Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry

Mareike Keller¹, Heiko Brennenstuhl¹, Oya Kuseyri Hübschmann¹, Filippo Manti², Natalia Alexandra Julia Palacios³, Jennifer Friedman⁴, Yılmaz Yıldız⁵, Jeanette Aimee Koht⁶, Suet-Na Wong⁷, Dimitrios I Zafeiriou⁸, Eduardo López-Laso⁹, Roser Pons¹⁰, Jan Kulhánek¹¹, Kathrin Jeltsch¹, Jesus Serrano-Lomelin¹², Sven F Garbade^{1

13}, Thomas Opladen¹, Helly Goez¹⁴; International Working Group on Neurotransmitter related Disorders (iNTD); Alberto Burlina¹⁵, Elisenda Cortès-Saladelafont^{3

16}, Joaquín Alejandro Fernández Ramos⁹, Angeles García-Cazorla³, Georg F Hoffmann¹, Stacey Tay Kiat Hong¹⁷, Tomáš Honzík¹¹, Ivana Kavecan¹⁸, Manju A Kurian¹⁹, Vincenzo Leuzzi², Thomas Lücke²⁰, Francesca Manzoni¹⁵, Mario Mastrangelo², Saadet Mercimek-Andrews^{21

22}, Pablo Mir²³, Mari Oppebøen²⁴, Toni S Pearson²⁵, H Serap Sivri⁵, Dora Steel¹⁹, Galina Stevanović²⁶, Cheuk-Wing Fung⁷

Affiliations

¹ Division of Child Neurology and Metabolic Medicine, University Children's Hospital Heidelberg, Heidelberg, Germany.
² Department of Human Neuroscience, Unit of Child Neurology and Psychiatry, Università degli Studi di Roma La Sapienza, Rome, Italy.
³ Inborn errors of metabolism Unit, Department of Neurology, Institut de Recerca Sant Joan de Déu and CIBERER-ISCIII, Barcelona, Spain.
⁴ UCSD Departments of Neuroscience and Pediatrics; Rady Children's Hospital Division of Neurology, Rady Children's Institute for Genomic Medicine, San Diego, California, USA.
⁵ Hacettepe University, Faculty of Medicine, Department of Pediatrics, Section of Pediatric Metabolism, Ankara, Turkey.
⁶ Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁷ Department of Pediatrics and Adolescent Medicine, The Hong Kong Children's Hospital, Hong Kong, Hong Kong.
⁸ First Department of Pediatrics Aristotle University of Thessaloniki, Thessaloniki, Greece.
⁹ Pediatric Neurology Unit, Department of Pediatrics, University Hospital Reina Sofía, IMIBIC and CIBERER, Córdoba, Spain.
¹⁰ First Department of Pediatrics of the University of Athens, Aghia Sofia Hospital, Athens, Greece.
¹¹ Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
¹² Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada.
¹³ Dietmar-Hopp Metabolic Center, University Children's Hospital Heidelberg, Heidelberg, Germany.
¹⁴ Department of Pediatrics, University of Alberta, Glenrose Rehabilitation Hospital, Edmonton, Alberta, Canada.
¹⁵ 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.
¹⁶ 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.
¹⁷ KTP-National University Children's Medical Institute, National University Health System, Singapore, Singapore.
¹⁸ Faculty of Medicine, University of Novi Sad, Institute for Children and Youth Health Care of Vojvodina, Novi Sad, Serbia.
¹⁹ Developmental Neurosciences, UCL Great Ormond Street-Institute of Child Health and Department of Neurology, Great Ormond Street Hospital, London, UK.
²⁰ University Children's Hospital, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
²¹ Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
²² Department of Medical Genetics, University of Alberta, Women and Children's Health Research Institute, Stollery Children's Hospital, Edmonton, Alberta, Canada.
²³ Unidad de Trastornos del Movimiento Servicio de Neurología y Neurofisiología Clínica Unidad de Gestión Clínica de Neurociencias Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, Sevilla, Spain.
²⁴ Children's Department Division of Child Neurology Oslo University Hospital Rikshospitalet, Oslo, Norway.
²⁵ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
²⁶ Clinic of Neurology and Psychiatry for Children and Youth, School of Medicine, University of Belgrade, Belgrade, Serbia.

PMID: 34245036
DOI: 10.1002/jimd.12416

Free article

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry

Mareike Keller et al. J Inherit Metab Dis. 2021 Nov.

Free article

. 2021 Nov;44(6):1489-1502.

doi: 10.1002/jimd.12416. Epub 2021 Aug 2.

Authors

Affiliations

¹ Division of Child Neurology and Metabolic Medicine, University Children's Hospital Heidelberg, Heidelberg, Germany.
² Department of Human Neuroscience, Unit of Child Neurology and Psychiatry, Università degli Studi di Roma La Sapienza, Rome, Italy.
³ Inborn errors of metabolism Unit, Department of Neurology, Institut de Recerca Sant Joan de Déu and CIBERER-ISCIII, Barcelona, Spain.
⁴ UCSD Departments of Neuroscience and Pediatrics; Rady Children's Hospital Division of Neurology, Rady Children's Institute for Genomic Medicine, San Diego, California, USA.
⁵ Hacettepe University, Faculty of Medicine, Department of Pediatrics, Section of Pediatric Metabolism, Ankara, Turkey.
⁶ Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁷ Department of Pediatrics and Adolescent Medicine, The Hong Kong Children's Hospital, Hong Kong, Hong Kong.
⁸ First Department of Pediatrics Aristotle University of Thessaloniki, Thessaloniki, Greece.
⁹ Pediatric Neurology Unit, Department of Pediatrics, University Hospital Reina Sofía, IMIBIC and CIBERER, Córdoba, Spain.
¹⁰ First Department of Pediatrics of the University of Athens, Aghia Sofia Hospital, Athens, Greece.
¹¹ Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
¹² Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada.
¹³ Dietmar-Hopp Metabolic Center, University Children's Hospital Heidelberg, Heidelberg, Germany.
¹⁴ Department of Pediatrics, University of Alberta, Glenrose Rehabilitation Hospital, Edmonton, Alberta, Canada.
¹⁵ 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.
¹⁶ 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.
¹⁷ KTP-National University Children's Medical Institute, National University Health System, Singapore, Singapore.
¹⁸ Faculty of Medicine, University of Novi Sad, Institute for Children and Youth Health Care of Vojvodina, Novi Sad, Serbia.
¹⁹ Developmental Neurosciences, UCL Great Ormond Street-Institute of Child Health and Department of Neurology, Great Ormond Street Hospital, London, UK.
²⁰ University Children's Hospital, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
²¹ Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
²² Department of Medical Genetics, University of Alberta, Women and Children's Health Research Institute, Stollery Children's Hospital, Edmonton, Alberta, Canada.
²³ Unidad de Trastornos del Movimiento Servicio de Neurología y Neurofisiología Clínica Unidad de Gestión Clínica de Neurociencias Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, Sevilla, Spain.
²⁴ Children's Department Division of Child Neurology Oslo University Hospital Rikshospitalet, Oslo, Norway.
²⁵ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
²⁶ Clinic of Neurology and Psychiatry for Children and Youth, School of Medicine, University of Belgrade, Belgrade, Serbia.

PMID: 34245036
DOI: 10.1002/jimd.12416

Abstract

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.

Keywords: behavioral phenotype; cognitive impairment; iNTD; intelligence; neurotransmitter deficiencies; quality of life.

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References

REFERENCES

1. 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.
1. 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.
1. Ng J, Papandreou A, Heales SJ, Kurian MA. Monoamine neurotransmitter disorders-clinical advances and future perspectives. Nat Rev Neurol. 2015;11:567-584.
1. 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.
1. 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.

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Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry

Affiliations

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry

Authors

Affiliations

Abstract

References

REFERENCES

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Substances

LinkOut - more resources

Full Text Sources