Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction.

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

Child Neurology and Developmental Pediatrics 1st Department of Pediatrics Aristotle University of Thessaloniki Thessaloniki Greece

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

Department of Child Neurology and Metabolic Disorders University Children's Hospital Heidelberg Germany

Department of Human Neuroscience Sapienza University of Rome Rome Italy

Department of Neurology Neurometabolic Unit and Synaptic Metabolism Laboratory Hospital Sant Joan de Déu Esplugues de Llobregat Barcelona Spain

Department of Neurology Oslo University Hospital Oslo Norway

Department of Neuroradiology University Hospital Heidelberg Heidelberg Germany

Department of Pediatric Neurology Hospital Gregorio Marañón Madrid Spain

Department of Pediatric Neurology Hospital Virgen de la Arrixaca Murcia Madrid Spain

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

Department of Pediatrics UKE Hamburg

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

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

IMIB Arrixaca Murcia CIBERER ISCIII Madrid Spain

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

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

Service of Psychiatry Hospital Benito Menni Hospital General de Granollers Barcelona Spain

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

Unit of Child Neurology and Psychiatry Department of Human Neuroscience Sapienza University of Rome Rome Italy

Unit of Pediatric Neurology and Metabolic Disorders Department of Pediatrics Hospital Germans Trias i Pujol and Faculty of Medicine Universitat Autònoma de Barcelona Barcelona Spain

Universitat de Barcelona Barcelona Spain

University of British Columbia Department of Pediatrics Division of Biochemical Genetics BC Children's Hospital Vancouver British Columbia Canada

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Ng J, Papandreou A, Heales SJ, Kurian MA. Monoamine neurotransmitter disorders-clinical advances and future perspectives. Nat Rev Neurol. 2015;11(10):567-584. https://doi.org/10.1038/nrneurol.2015.172.

Jung-Klawitter S, Kuseyri Hubschmann O. Analysis of catecholamines and pterins in inborn errors of monoamine neurotransmitter metabolism-from past to future. Cell. 2019;8(8):867. https://doi.org/10.3390/cells8080867.

Brennenstuhl H, Jung-Klawitter S, Assmann B, Opladen T. Inherited disorders of neurotransmitters: classification and practical approaches for diagnosis and treatment. Neuropediatrics. 2019;50(1):2-14. https://doi.org/10.1055/s-0038-1673630.

Opladen T, Hoffmann GF, Blau N. An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inherit Metab Dis. 2012;35(6):963-973. https://doi.org/10.1007/s10545-012-9506-x.

Opladen T, López-Laso E, Cortès-Saladelafont E, et al. Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies. Orphanet J Rare Dis. 2020;15(1):126. https://doi.org/10.1186/s13023-020-01379-8.

Wassenberg T, Molero-Luis M, Jeltsch K, et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis. 2017;12(1):12. https://doi.org/10.1186/s13023-016-0522-z.

Schiffmann R, van der Knaap M. An MRI-based approach to the diagnosis of white matter disorders. Neurology. 2009;72(8):750-759. https://doi.org/10.1212/01.wnl.0000343049.00540.c8.

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(1):127-134. https://doi.org/10.1007/s10545-006-0080-y.

Friedman J, Roze E, Abdenur JE, et al. Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann Neurol. 2012;71(4):520-530. https://doi.org/10.1002/ana.22685.

Furujo M, Kinoshita M, Ichiba Y, Romstad A, Shintaku H, Kubo T. Clinical characteristics of epileptic seizures in a case of dihydropteridine reductase deficiency. Epilepsy Behav Case Rep. 2014;2:37-39. https://doi.org/10.1016/j.ebcr.2014.01.007.

Hoffmann GF, Assmann B, Brautigam C, et al. Tyrosine hydroxylase deficiency causes progressive encephalopathy and dopa-nonresponsive dystonia. Ann Neurol. 2003;54(suppl 6):S56-S65. https://doi.org/10.1002/ana.10632.

Karam PE, Daher RT, Moller LB, Mikati MA. Experience with hyperphenylalaninemia in a developing country: unusual clinical manifestations and a novel gene mutation. J Child Neurol. 2011;26(2):142-146. https://doi.org/10.1177/0883073810375116.

Kurian MA, Li Y, Zhen J, et al. Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study. Lancet Neurol. 2011;10(1):54-62. https://doi.org/10.1016/S1474-4422(10)70269-6.

Lee WT, Weng WC, Peng SF, Tzen KY. Neuroimaging findings in children with paediatric neurotransmitter diseases. J Inherit Metab Dis. 2009;32(3):361-370. https://doi.org/10.1007/s10545-009-1106-z.

Willemsen MA, Verbeek MM, Kamsteeg EJ, et al. Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. Brain: J Neurol. 2010;133(Pt 6):1810-1822. https://doi.org/10.1093/brain/awq087.

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. https://doi.org/10.1016/j.ymgmr.2016.09.006.

Garbade SF, Boy N, Heringer J, Kolker S, Harting I. Age-related changes and reference values of bicaudate ratio and sagittal brainstem diameters on MRI. Neuropediatrics. 2018;49(4):269-275. https://doi.org/10.1055/s-0038-1660475.

Wright JN, Shaw DWW, Ishak G, Doherty D, Perez F. Cerebellar watershed injury in children. AJNR Am J Neuroradiol. 2020;41(5):923-928. https://doi.org/10.3174/ajnr.A6532.

Harting I, Wolf N. Neuroradiology. In: Hoffmann GZJ, Nyhan W, eds. Inherited Metabolic Diseases. A Clinical Approach. 2nd ed. Berlin, Heidelberg: Springer Verlag; 2016:555-570. https://doi.org/10.1007/978-3-662-49410-3_45.

Wolf NI, ffrench-Constant C, van der Knaap MS. Hypomyelinating leukodystrophies-unravelling myelin biology. Nat Rev Neurol. 2020. https://doi.org/10.1038/s41582-020-00432-1.

Cury C, Scelsi MA, Toro R, et al. Genome wide association study of incomplete hippocampal inversion in adolescents. PLoS One. 2020;15(1):e0227355. https://doi.org/10.1371/journal.pone.0227355.

Aguilera-Albesa S, Poretti A, Honnef D, et al. T2 hyperintense signal of the central tegmental tracts in children: disease or normal maturational process? Neuroradiology. 2012;54(8):863-871. https://doi.org/10.1007/s00234-012-1006-z.

Verbeek MM, Willemsen MA, Wevers RA, et al. Two Greek siblings with sepiapterin reductase deficiency. Mol Genet Metab. 2008;94(4):403-409. https://doi.org/10.1016/j.ymgme.2008.04.003.

Lim YT, Mankad K, Kinali M, Tan AP. Neuroimaging spectrum of inherited neurotransmitter disorders. Neuropediatrics. 2019;51:6-21. https://doi.org/10.1055/s-0039-1698422.

Brun L, Ngu LH, Keng WT, et al. Clinical and biochemical features of aromatic l-amino acid decarboxylase deficiency. Neurology. 2010;75(1):64-71. https://doi.org/10.1212/WNL.0b013e3181e620ae.

Elsayed S, Thöny B. BH4 deficiency with unusual presentations: challenges and lessons. Egypt J Med Hum Genet. 2016;17(3):241-302. https://doi.org/10.1016/j.ejmhg.2015.10.003.

Gudinchet F, Maeder P, Meuli RA, Deonna T, Mathieu JM. Cranial CT and MRI in malignant phenylketonuria. Pediatr Radiol. 1992;22(3):223-224. https://doi.org/10.1007/bf02012503.

Erdem E, Agildere M, Eryilmaz M, Ozdirim E. Intracranial calcification in children on computed tomography. Turk J Pediatr. 1994;36(2):111-122.

Sugita R, Takahashi S, Ishii K, et al. Brain CT and MR findings in hyperphenylalaninemia due to dihydropteridine reductase deficiency (variant of phenylketonuria). J Comput Assist Tomogr. 1990;14(5):699-703. https://doi.org/10.1097/00004728-199009000-00003.

Lee LK, Cheung KM, Cheng WW, et al. A rare cause of severe diarrhoea diagnosed by urine metabolic screening: aromatic l-amino acid decarboxylase deficiency. Hong Kong Med J. 2014;20(2):161-164. https://doi.org/10.12809/hkmj133922.

Pearl PL. Monoamine neurotransmitter deficiencies. Handb Clin Neurol. 2013;113:1819-1825. https://doi.org/10.1016/B978-0-444-59565-2.00051-4.

Swoboda KJ, Saul JP, McKenna CE, Speller NB, Hyland K. Aromatic l-amino acid decarboxylase deficiency: overview of clinical features and outcomes. Ann Neurol. 2003;54(suppl 6):S49-S55. https://doi.org/10.1002/ana.10631.

Xu F, Sudo Y, Sanechika S, et al. Disturbed biopterin and folate metabolism in the QDPR-deficient mouse. FEBS Lett. 2014;588(21):3924-3931. https://doi.org/10.1016/j.febslet.2014.09.004.

Crabtree MJ, Tatham AL, Al-Wakeel Y, et al. Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status: insights from cells with tet-regulated GTP cyclohydrolase I expression. J Biol Chem. 2009;284(2):1136-1144. https://doi.org/10.1074/jbc.M805403200.

Chuaiphichai S, McNeill E, Douglas G, et al. Cell-autonomous role of endothelial GTP cyclohydrolase 1 and tetrahydrobiopterin in blood pressure regulation. Hypertension. 2014;64(3):530-540. https://doi.org/10.1161/HYPERTENSIONAHA.114.03089.

Simonet S, Gosgnach W, Billou L, et al. GTP-cyclohydrolase deficiency induced peripheral and deep microcirculation dysfunction with age. Microvasc Res. 2020;133:104078. https://doi.org/10.1016/j.mvr.2020.104078.

Miladi N, Larnaout A, Dhondt JL, Vincent MF, Kaabachi N, Hentati F. Dihydropteridine reductase deficiency in a large consanguineous Tunisian family: clinical, biochemical, and neuropathologic findings. J Child Neurol. 1998;13(10):475-480. https://doi.org/10.1177/088307389801301002.

Tada K, Narisawa K, Arai N, Ogasawara Y, Ishizawa S. A sibling case of hyperphenylalaninemia due to a deficiency of dihydropteridine reductase: biochemical and pathological findings. Tohoku J Exp Med. 1980;132(2):123-131. https://doi.org/10.1620/tjem.132.123.

Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines

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