-processing peptidase beta deficiency
  • Mitochondrial intermediate peptidase deficiency (Combined oxidative phosphorylation deficiency type 31)
  • CLPB deficiency (3-methylglutaconic aciduria type 7, with cataracts, neurologic involvement and neutropenia)
  • CLPP deficiency (Perrault syndrome type 3)
  • CLPX deficiency (Erythropoietic protoporphyria type 2)
  • LONP1 deficiency (Cerebral, ocular, dental, auricular, and skeletal syndrome – CODAS syndrome)
  • HSPA9 deficiency (Sideroblastic anemia type 4; epiphyseal, vertebral, ear, nose, plus associated malformations syndrome – EVEN-plus syndrome)
  • HSP60 deficiency (Hypomyelinating leukodystrophy type 4, recessive; autosomal dominant spastic paraplegia type 13)
  • HSPE1 deficiency
  • FBXL4 deficiency (Mitochondrial DNA depletion syndrome type 13)
  • Sacsin deficiency (Autosomal recessive spastic ataxia of Charlevoix-Saguenay)
  • m-AAA protease subunit AFG3L2 deficiency (Autosomal recessive spastic ataxia type 5; spinocerebellar ataxia type 28)
  • Paraplegin deficiency (Spastic paraplegia type 7)
  • ATAD3A deficiency (Harel-Yoon syndrome)
  • HTRA2 deficiency (3-methylglutaconic aciduria type 8)
  • Parkin deficiency (Early-onset Parkinson disease type 2)
  • PINK1 deficiency (Early-onset Parkinson disease type 6)
  • Pitrilysin metallopeptidase 1 deficiency
  • YME1L1 deficiency (Optic atrophy type 11)
  • Oxa1-like deficiency

d. Miscellaneous disorders associated with mitochondrial dysfunction

  • Mitochondrial inorganic pyrophosphatase 2 deficiency
  • Mitochondrial thioredoxin 2 deficiency (Combined oxidative phosphorylation deficiency type 29)
  • Mitochondrial thioredoxin reductase 2 deficiency
  • Sideroflexin 4 deficiency (Combined oxidative phosphorylation deficiency type 18)
  • AIFM1 deficiency (Combined oxidative phosphorylation deficiency type 6; Cowchock syndrome)
  • C1q binding protein deficiency (Combined oxidative phosphorylation deficiency type 33)
  • Nogo-interacting mitochondrial protein deficiency (Optic atrophy type 1)
  • DIABLO deficiency
  • Peptidyl-tRNA hydrolase 2 deficiency (Infantile-onset multisystem neurologic, endocrine, and pancreatic disease)
  • GFER deficiency
  • Nucleoside diphosphate kinase 3 deficiency

1.12 Disorders of metabolite repair/proofreading

a. Disorders of mitochondrial metabolite repair

  • D-2-hydroxyglutarate dehydrogenase deficiency (D-2-hydroxyglutaric aciduria type 1)
  • L-2-hydroxyglutarate dehydrogenase deficiency (L-2-hydroxyglutaric aciduria)
  • Combined malonic and methylmalonic aciduria (Combined malonic and methylmalonic aciduria)

b. Disorders of non-mitochondrial metabolite repair

  • Ubiquitous glucose-6-phosphatase deficiency (Severe congenital neutropenia type 4; Dursun syndrome)

1.13 Miscellaneous disorders of intermediary metabolism

a. Disorders of glyoxylate and oxalate metabolism

  • Glyoxylate reductase/hydroxypyruvate reductase deficiency (Primary hyperoxaluria type 2)
  • Hydroxyacid oxidase 1 deficiency (Glycolate oxidase deficiency; isolated glycolic aciduria)
  • Alanine-glyoxylate aminotransferase deficiency (Primary hyperoxaluria type 1)
  • Oxalate transporter deficiency

b. Unassigned disorders of intermediary metabolism

  • Catalase deficiency (Acatalasemia)

Hey, want to upgrade to pro plan?

18748

Upgrade Now

& get 25% off

Offer valid only for 24 hrs.

18749
Scroll to Top