Table 1
Included case series studies reporting prevalence of chorea in cohort of Inborn Errors of Metabolism.
| REFERENCE | DISORDERS | CATEGORY OF DISORDERS BASED ON THE ICIMD CLASSIFICATION. | SUBCATEGORY OF DISORDERS BASED ON THE ICIMD CLASSIFICATION. | TYPE OF ARTICLE | PATIENTS WITH CHOREA (PERCENTAGE OF TOTAL PATIENTS REPORTED IN THE ARTICLES WHO EXHIBIT THIS SYMPTOM) |
|---|---|---|---|---|---|
| François Haude et la., 2022 [1] | 3-hydroxyisobutyryl-CoA hydrolase deficiency (HIBCH) and Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1) | 1. DISORDERS OF AMINO ACID METABOLISM | 1.2 Organic acidurias | Case series | HIBCH 1 out of 24 patients (4%) and ECHS110 out of 61 patients (16%) |
| Ktena et al., 2015 [2] | Methylmalonic Acidemia | 1. DISORDERS OF AMINO ACID METABOLISM | 1.2 Organic acidurias | Case series | 13 patients |
| Dreifuss et al., 2008 [3] | Hypoxanthine guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome) | 16. DISORDERS OF NUCLEOBASE, NUCLEOTIDE AND NUCLEIC ACID METABOLISM | 16.2 Disorders of purine metabolism | Case series | 29 out of 29 patients (100%) |
| Lam et al., 2017 [4] | N-glycanase 1 deficiency | 18. CONGENITAL DISORDERS OF GLYCOSYLATION | 18.5 Other disorders of glycan metabolism | Case series | 12 out of 12 patients (100%) |
| Oates et al., 2008 [5] | GM2 gangliosidosis | 20. DISORDERS OF COMPLEX MOLECULE DEGRADATION | 20.1 Disorders of sphingolipid degradation | Case series | 7 out of 36 patients (19%) |
| Kalita et al., 2021 [6] | Copper-transporting ATPase subunit beta deficiency (Wilson disease) | 22. DISORDERS OF TRACE ELEMENTS AND METALS | 22.1 Disorders of copper metabolism | Case series | 31 out of 82 patients (38%) |
| Kalita et al., 2022 [7] | Copper-transporting ATPase subunit beta deficiency (Wilson disease) | 22. DISORDERS OF TRACE ELEMENTS AND METALS | 22.1 Disorders of copper metabolism | Case series | 2 out of 20 patients (10%) |
| Machado et al., 2006 [8] | Copper-transporting ATPase subunit beta deficiency (Wilson disease) | 22. DISORDERS OF TRACE ELEMENTS AND METALS | 22.1 Disorders of copper metabolism | Case series | 19 patients |
| Mihaylova et al., 2012 [9] | Copper-transporting ATPase subunit beta deficiency (Wilson disease) | 22. DISORDERS OF TRACE ELEMENTS AND METALS | 22.1 Disorders of copper metabolism | Case series | 82 patients (10%) |
| Prashanth et al., 2004 [10] | Copper-transporting ATPase subunit beta deficiency (Wilson disease) | 22. DISORDERS OF TRACE ELEMENTS AND METALS | 22.1 Disorders of copper metabolism | Case series | 1 out of 307 patients (0,3%) |
| Starosta-Rubinstein et al., 1987 [11] | Copper-transporting ATPase subunit beta deficiency (Wilson disease) | 22. DISORDERS OF TRACE ELEMENTS AND METALS | 22.1 Disorders of copper metabolism | Case series | 3 out of 31 patients (9,6%) |
| Taly et al., 2007 [12] | Copper-transporting ATPase subunit beta deficiency (Wilson disease) | 22. DISORDERS OF TRACE ELEMENTS AND METALS | 22.1 Disorders of copper metabolism | Case series | 24 of 282 patients (8,5%) |
| Youn et al., 2012 [13] | Copper-transporting ATPase subunit beta deficiency (Wilson disease) | 22. DISORDERS OF TRACE ELEMENTS AND METALS | 22.1 Disorders of copper metabolism | Case series | 1 out of 45 patients (2%) |
| Ranjan et al., 2015 [14] | Copper-transporting ATPase subunit beta deficiency (Wilson disease) | 22. DISORDERS OF TRACE ELEMENTS AND METALS | 22.1 Disorders of copper metabolism | Case series | 12 out of 34 patients (35%) |
[i] ICIMD: International Classification of Inherited Metabolic Disorders, available at http://www.iembase.org/.
Table 2
GeneReviews Chapters on Chorea in Inborn Errors of Metabolism.
| REFERENCE | DISORDERS | TYPE OF DISORDERS | TYPE OF DISORDERS | COMMENTARIES |
|---|---|---|---|---|
| Bindu et al., [106] | Isolated Sulfite Oxidase Deficiency | 1. DISORDERS OF AMINO ACID METABOLISM | 1.5 Disorders of the metabolism of sulfur-containing amino acids and hydrogen sulfide | Late-onset ISOD manifests between ages six and 18 months and is characterized by ectopia lentis (variably present), developmental delay/regression, movement disorder characterized by dystonia and choreoathetosis, ataxia, and (rarely) acute hemiplegia as a result of metabolic stroke. The clinical course may be progressive or episodic. In the episodic form encephalopathy, dystonia, choreoathetosis, and/or ataxia are intermittent. |
| Gregory et al., [107] | Pantothenate kinase 2 deficiency | 21. DISORDERS OF VITAMIN AND COFACTOR METABOLISM | 21.5 Disorders of pantothenate and CoA metabolism | PKAN is characterized by early-childhood onset of progressive dystonia, dysarthria, rigidity, and choreoathetosis. Pigmentary retinal degeneration is common. Atypical PKAN is characterized by later onset (age >10 years), prominent speech defects, psychiatric disturbances, and more gradual progression of disease. |
| Kurian et al., [108] | Dopamine transporter deficiency | 23. NEUROTRANSMITTER DISORDERS | 23.1 Monoamine neurotransmission | Classic DTDS. Infants typically manifest nonspecific findings (irritability, feeding difficulties, axial hypotonia, and/or delayed motor development) followed by a hyperkinetic movement disorder (with features of chorea, dystonia, ballismus, orolingual dyskinesia). Over time, affected individuals develop parkinsonism-dystonia characterized by bradykinesia (progressing to akinesia), dystonic posturing, distal tremor, rigidity, and reduced facial expression. Tetrabenazine and benzodiazepines may be useful in controlling chorea and dyskinesia in early stages of the disease. |
| Heimer et al., [109] | Mitochondrial enoyl-CoA reductase deficiency | 14. DISORDERS OF LIPID METABOLISM | 14.1 Disorders of fatty acyl synthesis, elongation, and recycling | MECR-related neurologic disorder is characterized by a progressive childhood-onset movement disorder and optic atrophy; intellect is often – but not always – preserved. The movement disorder typically presents between ages one and 6.5 years and is mainly dystonia that can be accompanied by chorea and/or ataxia. Over time some affected individuals require assistive devices for mobility. |
| Cohen et al., [110] | Mitochondrial DNA polymerase gamma catalytic subunit deficiency | 9. DISORDERS OF MITOCHONDRIAL DNA MAINTENANCE AND REPLICATION | 9.2 Disorders of mtDNA replication and maintenance | POLG-related disorders comprise a continuum of overlapping phenotypes. A POLG-related disorder should be suspected in individuals with combinations of the following clinical features and laboratory findings: Movement disorder (e.g., myoclonus, dysarthria, choreoathetosis, parkinsonism) |
Figure 1
Overview of characteristics in patients with chorea and inborn errors of metabolism. a) Distribution by gender b) Distribution by genetically confirmed or biochemically diagnosed cases c) Distribution by types of movement disorders: chorea, athetosis, or paroxysmal disorders d) Frequency of chorea distribution e) Other associated movement disorders f) Other associated neurological symptoms g) Other associated non-neurological symptoms h) Distribution by specific types of inborn errors of metabolism.
Table 3
Inborn Errors of Metabolism Associated with Chorea Distributed by Neuroimaging Abnormalities.
| NORMAL NEUROIMAGE | GENERAL BRAIN OBSERVATIONS | CEREBELLUM | WHITE MATTER | BASAL GANGLIA | OTHERS |
|---|---|---|---|---|---|
| Galactose-1-phosphate uridylyltransferase deficiency [94] SUCLG1 deficiency [29] Hypoxanthine guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome) [35] OPA3 deficiency [47] Birk-Landau-Perez syndrome [78] | Enlarged basal cisterns and Sylvian fissures Glutaryl-CoA dehydrogenase deficiency [24] Brain atrophy GLUT1 deficiency [95] a-ketoglutarate dehydrogenase deficiency [27] Dihydrolipoamide dehydrogenase deficiency [28] Niemann-Pick C disease [53] Iduronate sulfatase deficiency (Mucopolysaccharidosis type 2) [54] Neuronal Ceroid Lipofuscinosis [58] Biotinidase deficiency [27] GABA transaminase deficiency [70] FBXL4 deficiency [74] Mitochondrial NAD kinase 2 deficiency [75] Phosphatidylserine flippase deficiency [77] | Enhancement of cerebellar folia Nonketotic hyperglycinemia [90] Cerebellar atrophy ALG6-CDG [90] ALG8-CDG [90] PIGN-CDG [19] PMM2-CDG [90] Hereditary ceruloplasmin deficiency [64] Dentate nuclei hyperintensity COG5-CDG [90] Dentate nuclei hypointensity Hereditary hemochromatosis type 1 [65] | Subcortical white matter hyperintensity Mitochondrial tRNA-Leu 1 deficiency [31] ALG8-CDG [90] PMM2-CDG [90] COG5-CDG [90] Multiple carboxylase deficiency [27] Succinic Semialdehyde Dehydrogenase Deficiency [71] FBXL4 deficiency [74] Mitochondrial NAD kinase 2 deficiency [75] Birk-Landau-Perez syndrome [78] Hypomyelination GABA transaminase deficiency [70] Delayed myelination Creatine transporter deficiency [72] Phosphatidylserine flippase deficiency [77] | Putamen and caudate hyperintensity Beta-Ketothiolase Deficiency [26] Mitochondrial ATP synthase F0 subunit 6 deficiency [27] NADH dehydrogenase alpha subcomplex subunit 10 deficiency [32] VPS13D deficiency [51] Multiple carboxylase deficiency [27] Copper-transporting ATPase subunit beta deficiency (Wilson disease) [62, 61] FBXL4 deficiency [74] Mitochondrial NAD kinase 2 deficiency [75] Ornithine transcarbamylase deficiency [76] Putamen and caudate hypointensity Hereditary ceruloplasmin deficiency [64] Globus palidus hyperintensity Copper-transporting ATPase subunit beta deficiency (Wilson disease) [62, 61] Succinic Semialdehyde Dehydrogenase Deficiency [71] Creatine transporter deficiency [72] Thalamic hyperintensity Nonketotic hyperglycinemia [79] a-ketoglutarate dehydrogenase deficiency [27] COG5-CDG [90] Copper-transporting ATPase subunit beta deficiency (Wilson disease) [62, 61] GABA transaminase deficiency [69] Thalamic hypointensity Hereditary ceruloplasmin deficiency [64] | Peduncles hyperintensity Beta-Ketothiolase Deficiency [26] Copper-transporting ATPase subunit beta deficiency (Wilson disease) [62, 61] Dilated basal ganglia Virchow–Robin spaces ALG8-CDG [90] Pons atrophy PMM2-CDG [90] Hypoplastic optic nerve Phosphatidylserine flippase deficiency [77] Thin corpus callosum Creatine transporter deficiency [72] Phosphatidylserine flippase deficiency [77] MRS increase Cr peak Guanidinoacetate methyltransferase deficiency [30] MRS absence Cr peak Creatine transporter deficiency [72] MRS increase lactate peak Mitochondrial tRNA-Leu 1 deficiency [31] MRS increase GABA peak GABA transaminase deficiency [69] Succinic Semialdehyde Dehydrogenase Deficiency [71] |
Figure 2
displays the essential minimum laboratory tests recommended for patients presenting with chorea and suspected movement disorders. ASAT: Aspartate Aminotransferase, ALAT: Alanine Aminotransferase, TPP1: Tripeptidyl Peptidase 1, GALT: Galactose-1-Phosphate Uridyltransferase, 5-Methyl-THF: 5-Methyltetrahydrofolate and Galactose-1-P: Galactose-1-Phosphate.
Table 4
Disease-specific treatment for inborn errors of metabolism presenting with chorea.
| DISORDERS | TREATMENT |
|---|---|
| Mitochondrial disorders | Mitochondrial cocktail (may include biotin, thiamine, coenzyme Q10, riboflavin, carnitine, etc) |
| Glutaryl-CoA dehydrogenase deficiency | Adherence to emergency protocol in infancy and early childhood. Carnitine 100 mg/kg/d. Diet (Lys and Trp-restricted) |
| Nonketotic hyperglycinemia | Experimental dextromethorphan (5–20 mg/kg/day), Na-benzoate (250 – 750 mg/kg/day), folinic acid (15 mg/day) |
| Galactose-1-phosphate uridylyltransferase deficiency | Lactose-free infant formula, lactose-free, galactose-restricted diet |
| GLUT1 deficiency | Ketogenic diet. Avoidance of certain drugs (barbiturates, ethanol, methylxanthines, and tricyclic antidepressants) |
| Guanidinoacetate methyltransferase deficiency | Creatine 400 mg/kg/day, ornithine supplementation 100–800 mg/kg/day + arginine restriction 15–25 mg/kg/day |
| Niemann-Pick C disease | Substrate inhibition therapy (Miglustat), HSCT in early diagnosed patients with NPC2 mutations |
| Metachromatic leukodystrophy | HSCT in pre-symptomatic or early symptomatic |
| Multiple carboxylase deficiency | Biotin 10–40 mg/day |
| Partial biotinidase deficiency | Biotin 5–10mg/day |
| Wilson disease | Avoid copper in food and drinking water, zinc, trientene, D-penicillamine, liver transplantation |
| Hereditary hemochromatosis type 1 | Ifiron overload/symptoms: regular phlebotomy |
| 6-pyruvoyl-tetrahydropterin synthase deficiency | BH4(1–20 mg/kg/day), L-dopa/carbidopa (2–11 mg/kg/day) and 5-hydroxytryptophan (0.5–8.5 mg/kg/day) |
| Aromatic L-amino acid decarboxylase deficiency | Bromocriptine, trihexyphenidyl, pergolide, tranylcypromine, vitamin B6, MAO inhibitors, gene therapy |
| Succinic Semialdehyde Dehydrogenase Deficiency | Symptomatic, including methylphenidate, thioridazine, risperidone and BZD |
| Ornithine transcarbamylase deficiency | Acute inpatient treatment: maintain anabolic state, limit protein intake, arginine 100 – 200 mg/kg/day, ammonia remotion: Na-benzoate 250 – 400 mg/kg/day or Na-phenylbutyrate 250 – 500 mg/kg/day, |
| Neuronal Ceroid Lipofuscinosis | CLN2: Cerliponase alfa. |