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. 2021 Sep 20;12(1):5529.
doi: 10.1038/s41467-021-25515-5.

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

Oya Kuseyri Hübschmann  1 , Gabriella Horvath  2 , Elisenda Cortès-Saladelafont  3   4 , Yılmaz Yıldız  5 , Mario Mastrangelo  6 , Roser Pons  7 , Jennifer Friedman  8 , Saadet Mercimek-Andrews  9 , Suet-Na Wong  10 , Toni S Pearson  11 , Dimitrios I Zafeiriou  12 , Jan Kulhánek  13 , Manju A Kurian  14 , Eduardo López-Laso  15 , Mari Oppebøen  16 , Sebile Kılavuz  17 , Tessa Wassenberg  18   19 , Helly Goez  20 , Sabine Scholl-Bürgi  21 , Francesco Porta  22 , Tomáš Honzík  13 , René Santer  23 , Alberto Burlina  24 , H Serap Sivri  5 , Vincenzo Leuzzi  6 , Georg F Hoffmann  1 , Kathrin Jeltsch  1 , Daniel Hübschmann  25   26   27   28 , Sven F Garbade  29 ; iNTD Registry Study Group; Angeles García-Cazorla  3 , Thomas Opladen  30
Collaborators, Affiliations

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

Oya Kuseyri Hübschmann et al. Nat Commun. .

Abstract

Inherited disorders of neurotransmitter metabolism are rare neurodevelopmental diseases presenting with movement disorders and global developmental delay. This study presents the results of the first standardized deep phenotyping approach and describes the clinical and biochemical presentation at disease onset as well as diagnostic approaches of 275 patients from the registry of the International Working Group on Neurotransmitter related Disorders. The results reveal an increased rate of prematurity, a high risk for being small for gestational age and for congenital microcephaly in some disorders. Age at diagnosis and the diagnostic delay are influenced by the diagnostic methods applied and by disease-specific symptoms. The timepoint of investigation was also a significant factor: delay to diagnosis has decreased in recent years, possibly due to novel diagnostic approaches or raised awareness. Although each disorder has a specific biochemical pattern, we observed confounding exceptions to the rule. The data provide comprehensive insights into the phenotypic spectrum of neurotransmitter disorders.

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Conflict of interest statement

A.G.C. receives teaching honorarium from PTC Therapeutics GT, Inc. C.M. and E.L.L. have received consultancy honorarium as part of the Advisory Board of PTC Therapeutics GT, Inc. G.F.H. receives teaching as well as consultancy honorarium from PTC Therapeutics GT, Inc. J.F. had trials with Biogen (Angelman’s Syndrome) and Stealth Biotherapeutics (Mitochondrial Disorders); J.F.’s spouse is Founder and Principal of Friedman Bioventure, which holds a variety of publicly traded and private biotechnology interests. O.K.H. and T.W. have received teaching honorarium from PTC Therapeutics GT, Inc. R.P. has received honoraria as a speaker from Genesis Pharma, PTC Therapeutics GT, Inc. and as consultant in Advisory board of PTC Therapeutics GT, Inc. T.O. receives teaching honorarium and research support from PTC Therapeutics GT, Inc. V.L. has received consultancy honoraria as part of Advisory Boards organized by PTC Therapeutics GT, Inc., BioMarin Pharmaceutical Inc. and Homology Medicines. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Birth metrics.
Distribution of birth metrics in primary disorders of biogenic amine metabolism (a–c) and BH deficiencies (d–f). White spot: median, black bars: interquartile range (25% and 75%), n: number reported.
Fig. 2
Fig. 2. Symptoms at disease onset.
Initial symptoms in primary disorders of biogenic amine metabolism (a) and BH deficiencies (b), age independent analysis.
Fig. 3
Fig. 3. Age dependency of initial symptoms.
Age-dependent onset of initial symptoms in primary disorders of biogenic amine metabolism (a) and BH deficiencies (b). Initial symptoms reported in minimum 5 patients––except in arGTPCHD, DHPRD and SRD in minimum 3 patients. The percentages correlate with available data about both occurrence of the symptom and age at onset of disease and not to the whole disease group.
Fig. 4
Fig. 4. Effects on diagnostic delay in different diseases.
a Diagnostic delay in disorders of biogenic amine metabolism and BH deficiencies. White spot: median, black bars: interquartile range (25% and 75%), n: number reported. b Effect of date of birth on diagnostic delay; bold line: significant, two-sided WMW-test, p < 0.05, cDiagnostic delay in arGTPCHD, PTPSD and DHPRD in patients without any or normal newborn screening (NBS) results (n = 24) vs. patients with hyperphenylalaninemia (HPA) on NBS (n = 47); two-sided t-test, p = 0.006. dDiagnostic delay in arGTPCHD regarding HPA on NBS (n = 5) vs. normal NBS (n = 6); two-sided t-test, p = 0.11. eDiagnostic delay in DHPRD in patients having HPA on NBS diagnosed directly after NBS (n = 6) vs. via selective screening (n = 14); two-sided t-test, p = 0.08. Diamond: arithmetic mean, bold line: median, boxes present interquartile range (25% and 75%).
Fig. 5
Fig. 5. Association between initial symptoms and age at diagnosis vs. diagnostic delay.
Association between initial symptoms and age at diagnosis vs. diagnostic delay in disorders of primary biogenic amine metabolism (a, b) and BH metabolism (c, d). Diamond: arithmetic mean, bold line: median, boxes present interquartile range (25% and 75%).
Fig. 6
Fig. 6. Biochemical pattern.
Disease-specific changes of biochemical parameters in plasma (P), dried blood spot (DBS), urine (U) and cerebrospinal fluid (CSF) before treatment.
See this image and copyright information in PMC

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