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1 Treatable inborn errors of metabolism presenting as cerebral palsy mimics: Systematic literature review Emma L. Leach, MSc ([email protected])1,2, Michael Shevell, MD, CM, FRCPC ([email protected])3,4, Kristin Bowden, PhD ([email protected])2, Sylvia Stockler-Ipsirogly, MD, PhD ([email protected])2,5,6, Clara D.M. van Karnebeek, MD, PhD, FCCMG ([email protected]) 2,5,6,7* Affiliations: 1. Provincial Medical Genetics Program, B.C. Women’s Hospital; 2. University of British Columbia, Vancouver, B.C., Canada; 3. Department of Pediatrics, Montreal Children’s Hospital, McGill University, Montreal, Canada; 4. Department of Neurology/Neurosurgery, Montreal Children’s Hospital, McGill University, Montreal, Canada; 5. Division of Biochemical Diseases, Department of Pediatrics, B.C. Children’s Hospital, Vancouver, Canada; 6. Treatable Intellectual Disability Endeavour in British Columbia (www.tidebc.org), Vancouver, Canada; 7. Centre for Molecular Medicine and Therapeutics; Child and Family Research Institute, Vancouver, Canada; *Corresponding author (Dr. C. van Karnebeek): Biochemical Diseases, Department of Pediatrics, UBC, Rm K3-201, 4480 Oak Street, Vancouver, BC V6H 3V4, Canada. Tel: +1 604-875-2628 / Fax: +1 604 875 2349. Email address: [email protected]. 2 Supplementary Data Table S1. Overview of all 50 treatable IEMs presenting as CP mimics identified through systematic literature review. The IEMs are grouped according to the biochemical phenotype as presented in standard textbooks, and alphabetically. Biochemical Level of CP mimic Disease name OMIM# Gene(s) Treatment Effect CP symptoms category Evidence reference stabilizing/ Amnio acids Hartnup disease 234500 SLC6A19 (AR) High protein diet preventative IV Dystonia [30] treatment Hyperornithinemia- Dietary protein restriction, ornithine stabilizing/ hyperammonemia- 238970 SLC25A15 (AR) supplement, sodium benzoate, preventative IV Spasticity [31, 32] homocitrullinuria (HHH) syndrome phenylacetate treatment Glycine restriction, +/- sodium stabilizing/ Late onset non-ketotic AMT/GLDC/ benzoate, NMDA receptor 605899 preventative IV Spastic diplegia [33] hyperglycinemia GCSH (AR) antagonists, other neuromodulating treatment agents Dietary phenylalanine restriction +/- stabilizing/ Phenylketonuria (PKU) 261600 PAH (AR) amino acid supplements (BH(4) preventative II Spastic diplegia [34, 35] supplement) treatment primary / targeting PHGDH deficiency (Serine Spastic diplegia/ 601815 PHGDH (AR) L-serine & +/glycine supplements underlying IV [36, 37] deficiency) tetraparesis pathophysiology primary / targeting Cerebral glucose Blood brain-barrier glucose- Spasticity, 606777 SLC2A1 (AR) Ketogenic diet underlying IV [38] transport transporter (GLUT1) defect dystonia, ataxia pathophysiology Movement primary / targeting disorder: Arginine restriction, creatine & Creatine GAMT deficiency 612736 GAMT (AR) underlying IV extrapyramidal [39, 40] ornithine supplements pathophysiology signs, athetosis, & ataxia Medium-chain acyl-coenzyme A Sick day formula, L-carnitine, avoid stabilizing/prevent Fatty acid oxidation dehydrogenase (MCAD) 201450 ACADM (AR) III CP symptoms [41] fasting ative treatment deficiency Short-chain acyl-CoA 201470 ACADS (AR) Sick day formula, L-carnitine stabilizing/prevent III Spastic diplegia [42] dehydrogenase ative treatment (SCAD) deficiency 3 Biochemical Level of CP mimic Disease name OMIM# Gene(s) Treatment Effect CP symptoms category Evidence reference Homocystinuria due to Hyperhomo- Methionine restriction, +/- stabilizing/prevent Cystathionine -synthase 236200 CBS (AR) III Dystonia [43, 44] cysteinemia pyridoxine, +/- betaine ative treatment deficiency Ataxic gait, hypotonia, Betaine supplements, +/- folate, stabilizing/prevent extrapyramidal MTHFR Deficiency 236250 MTHFR (AR) IV [45] carnitine, methionine supplements ative treatment movements, upper motor neuron signs Severe spasticity; stabilizing/prevent Lysosomal Fucosidosis 230000 FUCA1 (AR) Haematopoietic stem cell transplant IV spastic paresis, [46, 47] ative treatment generalized dystonia stabilizing/prevent Progressive Krabbe disease 245200 GALC (AR) Haematopoietic stem cell transplant III [48] ative treatment spasticity Loss of all gross Metachromatic leucodystrophy stabilizing/prevent motor function 250100 ARSA (AR) Haematopoietic stem cell transplant IV [49] (MLD) ative treatment measured by CP scale Axial hypotonia, spastic stabilizing/prevent diparesis, Neimann-Pick, type C 257220 NPC1, NPC2 Miglustat I [50] ative treatment dystonic posturing of the hands Progressive stabilizing/prevent Metals Menkes Disease 309400 ATP7A Copper histidine IV spasticity, [51] ative treatment hypotonia Wilson Disease 277900 ATP7B Zinc & tetrathiomolybdate; stabilizing/prevent III Neurological [52] oxcarbazepine ative treatment symptoms, dystonia 4 Biochemical Level of CP mimic Disease name OMIM# Gene(s) Treatment Effect CP symptoms category Evidence reference COQ2, APTX, Spastic paresis; PDSS1, primary / targeting progressive Mitochondria Coenzyme Q10 deficiency 607426 PDSS2, CoQ supplements underlying IV [53, 54] ataxia and CABC1, COQ9 pathophysiology dystonia (most AR) mtDNA 8993 stabilizing/prevent MELAS 540000 Arginine supplements IV dx. CP [55] (NARP) ative treatment PDHA1 (X- linked primary / targeting Spastic Pyruvate dehydrogenase 312170, [56, 57, recessive), Ketogenic diet & thiamine underlying IV quadriplegia; deficiency 245348 58] DLAT (AR), pathophysiology dystonia PDHX (AR) primary / targeting Limb dystonia, Aromatic-L-amino-acid MAO inhibitors, B6, anti- Neurotransmission 608643 DDC (AR) underlying IV athetoid [59, 60] decarboxylase deficiency cholinergics, dopa agonists) pathophysiology movement Ataxia, gait primary / targeting DHPR deficiency (biopterin BH4,diet, amine replacement, disorder, 261630 QDPR (AR) underlying IV [61] deficiency) folinic acid peripheral pathophysiology spasticity primary / targeting Dopamine transporter deficiency 126455 SLC6A3 Dopamine antagonist (Ropinirole) underlying IV dx. CP [62] syndrome pathophysiology primary / targeting GTPCH1-deficient dopa- dx. CP; spastic 233910 GCH1 (AR) BH4, amine replacement underlying IV [63, 64] responsive dystonia diplegia pathophysiology PTPS deficiency (biopterin PTS 261640 PTS (AR) BH4, diet, amine replacement primary / targeting IV Dystonia; [65, 66, PTSP deficiency underlying spastic 67] pathophysiology extremities; generalized dystonia, choreoathetoid arm movements & axial hypotonia 5 Biochemical Level of CP mimic Disease name OMIM# Gene(s) Treatment Effect CP symptoms category Evidence reference Limb spasticity, dystonic signs; primary / targeting ‘‘hypotonic [68, 69, Neurotransmission Sepiapterin reductase deficiency 612716 SPR (AR) Amine replacement underlying IV cerebral palsy’’; 70] pathophysiology dystonia, axial hypotonia; misdx. CP Hypotonia, Succinic semialdehyde stabilizing/prevent ataxia; gait dehydrogenase deficiency 271980 ALDH5A1 (AR) Vigabatrin IV [71, 72] ative treatment clumsiness, (SSADH) dystonia primary / targeting Spastic Tyrosine hydroxylase deficiency 605407 TH (AR) L-dopa substitution underlying IV paraplegia [73, 74] pathophysiology /tetraparesis primary / targeting Vesicular monoamine transporter 193001 SLC18A2 Dopamine aginist underlying IV Dystonia [75] 2 (VMAT2) pathophysiology Avoid fasting, sickday stabilizing/prevent Ataxia, diplegia, Organic acids -Ketothiolase deficiency 203750 ACAT1 (AR) IV [76, 77] management, protein restriction ative treatment hypotonia Ataxia, dystonia, 2-Methyl-3-hydroxybutyryl-CoA Avoid fasting, sick HSD17B10 (X- stabilizing/prevent choreoathetosis dehydrogenase (MHBD) 300438 daymanagement, isoleucine IV [78] linked) ative treatment , spastic di- deficiency restricted diet /tetra-plegia, hypotonia Dietary protein restriction; carnitine, 3-Methylcrotonyl-CoA 210200; MCC1/MCC2 stabilizing/prevent glycine, biotin supplements; avoid IV dx. CP [79] carboxylase (MCC) deficiency 210210 (AR) ative treatment fasting; sick day management 3-Methylglutaconic aciduria type Carnitine supplements, avoid stabilizing/prevent 250950 AUH (AR) IV dx. CP [80, 81] 1 fasting, sick day management ative treatment Ethylmalonic encephalopathy 602473 ETHE1 (AR) N-acetylcysteine, oral metronidazol stabilizing/prevent IV CNS [82, 83] ative treatment malformations, episodic ataxia; pyramidal tract signs 6 Biochemical Level of CP mimic Disease name OMIM# Gene(s) Treatment Effect CP symptoms category Evidence reference Generalized spasticity, Glutaric aciduria type I (GA1) aka dystonia with [84, 85, Lysine restriction, carnitine stabilizing/prevent Organic acids glutaryl-CoA dehydrogenase 231670 GCDH (AR) III athethosis; dx. 86, 87, 88, supplements ative treatment deficiency CP; dyskinesia, 89] dystonic tetraparesis Dietary protein restriction, carnitine stabilizing/prevent Hypotonia, Isovaleric acidemia 243500 IVD (AR) supplements, avoid fasting, sick III [90, 91] ative treatment paresis day management Multiple acyl-CoA-dehydrogenase Carnitine, riboflavin, - primary / targeting ETFA , ETFB, deficiency (MADD) (aka Glutaric 231680 hydroxybutyrate supplements; sick underlying IV Encephalopathy [92] ETFDH (AR) aciduria type II) day management pathophysiology stabilizing/prevent Spastic diplegic Dietary restriction, branched amino- DBT, BCKDHB, ative treatment CP ; Maple syrup urine disease 248600 acids, avoid fasting, (liver IV [93, 94] BCKDHA (AR) (liver tx= primary paroxysmal transplantation) treatment) dystonia Dietary protein restriction, carnitine Methylmalonic acidemia
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  • Massive Parallel Sequencing As a New Diagnostic Approach For

    Massive Parallel Sequencing As a New Diagnostic Approach For

    Chaiyasap et al. BMC Medical Genetics (2017) 18:102 DOI 10.1186/s12881-017-0464-x RESEARCH ARTICLE Open Access Massive parallel sequencing as a new diagnostic approach for phenylketonuria and tetrahydrobiopterin-deficiency in Thailand Pongsathorn Chaiyasap1, Chupong Ittiwut1,2, Chalurmpon Srichomthong1,2, Apiruk Sangsin3, Kanya Suphapeetiporn1,2,4* and Vorasuk Shotelersuk1,2 Abstract Background: Hyperphenylalaninemia (HPA) can be classified into phenylketonuria (PKU) which is caused by mutations in the phenylalanine hydroxylase (PAH) gene, and BH4 deficiency caused by alterations in genes involved in tetrahydrobiopterin (BH4) biosynthesis pathway. Dietary restriction of phenylalanine is considered to be the main treatment of PKU to prevent irreversible intellectual disability. However, the same dietary intervention in BH4 deficiency patients is not as effective, as BH4 is also a cofactor in many neurotransmitter syntheses. Method: We utilized next generation sequencing (NGS) technique to investigate four unrelated Thai patients with hyperphenylalaninemia. Result: We successfully identified all eight mutant alleles in PKU or BH4-deficiency associated genes including three novel mutations, one in PAH and two in PTS, thus giving a definite diagnosis to these patients. Appropriate management can then be provided. Conclusion: This study identified three novel mutations in either the PAH or PTS gene and supported the use of NGS as an alternative molecular genetic approach for definite diagnosis of hyperphenylalaninemia, thus leading to proper management of these patients in Thailand. Keywords: Next generation sequencing, Exome, Hyperphenylalaninemia, Phenylketonuria, Tetrahydrobiopterin deficiency, Newborn screening Background 120 μmol/l (2 mg/dl), the individual is considered to be Phenylketonuria (PKU) is an autosomal recessive metabolic hyperphenylalaninemia (HPA) and needs further diagnosis disorder, characterized by progressive intellectual disability, [4].