Skip to main content

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.