Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.

1st Department of Pediatrics Aristotle University of Thessaloniki Thessaloniki Greece

1st Department of Pediatrics of the University of Athens Aghia Sofia Hospital Athens Greece

Children's Department Division of Child Neurology Oslo University Hospital Rikshospitalet Oslo Norway

Clinic of Neurology and Psychiatry for Children and Youth School of Medicine University of Belgrade Belgrade Serbia

Department of Human Neuroscience Unit of Child Neurology and Psychiatry Università degli Studi di Roma La Sapienza Rome Italy

Department of Medical Genetics University of Alberta Women and Children's Health Research Institute Stollery Children's Hospital Edmonton Alberta Canada

Department of Neurology Oslo University Hospital Oslo Norway

Department of Neurology Washington University School of Medicine St Louis Missouri USA

Department of Pediatrics and Adolescent Medicine The Hong Kong Children's Hospital Hong Kong Hong Kong

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Pediatrics University of Alberta Glenrose Rehabilitation Hospital Edmonton Alberta Canada

Developmental Neurosciences UCL Great Ormond Street Institute of Child Health and Department of Neurology Great Ormond Street Hospital London UK

Dietmar Hopp Metabolic Center University Children's Hospital Heidelberg Heidelberg Germany

Division of Child Neurology and Metabolic Medicine University Children's Hospital Heidelberg Heidelberg Germany

Division of Clinical and Metabolic Genetics Department of Pediatrics University of Toronto The Hospital for Sick Children Toronto Ontario Canada

Faculty of Medicine University of Novi Sad Institute for Children and Youth Health Care of Vojvodina Novi Sad Serbia

Hacettepe University Faculty of Medicine Department of Pediatrics Section of Pediatric Metabolism Ankara Turkey

Inborn Errors of Metabolism and Child Neurology Unit Department of Pediatrics Hospital Germans Trias i Pujol Badalona and Faculty of Medicine Universitat Autònoma de Barcelona Barcelona Spain

Inborn errors of metabolism Unit Department of Neurology Institut de Recerca Sant Joan de Déu and CIBERER ISCIII Barcelona Spain

KTP National University Children's Medical Institute National University Health System Singapore Singapore

Pediatric Neurology Unit Department of Pediatrics University Hospital Reina Sofía IMIBIC and CIBERER Córdoba Spain

U O C Malattie Metaboliche Ereditarie Dipartimento della Salute della Donna e del Bambino Azienda Ospedaliera Universitaria di Padova Campus Biomedico Pietro d'Abano Padova Italy

UCSD Departments of Neuroscience and Pediatrics; Rady Children's Hospital Division of Neurology Rady Children's Institute for Genomic Medicine San Diego California USA

Unidad de Trastornos del Movimiento Servicio de Neurología y Neurofisiología Clínica Unidad de Gestión Clínica de Neurociencias Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío Sevilla Spain

University Children's Hospital St Josef Hospital Ruhr University Bochum Bochum Germany

Women and Children's Health Research Institute University of Alberta Edmonton Alberta Canada

See more in PubMed

Brennenstuhl H, Jung-Klawitter S, Assmann B, Opladen T. Inherited disorders of neurotransmitters: classification and practical approaches for diagnosis and treatment. Neuropediatrics. 2019;50:2-14.

Kurian MA, Gissen P, Smith M, Heales S Jr, Clayton PT. The monoamine neurotransmitter disorders: an expanding range of neurological syndromes. Lancet Neurol. 2011;10:721-733.

Ng J, Papandreou A, Heales SJ, Kurian MA. Monoamine neurotransmitter disorders-clinical advances and future perspectives. Nat Rev Neurol. 2015;11:567-584.

Opladen T, Cortes-Saladelafont E, Mastrangelo M, et al. The International Working Group on Neurotransmitter related Disorders (iNTD): a worldwide research project focused on primary and secondary neurotransmitter disorders. Mol Genet Metab Rep. 2016;9:61-66.

Opladen T, Lopez-Laso E, Cortes-Saladelafont E, et al. Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies. Orphanet J Rare Dis. 2020;15:126.

Schalock RL, Luckasson R, Tassé MJ. Intellectual Disability: Definition, Diagnosis, Classification, and Systems of Supports. 12th ed. Washington, DC: American Association on Intellectual and Developmental Disabilities; 2021.

Esser G, Blanz B, Geisel B, Laucht M. Mannheimer Elterninterview. Strukturiertes Interview zur Erfassung von kinderpsychiatrischen Auffälligkeiten; 1989.

Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care. 2001;39:800-812.

Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life inventory. Med Care. 1999;37:126-139.

Skevington SM, Lotfy M, O'Connell KA, Group W. The World Health Organization's WHOQOL-BREF quality of life assessment: psychometric properties and results of the international field trial. A report from the WHOQOL group. Qual Life Res. 2004;13:299-310.

The WHOQOL Group. Development of the World Health Organization WHOQOL-BREF quality of life assessment. The WHOQOL Group. Psychol Med. 1998;28:551-558.

Breiman L, Friedman J, Stone CJ, Olshen RA. Classification and Regression Trees (Wadsworth Statistics/Probability). Boca Raton: Taylor & Francis; 1984.

Kaminski JA, Schlagenhauf F, Rapp M, et al. Epigenetic variance in dopamine D2 receptor: a marker of IQ malleability? Transl Psychiatry. 2018;8:169.

Marsman A, Mandl RCW, Klomp DWJ, et al. Intelligence and brain efficiency: investigating the association between working memory performance, glutamate, and GABA. Front Psych. 2017;8:154.

Previc FH. Dopamine and the origins of human intelligence. Brain Cogn. 1999;41:299-350.

Tseng PY, Lee IH, Chen KC, et al. The correlation between mid-brain serotonin transporter availability and intelligence quotient in healthy volunteers. Eur Psychiatry. 2015;30:193-197.

Leuzzi V, Carducci CA, Carducci CL, et al. Phenotypic variability, neurological outcome and genetics background of 6-pyruvoyl-tetrahydropterin synthase deficiency. Clin Genet. 2010;77:249-257.

Leuzzi V, Mastrangelo M, Polizzi A, et al. Report of two never treated adult sisters with aromatic L-amino acid decarboxylase deficiency: a portrait of the natural history of the disease or an expanding phenotype? JIMD Rep. 2015;15:39-45.

Lopez-Laso E, Sanchez-Raya A, Moriana JA, et al. Neuropsychiatric symptoms and intelligence quotient in autosomal dominant Segawa disease. J Neurol. 2011;258:2155-2162.

Manti F, Nardecchia F, Banderali G, et al. Long-term clinical outcome of 6-pyruvoyl-tetrahydropterin synthase-deficient patients. Mol Genet Metab. 2020;131:155-162.

Liu KM, Liu TT, Lee NC, Cheng LY, Hsiao KJ, Niu DM. Long-term follow-up of Taiwanese Chinese patients treated early for 6-pyruvoyl-tetrahydropterin synthase deficiency. Arch Neurol. 2008;65:387-392.

Ye J, Yang Y, Yu W, et al. Demographics, diagnosis and treatment of 256 patients with tetrahydrobiopterin deficiency in mainland China: results of a retrospective, multicentre study. J Inherit Metab Dis. 2013;36:893-901.

Luhmann HJ, Fukuda A, Kilb W. Control of cortical neuronal migration by glutamate and GABA. Front Cell Neurosci. 2015;9:4.

Manent JB, Represa A. Neurotransmitters and brain maturation: early paracrine actions of GABA and glutamate modulate neuronal migration. Neuroscientist. 2007;13:268-279.

Ruediger T, Bolz J. Neurotransmitters and the development of neuronal circuits. Adv Exp Med Biol. 2007;621:104-115.

Wehry AM, Beesdo-Baum K, Hennelly MM, Connolly SD, Strawn JR. Assessment and treatment of anxiety disorders in children and adolescents. Curr Psychiatry Rep. 2015;17:52.

Iversen SD, Iversen LL. Dopamine: 50 years in perspective. Trends Neurosci. 2007;30:188-193.

England SJ, Picchietti DL, Couvadelli BV, et al. L-Dopa improves restless legs syndrome and periodic limb movements in sleep but not attention-deficit-hyperactivity disorder in a double-blind trial in children. Sleep Med. 2011;12:471-477.

Cools R, Barker RA, Sahakian BJ, Robbins TW. L-Dopa medication remediates cognitive inflexibility, but increases impulsivity in patients with Parkinson's disease. Neuropsychologia. 2003;41:1431-1441.

Knerr I, Gibson KM, Jakobs C, Pearl PL. Neuropsychiatric morbidity in adolescent and adult succinic semialdehyde dehydrogenase deficiency patients. CNS Spectr. 2008;13:598-605.

Lapalme-Remis S, Lewis EC, De Meulemeester C, et al. Natural history of succinic semialdehyde dehydrogenase deficiency through adulthood. Neurology. 2015;85:861-865.

Pearl PL, Gibson KM, Acosta MT, et al. Clinical spectrum of succinic semialdehyde dehydrogenase deficiency. Neurology. 2003;60:1413-1417.

Pearl PL, Wiwattanadittakul N, Roullet JB, Gibson KM. Succinic semialdehyde dehydrogenase deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews(R). Seattle, WA; University of Washington; 1993.

Anikster Y, Haack TB, Vilboux T, et al. Biallelic mutations in DNAJC12 cause hyperphenylalaninemia, dystonia, and intellectual disability. Am J Hum Genet. 2017;100:257-266.

Blau N, Martinez A, Hoffmann GF, Thony B. DNAJC12 deficiency: a new strategy in the diagnosis of hyperphenylalaninemias. Mol Genet Metab. 2018;123:1-5.

Bortolato M, Floris G, Shih JC. From aggression to autism: new perspectives on the behavioral sequelae of monoamine oxidase deficiency. J Neural Transm (Vienna). 2018;125:1589-1599.

Al Hawsawi K, Pope E. Pediatric psychocutaneous disorders: a review of primary psychiatric disorders with dermatologic manifestations. Am J Clin Dermatol. 2011;12:247-257.

Cauwels RG, Martens LC. Self-mutilation behaviour in Lesch-Nyhan syndrome. J Oral Pathol Med. 2005;34:573-575.

Iwata BA, Pace GM, Willis KD, Gamache TB, Hyman SL. Operant studies of self-injurious hand biting in the Rett syndrome. Am J Med Genet Suppl. 1986;1:157-166.

Mercimek-Andrews S, Salomons GS. Creatine deficiency syndromes. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews(R). Seattle, WA; University of Washington; 1993.

Simeon D, Stanley B, Frances A, Mann JJ, Winchel R, Stanley M. Self-mutilation in personality disorders: psychological and biological correlates. Am J Psychiatry. 1992;149:221-226.

Haavik J, Blau N, Thony B. Mutations in human monoamine-related neurotransmitter pathway genes. Hum Mutat. 2008;29:891-902.

Barbarich NC, Kaye WH, Jimerson D. Neurotransmitter and imaging studies in anorexia nervosa: new targets for treatment. Curr Drug Targets CNS Neurol Disord. 2003;2:61-72.

Gurcu S, Girgin G, Yorulmaz G, Kilicarslan B, Efe B, Baydar T. Neopterin and biopterin levels and tryptophan degradation in patients with diabetes. Sci Rep. 2020;10:17025.

Roze E, Vidailhet M, Blau N, et al. Long-term follow-up and adult outcome of 6-pyruvoyl-tetrahydropterin synthase deficiency. Mov Disord. 2006;21:263-266.

Wang L, Yu WM, He C, et al. Long-term outcome and neuroradiological findings of 31 patients with 6-pyruvoyltetrahydropterin synthase deficiency. J Inherit Metab Dis. 2006;29:127-134.

Friedman J. Sepiapterin reductase deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews(R). Seattle, WA; University of Washington; 1993.

Friedman J, Hyland K, Blau N, MacCollin M. Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Neurology. 2006;67:2032-2035.

Friedman J, Roze E, Abdenur JE, et al. Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann Neurol. 2012;71:520-530.

Lim Y, Velozo C, Bendixen RM. The level of agreement between child self-reports and parent proxy-reports of health-related quality of life in boys with Duchenne muscular dystrophy. Qual Life Res. 2014;23:1945-1952.

Longo E, Badia M, Begona Orgaz M, Gomez-Vela M. Comparing parent and child reports of health-related quality of life and their relationship with leisure participation in children and adolescents with Cerebral Palsy. Res Dev Disabil. 2017;71:214-222.

Murray CB, Holmbeck GN, Ros AM, Flores DM, Mir SA, Varni JW. A longitudinal examination of health-related quality of life in children and adolescents with spina bifida. J Pediatr Psychol. 2015;40:419-430.

Olafsdottir LB, Egilson ST, Arnadottir U, Hardonk SC. Child and parent perspectives of life quality of children with physical impairments compared with non-disabled peers. Scand J Occup Ther. 2019;26:496-504.

White-Koning M, Grandjean H, Colver A, Arnaud C. Parent and professional reports of the quality of life of children with cerebral palsy and associated intellectual impairment. Dev Med Child Neurol. 2008;50:618-624.

Ali A, Ambler G, Strydom A, et al. The relationship between happiness and intelligent quotient: the contribution of socio-economic and clinical factors. Psychol Med. 2013;43:1303-1312.

Chaplin R, Barley M, Cooper SJ, et al. The impact of intellectual functioning on symptoms and service use in schizophrenia. J Intellect Disabil Res. 2006;50:288-294.

Hallin AL, Stjernqvist K. Adolescents born extremely preterm: behavioral outcomes and quality of life. Scand J Psychol. 2011;52:251-256.

Fayed N, Davis AM, Streiner DL, et al. Children's perspective of quality of life in epilepsy. Neurology. 2015;84:1830-1837.

Hrabok M, Sherman EM, Bello-Espinosa L, Hader W. Memory and health-related quality of life in severe pediatric epilepsy. Pediatrics. 2013;131:e525-e532.

Nota L, Ferrari L, Soresi S, Wehmeyer M. Self-determination, social abilities and the quality of life of people with intellectual disability. J Intellect Disabil Res. 2007;51:850-865.

Szumski G, Firkowska-Mankiewicz A, Lebuda I, Karwowski M. Predictors of success and quality of life in people with borderline intelligence: the special school label, personal and social resources. J Appl Res Intellect Disabil. 2018;31:1021-1031.

Irazabal M, Marsa F, Garcia M, et al. Family burden related to clinical and functional variables of people with intellectual disability with and without a mental disorder. Res Dev Disabil. 2012;33:796-803.

Austin JK, Smith MS, Risinger MW, McNelis AM. Childhood epilepsy and asthma: comparison of quality of life. Epilepsia. 1994;35:608-615.

Hoare P, Mann H, Dunn S. Parental perception of the quality of life among children with epilepsy or diabetes with a new assessment questionnaire. Qual Life Res. 2000;9:637-644.

Hergenroder H, Blank R. Subjective well-being and satisfaction with life in adults with spastic cerebral palsy: a pilot study of a randomized sample. Dev Med Child Neurol. 2009;51:389-396.

White-Koning M, Arnaud C, Dickinson HO, et al. Determinants of child-parent agreement in quality-of-life reports: a European study of children with cerebral palsy. Pediatrics. 2007;120:e804-e814.

Liang S, Zhang S, Hu X, et al. Anterior corpus callosotomy in school-aged children with Lennox-Gastaut syndrome: a prospective study. Eur J Paediatr Neurol. 2014;18:670-676.

Ceravolo R, Frosini D, Rossi C, Bonuccelli U. Spectrum of addictions in Parkinson's disease: from dopamine dysregulation syndrome to impulse control disorders. J Neurol. 2010;257:S276-S283.

Brusa L, Pavino V, Massimetti MC, Bove R, Iani C, Stanzione P. The effect of dopamine agonists on cognitive functions in non-demented early-mild Parkinson's disease patients. Funct Neurol. 2013;28:13-17.