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Table 2 Overview of all 54 treatable IEMs presenting as CP mimics identified through systematic literature review

From: Treatable inborn errors of metabolism presenting as cerebral palsy mimics: systematic literature review

Biochemical category Disease name OMIM# Gene(s) Treatment Effect Level of evidence CP symptoms
Amino acids Hartnup disease 234500 SLC6A19 (AR) High protein diet Stabilizing/preventative treatment 4-5 Dystonia
  Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome 238970 SLC25A15 (AR) Dietary protein restriction, ornithine supplement, sodium benzoate, phenylacetate Stabilizing/preventative treatment 4 Spasticity
  Late onset non-ketotic hyperglycinemia 605899 AMT/GLDC/GCSH (AR) Glycine restriction, +/− sodium benzoate, NMDA receptor antagonists, other neuromodulating agents Stabilizing/preventative treatment 4-5 Spastic diplegia
  Phenylketonuria (PKU) 261600 PAH (AR) Dietary phenylalanine restriction +/− amino acid supplements (BH(4) supplement) Stabilizing/preventative treatment 2a (4) Spastic diplegia
  PHGDH deficiency (Serine deficiency) 601815 PHGDH (AR) L-serine & +/−glycine supplements Primary/targeting underlying pathophysiology 4 Spastic diplegia/tetraparesis
Cerebral glucose transport Blood brain-barrier glucose-transporter (GLUT1) defect 606777 SLC2A1 (AR) Ketogenic diet Primary/targeting underlying pathophysiology 4 Spasticity, dystonia, ataxia
Creatine GAMT deficiency 612736 GAMT (AR) Arginine restriction, creatine & ornithine supplements Primary/targeting underlying pathophysiology 4 Movement disorder: extrapyramidal signs, athetosis, & ataxia
Fatty acid oxidation Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency 201450 ACADM (AR) Emergency regimen, L-carnitine, avoid fasting Stabilizing/preventative treatment 2a CP symptoms
  Short-chain acyl-CoA dehydrogenase (SCAD) deficiency 201470 ACADS (AR) Emergency regimen, L-carnitine Stabilizing/preventative treatment 2c Spastic diplegia
  Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency 201475 ACADVL (AR) Avoidance of fasting, low-fat diet, Medium Chain Triglyceride oild Stabilizing/preventative treatment 4 Neonatal asphyxia
Hyperhomo-cysteinemia Homocystinuria due to Cystathionine β-synthase deficiency 236200 CBS (AR) Methionine restriction, +/− pyridoxine, +/− betaine Stabilizing/preventative treatment 2c Dystonia
  MTHFR deficiency 236250 MTHFR (AR) Betaine supplements, +/− folate, carnitine, methionine supplements Stabilizing/preventative treatment 4 Ataxic gait, hypotonia, extrapyramidal movements, upper motor neuron signs
Lipids Abetalipoproteinemia 200100 MTTP (AR) Low long-chain fatty acid diet with fat-soluble vitamin (i.e., A, D, E, K) supplementation Primary/targeting underlying pathophysiology 4 Ataxia, abnormal gait
Lysosomal Fucosidosis 230000 FUCA1 (AR) Haematopoietic stem cell transplant Stabilizing/preventative treatment 5 Severe spasticity; spastic paresis, generalized dystonia
  Krabbe disease 245200 GALC (AR) Haematopoietic stem cell transplant Stabilizing/preventative treatment 2c Progressive spasticity
  Metachromatic leucodystrophy (MLD) 250100 ARSA (AR) Haematopoietic stem cell transplant Stabilizing/preventative treatment 4-5 Loss of all gross motor function measured by CP scale; ataxia
  Neimann-Pick, type C 257220 NPC1, NPC2 Miglustat Stabilizing/preventative treatment 1b Axial hypotonia, spastic diparesis, dystonic posturing of the hands
Metals Menkes Disease 309400 ATP7A Copper histidine Stabilizing/preventative treatment 4 Progressive spasticity, hypotonia
  Wilson Disease 277900 ATP7B Zinc & tetrathiomolybdate; oxcarbazepine Stabilizing/preventative treatment 1b Neurological symptoms, dystonia
Mitochondria Coenzyme Q10 deficiency 607426 COQ2, APTX, PDSS1, PDSS2, CABC1, COQ9 (most AR) CoQ supplements Primary/targeting underlying pathophysiology 4 Spastic paresis; progressive ataxia and dystonia
  MELAS 540000 mt.A3243G, mt.G13513A (mtDNA) Arginine supplements Stabilizing/preventative treatment 4-5 dx. CP
  Pyruvate dehydrogenase deficiency 312170, 245348 PDHA1 (X-linked recessive), DLAT (AR), PDHX (AR) Ketogenic diet & thiamine Primary/targeting underlying pathophysiology 4 Spastic quadriplegia; dystonia
Neurotransmission Aromatic-L-amino-acid decarboxylase deficiency 608643 DDC (AR) MAO inhibitors, B6, anti-cholinergics, dopa agonists) Primary/targeting underlying pathophysiology 4 Limb dystonia, athetoid movement
  DHPR deficiency (biopterin deficiency) 261630 QDPR (AR) BH4, diet, amine replacement, folinic acid Primary/targeting underlying pathophysiology 4 Ataxia, gait disorder, peripheral spasticity
  Dopamine transporter deficiency syndrome 126455 SLC6A3 Dopamine antagonist (Ropinirole) Primary/targeting underlying pathophysiology 4 dx. CP
  GTPCH1-deficient dopa-responsive dystonia (aka Segawa’s disease) 233910 GCH1 (AR) BH4, amine replacement Primary/targeting underlying pathophysiology 4 dx. CP; spastic diplegia
  PTPS deficiency (biopterin deficiency) 261640 PTS (AR) BH4, diet, amine replacement Primary/targeting underlying pathophysiology 4 Dystonia; spastic extremities; generalized dystonia, choreoathetoid arm movements & axial hypotonia
  Sepiapterin reductase deficiency 612716 SPR (AR) Amine replacement Primary/targeting underlying pathophysiology 4 Limb spasticity, dystonic signs; “hypotonic cerebral palsy”; dystonia, axial hypotonia; misdx. CP
  Succinic semialdehyde dehydrogenase deficiency (SSADH) 271980 ALDH5A1 (AR) Vigabatrin Stabilizing/preventative treatment 4 Hypotonia, ataxia; gait clumsiness, dystonia
  Tyrosine hydroxylase deficiency 605407 TH (AR) L-dopa substitution Primary/targeting underlying pathophysiology 4 Spastic paraplegia/tetraparesis
  Vesicular monoamine transporter 2 (VMAT2) 193001 SLC18A2 Dopamine aginist Primary/targeting underlying pathophysiology 4 Dystonia
Organic acids β-Ketothiolase deficiency 203750 ACAT1 (AR) Avoid fasting, emergency regimen, protein restriction Stabilizing/preventative treatment 5 Ataxia, diplegia, hypotonia
  2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency 300438 HSD17B10 (X-linked) Avoid fasting, emergency regimen, isoleucine restricted diet Stabilizing/preventative treatment 5 Ataxia, dystonia, choreoathetosis, spastic di-/tetra-plegia, hypotonia
  3-Methylcrotonyl-CoA carboxylase (MCC) deficiency 210200; 210210 MCC1/MCC2 (AR) Dietary protein restriction; carnitine, glycine, biotin supplements; avoid fasting; emergency regimen Stabilizing/preventative treatment 5 dx. CP
  3-Methylglutaconic aciduria type 1 250950 AUH (AR) Carnitine supplements, avoid fasting, emergency regimen Stabilizing/preventative treatment 5 dx. CP
  Ethylmalonic encephalopathy 602473 ETHE1 (AR) N-acetylcysteine, oral metronidazol Stabilizing/preventative treatment 4 CNS malformations, episodic ataxia; pyramidal tract signs
  Glutaric aciduria type I (GA1) aka glutaryl-CoA dehydrogenase deficiency 231670 GCDH (AR) Lysine restriction, carnitine supplements Stabilizing/preventative treatment 2a Generalized spasticity, dystonia with athethosis; dx. CP; dyskinesia, dystonic tetraparesis
  Isovaleric acidemia 243500 IVD (AR) Dietary protein restriction, carnitine supplements, avoid fasting, emergency regimen Stabilizing/preventative treatment 2c Hypotonia, paresis
  Multiple acyl-CoA-dehydrogenase deficiency (MADD) (aka Glutaric aciduria type II) 231680 ETFA, ETFB, ETFDH (AR) Carnitine, riboflavin, β-hydroxybutyrate supplements; emergency regimen Primary/targeting underlying pathophysiology 5 Encephalopathy
  Maple syrup urine disease 248600 DBT, BCKDHB, BCKDHA (AR) Dietary restriction, branched amino-acids, avoid fasting, (liver transplantation) Stabilizing/preventative treatment (liver tx = primary treatment) 4 (4) Spastic diplegic CP; paroxysmal dystonia; ataxia
  Methylmalonic acidemia (mutase deficiency) 251000 MUT (AR) Dietary protein restriction, carnitine supplements, avoid fasting, emergency regimen Stabilizing/preventative treatment 2c Total body dystonia
  Lesch-Nyhan syndrome 300322 HPRT1 (X-linked) Haematopoietic stem cell transplant Primary/targeting underlying pathophysiology 4-5 dx. Athetotic/dyskinetic CP; dystonia
  Propionic acidemia 606054 PCCA, PCCB (AR) Dietary protein restriction, carnitine supplements, avoid fasting, emergency regimen Stabilizing/preventative treatment 2c Dystonia, hypotonia
Urea cycle Argininemia 207800 ARG1 (AR) Dietary protein restriction, arginine supplement, sodium benzoate, phenylbutyrate (Liver transplantation) Stabilizing/preventative treatment (liver tx = primary treatment) 2b (4) Spastic diplegia, ataxia, dx. CP
  Argininosuccinic aciduria 207900 ASL (AR) Low protein diet, arginine-supplements, sodium benzoate, phenylbutyrate (liver transplantation) Stabilizing/preventative treatment (liver tx = primary treatment) 2b (4) Cerebellar ataxia
  Citrullinemia, type II 605814 SLC25A13 (AR) Dietary protein restriction, arginine supplement, sodium benzoate, phenylbutyrate (Liver transplantation) Stabilizing/preventative treatment (liver tx = primary treatment) 2b (4) dx. CP; spastic quadriplegia
  Ornithine transcarbamylase deficiency 311250 OTC (X-linked) Dietary protein restriction, citrulline supplements, sodium benzoate/phenylbutyrate (Liver transplantation) Stabilizing/preventative treatment (liver tx = primary treatment) 2b (4) Hemiplegia; ataxia; gait disturbance
Vitamins/Co-factors Biotinidase deficiency 2532760 BTD (AR) Biotin supplement Primary/targeting underlying pathophysiology 2c Spastic tetraparesis
  Biotin-thiamine-responsive basal ganglia disease 607483 SLC19A3 (AR) Biotin supplement Primary/targeting underlying pathophysiology 4 Ataxia, dystonia
  Cerebral folate deficiency syndrome 613068 FOLR1 (AR) Folinic acid Primary/targeting underlying pathophysiology 4 spastic paraplegia; perinatal asphyxia
  Holocarboxylase synthetase deficiency 253270 HLCS (AR) Biotin supplement Primary/targeting underlying pathophysiology 4 dx. CP
  Hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC) 613280 SLC30A10 (AR) Chelation therapy Primary/targeting underlying pathophysiology 4 Dystonia
  Molybdenum cofactor deficiency 252150 MOCS1, MOCS2, (AR) Precursor Z/cPMP Primary/targeting underlying pathophysiology 4 Spastic quadriplegia dx. CP
  Pyridoxamine 5’-phosphate oxidase deficiency 610090 PNPO (AR) Pyridoxal 5’-phosphate Stabilizing/preventative treatment 4 Spastic quadriplegia
  1. Emergency regimen is defined as: Adjustment in management of a particular IEM to prevent or minimize metabolic decompensations (and related complications) during illness, periods of decreased intake or increased energy demand. The mainstay includes high caloric intake, generous fluid management (oral, tube or intravenous), addition/increase of vitamins/co-factors or medications, along with avoidance of substances which cannot be metabolized in patients with this IEM [24].
  2. The IEMs are grouped according to the biochemical phenotype as presented in standard textbooks, and alphabetically.