Biomarkers in young individuals with 22q11.2 deletion syndrome, a population at high risk for dopaminergic neuropsychiatric disease

Biomarkers in young individuals with 22q11.2 deletion syndrome, a population at high risk for dopaminergic neuropsychiatric disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Biomarkers in young individuals with 22q11.2 deletion syndrome, a population at high risk for dopaminergic neuropsychiatric disease Franziska Radtke, Zuzana Fouskova, Julia Holweck, Marcel Romanos, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7518391/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 9 You are reading this latest preprint version Abstract Purpose Individuals with 22q11.2 deletion syndrome (22q11.2DS) show a wide range of somatic features. The syndrome also leads to increased risk of neuropsychiatric disorders including schizophrenia, attention deficit hyperactivity disorder and early-onset Parkinson’s disease, presumably mediated by alterations in dopaminergic neurotransmission. Potential biomarkers of these conditions are an increased size of the echogenic area of the substantia nigra (SN+) and reduced olfactory function. The aim of the study was to test potential biomarkers for the mentioned neuropsychiatric disorders in patients with 22q11.2DS. Methods Olfactory function (sensitivity and discrimination) was assessed with the Sniffin’ Sticks test. The maximal size of the echogenic area of the SN (SNmax in mm²) was evaluated by two blind raters. Findings of patients with 22q11.2DS and controls were compared in analyses of covariance. Results The sample for assessment of olfactory function comprised N = 60 patients (n = 37 males, m = 17.3 ± 8.8 years) and N = 60 controls. The sample for assessment of SN echogenicity comprised N = 50 patients (n = 30 males, m = 16.02 ± 7.8 years) and N = 50 controls. The group with 22q11.2DS showed impaired olfactory sensitivity (F 1,105 = 36.109, p < .001, partial eta² = .256) and discrimination (F 1,109 = 51.248, p < .001, partial eta² = .320) compared to controls. No significant group differences could be observed with regard to the SNmax ( p = 0.167). Conclusions In this young sample previous findings were replicated demonstrating reduced olfactory function in 22q11.2DS, whereas no significant changes in SN were detected. 22q11 Deletion Syndrome DiGeorge Syndrome biomarker olfaction transcranial sonography dopamine Figures Figure 1 Figure 2 Introduction 22q11.2 deletion syndrome (22q11.2DS) is one of the most common genetic disorders associated to a wide range of somatic diseases and abnormalities. It is also one of the strongest risk factors for Parkinson’s disease (PD), schizophrenia (SCZ) and attention deficit hyperactivity disorder (ADHD) (Butcher, Kiehl et al. 2013 , Hoeffding, Trabjerg et al. 2017 ). In all three conditions, dopaminergic dysfunction has been implied to contribute to the underlying pathophysiological mechanisms (Poewe, Seppi et al. 2017 , Cai, Xing et al. 2021 ). Due to haploinsufficiency of the gene encoding the catecholamine-o-methyltransferase (COMT), an enzyme responsible for inactivating and removing dopamine (DA) from the synaptic cleft, individuals with 22q11.2DS display increased synaptic DA concentrations (Boot, Booij et al. 2008 ) and therefore a certain disposition for disorders associated with abnormalities in the dopaminergic system. Two promising candidate biomarkers for these disorders - PD, SCZ and ADHD - are olfactory function as well as increased size of the echogenic area of the substantia nigra (SN+) assessed via transcranial sonography (TCS). Increased concentration of synaptic DA would be expected to lead to inhibited neurotransmission of interneurons in the olfactory bulb resulting in reduced sensory performance (Schecklmann, Schwenck et al. 2013 ). Several studies of relatively small sample size have already documented deficits in olfactory function in children and adults with 22q11.2DS (Moberg, Turetsky et al. 2020 ). However, the Sniffin’ sticks olfaction test has not been used consistently in previous studies, even though it has been shown to be most reliable in patients with increased inattentiveness, a symptom that would be expected in patients with 22q11.2DS with high comorbidity of ADHD (Hugh, Siu et al. 2015 ). Of two existing studies using this method in children, only in one small pilot study carried out by our working group age-matched controls were included (Romanos, Schecklmann et al. 2011 ). SN + is an established biomarker for patients with PD, present even before the onset of motor symptoms (Berg, Roggendorf et al. 2002 ). In adults with 22q11.2DS without PD, SN + has been demonstrated to be present in one study (Butcher, Marras et al. 2017 ). However, replication and data on the temporal development of SN + are missing. It was hypothesized that in 22q11.2DS, olfactory dysfunction and SN + can constitute early markers of disease disposition even before the appearance of any neuropsychiatric symptoms. Furthermore, it was expected that comorbid ADHD symptoms, IQ and comorbid ear-nose-throat (ENT) anomalies correlate with olfactory dysfunction as well as subclinical early signs of SCZ and PD. Methods Participants All participants in the 22q11.2DS group had a genetically confirmed diagnosis of the syndrome. Healthy controls were matched for age ± 1 year and sex. Patients were recruited via the specialized 22q11.2DS outpatient facility at the Center for Mental Health at the University Hospital of Würzburg and the self-help association “Wir sind 22Q e.V.” Healthy controls were recruited via another ongoing study at the Center for Mental Health and staff. N = 70 probands per group (22q11.2DS and controls) were enrolled in total. Assessment of olfactory function was performed on N = 60 of the participants per group. TCS was performed on N = 50 of the participants per group. Psychometric assessment Cognitive ability in all participants with 22q11.2DS and in a subsample of controls was assessed with a recognized and well-established procedure selected according to the linguistic and aging needs. The Wechsler test was applied appropriate for age and verbal ability: a) the Wechsler Intelligence Scale for Children - Fifth Edition (WISC-V) (D 2017 ) for age 7;3–16;11, or b) the Wechsler Preschool and Primary Scale of Intelligence - Third Edition (WPPSI-III) (D 2018 ) for age 3;0–7;2, or c) the Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV) (D 2012 ) from the age of 17, or d) the Wechsler Nonverbal Scale of Ability (WNV) (Wechsler D 2014 ) for age 4;0–21. For general psychopathology the parent and the self-report form of the Child Behaviour Checklist (Doepfner M 2014 ) was used. ADHD symptoms were assessed with the VSK (Koglin U 2016 ) for preschool children and with the FBB-ADHS (Döpfner M 2017 ) and DISYPS-II (Manfred Döpfner 2008 ) in school children and adolescents. Participants over the age of 18 completed the Adult ADHD Self-Report Scale (WHO, 2003). 22q11.2DS patients over 18 years were assessed with the Eppendorfer Schizophrenie-Inventar (ESI) (Maß 2001 ) for symptoms of psychosis and Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) for motor and non-motor symptoms of PD (International Parkinson and Movement Disorder Society, 2008). Assessment of olfactory function Olfactory function was assessed with the Sniffin' Sticks test from Burghart Messtechnik GmbH (Wedel, Germany). Odors are presented via felt pens (14 cm long, 1.3 cm diameter) containing a pad soaked with an odorant in propylene glycol solvent. To present the odors, the cap of the pen is removed and the tip of the pen is moved past both nostrils of the participant for about 3 seconds at a distance of 2 cm (Hummel, Kobal et al. 2007 ). The assessment was performed as described elsewhere with olfactory sensitivity defined as number of dilutions of last odor correctly identified and olfactory discrimination as number of correctly discriminated odors (Hummel, Kobal et al. 2007 ). Assessment of Substantia Nigra echogenicity by transcranial sonography TCS exams were performed with a 2.5-MHz phased array transducer (model PA240, Esaote) on the MyLab GoldTM25 (Esaote S.p.A., Genua, Italy) ultrasound machine following the consensus guidelines (Walter and Skoloudik 2014 ). Bilateral images were obtained through the temporal acoustic bone window at a penetration depth of 14–16 cm with a dynamic range of 45 dB. Videos of the entire scanning period were recorded. Subsequently the software MyLab Desk (Esaote) was used to extract images of the mesencephalic plane and assess the structures of interest. The outer circumference of the ipsilateral SN was circled in 2x magnification on the left and the right side and used the maximal area of the SN (SNmax) in mm² for analysis (see Fig. 1 ). All evaluations were performed by two experienced independent raters blind to the subjects’ clinical status. Statistical analysis Data were analysed with SPSS 25 (IBM). The significance level was set to p < 0.05. For SNmax, olfactory sensitivity and olfactory discrimination scores, separate analyses of covariance were performed with group and sex as between-subject factors and age as covariate. To compare the 22q11.2DS subgroups with and without ENT abnormalities, t-tests were used. To assess the relationship between IQ and SNmax, olfactory sensitivity and olfactory discrimination scores and psychometric assessment, correlations were calculated. Interrater reliability for SNmax was assessed with the intraclass correlation coefficient. In case of good agreement, the average SNmax of the assessments of both raters was analysed. Results Sample characteristics For details regarding clinical characteristics, see also Table 1 . Table 1 Clinical characteristics of the samples for assessment of olfactory function/ echogenicity of the substantia nigra. *TCS: transcranial sonography, **22q11.2DS: deletion syndrome 22q11.2, 1 anxiety disorder, 2 affective disorder, 3 developmental disorder, 4 autism spectrum disorder, 5 disorder of intellectual development, 6 psychosis. Olfaction sample TCS* sample Group 22q11.2DS** (N = 60) Controls (N = 60) 22q11.2DS (N = 50) Controls ( N = 50) Age (years) 17.27 ± 8.72 17.3 ± 8.64 16.02 ± 7.8 15.76 ± 7.6 Sex (m/f) 37/23 37/23 30/20 30/20 Diagnoses (N) ANX 1 AFD 2 DDD 3 ASD 4 DID 5 PSY 6 Other 12 12 16 5 12 9 16 none 8 7 12 6 8 8 10 none IQ 78.73 ± 13.48 105.76 ± 12.9 78.38 ± 13 16 110.42 ± 15 61 Olfaction sample : The olfaction sample comprised N = 60 patients with 22q11.2DS (n = 37 males, m = 17.3 ± 8.72 years, age range 6–44) and N = 60 healthy controls (m = 17.27 ± 8.64 years) matched for age ± 1 year and sex. Mean IQ was lower in the 22q11.2DS group (m = 78.73 ± 13.48) than in the control group (m = 105.76 ± 12.9), p < 0.001. TCS sample : The TCS sample comprised N = 50 patients with 22q11.2DS (n = 30 males, m = 16.02 ± 7.8 years, age range 4–44) and N = 50 healthy controls (m = 15.76 ± 7.6 years) matched for age (± 1 year) and sex. Mean IQ was lower in the 22q11.2DS group (m = 78.38 ± 13 16) compared to controls (m = 110.42 ± 15 61), p < 0.001. Olfactory assessment Olfactory sensitivity : A significant effect for group (Fig. 2 a) was observed, with 22q11.2DS subjects presenting with lower sensitivity scores (m = 5.91 ± 3.25) compared to controls (m = 9.48 ± 2.9) in the total sample (F 1,105 = 36.109, p < .001, partial eta² = .256). Furthermore a significant age effect was observed, with older subject showing higher sensitivity scores (F 1,105 = 4.987, p = .028, partial eta² = .045). Moreover, positive correlation of olfactory sensitivity with IQ (r = .342, p < .001) was calculated. Within the 22q11.2DS sample, the subgroup with ENT abnormalities had comparable sensitivity scores to 22q11.2DS subjects without ENT abnormalities, p = .914. There was no correlation with ADHD scores in psychometric assessment, all p s > .305. Olfactory discrimination : A significant effect for group (Fig. 2 b) was observed, with 22q11.2DS subjects showing with lower discrimination scores (m = 8.77 ± 2.6) compared to controls (m = 12.12 ± 2.59) in the total sample (F 1,109 = 51.248, p < .001, partial eta² = .320). Additionally a significant age effect was found, with older subjects showing better discrimination abilities (F 1,109 = 9.172, p = .003, partial eta² = .078). There was a positive correlation of olfactory discrimination scores with IQ (r = .513 p < .001). Within the 22q11.2DS sample, significantly lower discrimination scores were seen in the subgroup with ENT abnormalities (m = 8.00 ± 2.17) compared to 22q11.2DS subjects without ENT abnormalities (m = 9.91 ± 2.8), p = .009. There was no correlation of discrimination scores with ADHD scores (all p s > .581). In the 22q11.2DS sample, no relationships between olfactory functioning (sensitivity, discrimination) and symptoms of PD or SCZ in psychometric assessment were found. Transcranial sonography The intraclass correlation coefficient showed excellent agreement between the two blind rater assessing the SN (ICC = 0.863; CI 0.795–0.908) (Cicchetti 1994 ). In the total sample, no main effects for group ( p = 0.167), age ( p = 0.469), or sex ( p = .815) were observed regarding SNmax. The interaction between group and sex also did not reach statistical significance ( p = .769). There was no correlation between SNmax area and ADHD or SCZ scores, all p s > .421. Looking at the child (4–17 years) and adult (18 + years) subsamples separately, there were trend-level effects for group in adults (F 1,32 = 3.514, p = .07; m controls = 16.33 ± 10.39; m 22q11.2DS = 11.25 ± 7.10) and for sex (F 1,60 = 3,120, p = .82; m males = 14.03 ± 8.2 m females = 10.28 ± 6.76) in children. In the 22q11.2DS sample, a negative correlation between SNmax and PD symptoms was calculated (MDS-UPDRS motor domain: r=-.738, p = .023; non-motor domain: r=-.742, p = .022). Discussion In the present study the previous finding of reduced olfactory sensitivity and olfactory discrimination in 22q11.2DS was replicated. However, the hypothesis could not be confirmed that SN + is present in the relatively young sample with 22q11.2DS and there was no correlation of PD, SCZ or ADHD symptoms with olfactory dysfunction. SNmax in 22q11.2DS correlated negatively with the motor domain of PD symptoms, but not with ADHD or SCZ symptoms. Consistent with previous findings, the impairment in olfactory sensitivity in 22q11.2DS was not related to ENT abnormalities (Moberg, Turetsky et al. 2020 ). Of note ENT abnormalities in the 22q11.2DS group were found associated with worse olfactory discrimination. Many of the previous studies only controlled for velopharyngeal insufficiency, while we also included frequent ENT-infections, chronic effusions of the tympanic cavitas and general otorhinolaryngologic problems. Interestingly, smoking was shown to explain for part of the difference in olfaction before (Butcher, Marras et al. 2017 ). The ENT-component as part of the airways may still be underestimated, even if it is unlikely to explain for the overall rate of olfactory deficits. It may be most likely that ENT- and neuronal alterations combine in 22q11.2DS to enhance olfactory dysfunction of olfactory discrimination. Furthermore, a moderating effect of age and IQ on olfactory function was found. Regarding age, this is in line with previous reports of an age effect in children in the Sniffin’ sticks test (Hugh, Siu et al. 2015 ). Regarding IQ, it is conceivable that the simultaneous occurrence of lower IQ and olfactory deficits could be due to brain organic alterations affecting both functions. In addition, there is evidence that reduced olfactory function may also be associated with cognitive decline (Dintica, Marseglia et al. 2019 ). Cognitive decline has been described as occurring phenomenon over the lifespan in 22q11.2DS, especially preceding the outbreak of psychosis (Vorstman, Breetvelt et al. 2015). It is interesting that olfactory dysfunction was more severe in those patients who had lower IQ scores at the time of our study. Longitudinal data including assessment of the IQ at several time points are needed to investigate further whether there is correlation with the outbreak of PD and SCZ in this subgroup. Our examined 22q11.2DS patients are at a statistically increased risk for the development of early-onset PD with an outbreak in comparatively few years. We have found hyposmia in our patients, but no correlation with symptoms of PD. We did not find SN + in our 22q11.2DS sample. The only study that previously found SN + in patients with 22q11.2DS was carried out in a smaller sample with significantly older patients than in the present study (Butcher, Marras et al. 2017 ). Interestingly, in idiopathic PD, there is discussion in the field whether SN + already occurs as an early sign before onset of core symptoms or not (Berg 2011 ). The present study rather points to the side that SN+, at least in very young persons, can only be used for detection of prodromal stages of PD in a limited way. Otherwise, it could be argued, the present sample at risk for the development of PD, would presumably be affected by early changes in SN. So far, there are only scarce reports on post-mortems of 22q11.2DS patients who developed PD (Butcher, Kiehl et al. 2013 ) warranting further investigations to differentiate early-onset PD seen in 22q11.2DS compared to idiopathic PD. One might speculate that reduced olfactory function in 22q11.2DS is a result of increased dopamine concentration with consecutive increased inhibition of olfactory transmission per se and SN + may only appear later in life as part of a neurodegenerative process. In one previous study SN + was observed in children with ADHD (Romanos, Weise et al. 2010 ). However, in the present sample only clinically subthreshold ADHD symptoms were present, which may explain the deviating results. We found olfactory dysfunction (olfactory sensitivity and discrimination) in our sample independent of the presence of ADHD symptoms (inattention and/or hyperactivity/impulsivity). This was true for both children and adults. Interestingly, in a study investigating the inattentive subtype, which is diagnosed more frequently in 22q11.2DS (Niarchou, Martin et al. 2015 ), instead of the combined subtype of ADHD, reduced olfactory function (odor identification) was found before (Gansler, Fucetola et al. 1998 ). None of the subjects in our sample had a medication history for methylphenidate. Previous studies have shown a normalization of olfactory function in ADHD patients under continuous medication with methylphenidate (Romanos, Renner et al. 2008 ). In contrast, since methylphenidate acts mainly by providing dopamine in the synaptic cleft, it might be possible that olfactory function in 22q11.2DS might be further reduced by the medication. Systematic surveys are needed here to investigate this possible side effect of methylphenidate in 22q11.2DS. In a subsample, we investigated the correlation of SCZ symptoms with olfactory dysfunction or SN + and found no significant moderating effect. Regarding olfaction, it seems that the genetic risk factor 22q11.2DS leads to a profile like that found in adults at ultra-high risk for developing SCZ (severe schizotypal symptoms plus first degree relative of SCZ patient), who show consistent olfactory dysfunction (Brewer, Wood et al. 2003 ). In adolescent first degree relatives of SCZ patients an age and IQ effect on olfaction was found before, which is in agreement with the presumably developmental age effects found also in our study. Prodromal disorganisation correlated with olfactory deficits in this group, so it may be interesting to investigate this in 22q11.2DS in future (Keshavan, Vora et al. 2009 ). The present study is subject to several limitations. Different age-adapted ADHD questionnaires were used in children and adults requiring separate analyses of the relationship between ADHD symptoms and olfaction/ echogenicity of SN in both age groups, thus reducing statistical power. Correlations with severity of symptoms of PD, SCZ and ADHD could only be performed in a subsample of the patients. Conclusion To our knowledge, in the present study the largest cohort of subjects with 22q11.2DS to date was investigated with respect to olfactory function and to echogenicity of the SN. In this young cohort, while replicating reduced olfactory function, no increased SN echogenicity was measured, warranting further investigations on the temporal dynamics of this potential risk marker for the development of early-onset PD. Declarations Acknowledgements We thank the families who participated in this study and the self-help association “Wir sind 22Q e.V.” for their continued support. This work was partially supported by the •UNION-CVD-CSP Deutsche Forschungsgemeinschaft (DFG) Clinician Scientist program, project no. 413657723. Human Ethics and Consent to Participate Informed Consent Freely given informed consent was obtained prior to data collection for all participants or their legal guardian. Ethics Approval The study received appropriate ethics committee approval from the leading Ethics Committee (Ethics Committee of the Faculty of Medicine, Würzburg University, 45/17-sc, 12/23). The study including questionnaires and methodology was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All participants gave their informed consent and assent prior to their inclusion in the study. Funding Declaration This work was partially supported by the •UNION-CVD-CSP Deutsche Forschungsgemeinschaft Clinician Scientist program, project no. 413657723. Competing Interests R.T. and M.R. received grant research support from BfArM. M.R. received a research grant from Kids-Safe, Innovation Committee of the German Federal Joint Committee (G-BA grant number 01NVF16021). J.G. received research grants from the Bavarian State Ministry of Labour and Social Welfare, Family Affairs and Women (StMAS), and the Federal Ministry of Education and Research (BMBF). She receives royalties from Hogrefe for the publication of a treatment manual. F.R. and C.S. supported activities of the 22q11.2 patient organization “Wir sind 22Q” and were compensated for travel expenses and lodging. F.R. has received funding as part of the •UNION-CVD-CSP DFG Clinician Scientist program, project no. 413657723. Z.F., J.H., C.S. and T.S. report no potential conflicts of interest. Clinical Trial Number: not applicable References Berg, D. (2011). "Hyperechogenicity of the substantia nigra: pitfalls in assessment and specificity for Parkinson's disease." J Neural Transm (Vienna) 118(3): 453–461. Berg, D., W. Roggendorf, U. Schroder, R. Klein, T. 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"Structural abnormality of the substantia nigra in children with attention-deficit hyperactivity disorder." J Psychiatry Neurosci 35(1): 55–58. Schecklmann, M., C. Schwenck, R. Taurines, C. Freitag, A. Warnke, M. Gerlach and M. Romanos (2013). "A systematic review on olfaction in child and adolescent psychiatric disorders." J Neural Transm (Vienna) 120(1): 121–130. Vorstman, J. A., E. J. Breetvelt, S. N. Duijff, S. Eliez, M. Schneider, M. Jalbrzikowski, M. Armando, S. Vicari, V. Shashi, S. R. Hooper, E. W. Chow, W. L. Fung, N. J. Butcher, D. A. Young, D. M. McDonald-McGinn, A. Vogels, T. van Amelsvoort, D. Gothelf, R. Weinberger, A. Weizman, P. W. Klaassen, S. Koops, W. R. Kates, K. M. Antshel, T. J. Simon, O. Y. Ousley, A. Swillen, R. E. Gur, C. E. Bearden, R. S. Kahn, A. S. Bassett, B. International Consortium on and S. Behavior in 22q11.2 Deletion (2015). "Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome." JAMA Psychiatry 72(4): 377–385. Walter, U. and D. Skoloudik (2014). "Transcranial sonography (TCS) of brain parenchyma in movement disorders: quality standards, diagnostic applications and novel technologies." Ultraschall Med 35(4): 322–331. Wechsler D, N. J. (2014). "Wechsler Nonverbal Scale of Ability." Göttingen: Hogrefe. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 09 Dec, 2025 Reviews received at journal 05 Dec, 2025 Reviewers agreed at journal 14 Nov, 2025 Reviews received at journal 27 Oct, 2025 Reviewers agreed at journal 13 Oct, 2025 Reviewers invited by journal 09 Sep, 2025 Editor assigned by journal 09 Sep, 2025 Submission checks completed at journal 09 Sep, 2025 First submitted to journal 02 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7518391","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":513763852,"identity":"7afc35cc-2f6a-485f-8bf0-5955f949770a","order_by":0,"name":"Franziska Radtke","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAw0lEQVRIie3PIQ+CQBTA8UexUs9vcYyN5OCr3Mb2KBYKMzg9ChY26/ktMFnZ2LAwrFcpJIM2k3pzZO9shvu3F3577wHYbH9YxIE6HGC7h5kaZwaE1uDlirA5/5nQ2picm9MgVsB8iUggW+hJVGKaVx1sAoktgR71JISllw8FsEAmhXSKRk9896rIUx0mPuSlJ55QW45cvU+wVaTWEyrH9CBaYKQbkwfrYwNyiat7uQbm7tCntyzUk6npBWYMbDabzfa1N+7gQPPU6lcRAAAAAElFTkSuQmCC","orcid":"","institution":"University Hospital of Würzburg, University of Würzburg","correspondingAuthor":true,"prefix":"","firstName":"Franziska","middleName":"","lastName":"Radtke","suffix":""},{"id":513763853,"identity":"9d85725c-9c67-4bcf-8197-1adb264230ec","order_by":1,"name":"Zuzana Fouskova","email":"","orcid":"","institution":"University Hospital of Würzburg, University of Würzburg","correspondingAuthor":false,"prefix":"","firstName":"Zuzana","middleName":"","lastName":"Fouskova","suffix":""},{"id":513763854,"identity":"27794776-da17-45af-930f-f4e4f3a2e8c2","order_by":2,"name":"Julia Holweck","email":"","orcid":"","institution":"University Hospital of Würzburg, University of Würzburg","correspondingAuthor":false,"prefix":"","firstName":"Julia","middleName":"","lastName":"Holweck","suffix":""},{"id":513763855,"identity":"2fd0a7a4-266f-4ce2-9d41-c4ab0ee3f1d1","order_by":3,"name":"Marcel Romanos","email":"","orcid":"","institution":"University Hospital of Würzburg, University of Würzburg","correspondingAuthor":false,"prefix":"","firstName":"Marcel","middleName":"","lastName":"Romanos","suffix":""},{"id":513763856,"identity":"36cdea80-b885-434d-8a85-c490f430ddfe","order_by":4,"name":"Carina Sauter","email":"","orcid":"","institution":"University Hospital of Würzburg, University of Würzburg","correspondingAuthor":false,"prefix":"","firstName":"Carina","middleName":"","lastName":"Sauter","suffix":""},{"id":513763857,"identity":"bdae48da-ad99-45ef-9e00-38484b6ba2ec","order_by":5,"name":"Tabea Stork","email":"","orcid":"","institution":"University Hospital of Würzburg, University of Würzburg","correspondingAuthor":false,"prefix":"","firstName":"Tabea","middleName":"","lastName":"Stork","suffix":""},{"id":513763858,"identity":"5964d62f-a88a-476d-8852-7c87116383dd","order_by":6,"name":"Regina Taurines","email":"","orcid":"","institution":"University Hospital of Würzburg, University of Würzburg","correspondingAuthor":false,"prefix":"","firstName":"Regina","middleName":"","lastName":"Taurines","suffix":""},{"id":513763859,"identity":"e254b101-0102-4a44-94e5-a6d6c398ea1e","order_by":7,"name":"Julia Geissler","email":"","orcid":"","institution":"University Hospital of Würzburg, University of Würzburg","correspondingAuthor":false,"prefix":"","firstName":"Julia","middleName":"","lastName":"Geissler","suffix":""}],"badges":[],"createdAt":"2025-09-02 13:53:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7518391/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7518391/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91509508,"identity":"be6de5dc-8fac-43db-bd27-f3e849af9eea","added_by":"auto","created_at":"2025-09-17 08:39:29","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":147026,"visible":true,"origin":"","legend":"\u003cp\u003eOrbitomeatal plane in Transcranial sonography. Substantia nigra (1), butterfly-shaped brainstem (2), adapted from (Holweck 2021).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7518391/v1/c4e1460ca2f94ca6fcf18e42.jpeg"},{"id":91509539,"identity":"34b41b6e-49d6-4d99-a490-1eb1cbc7e195","added_by":"auto","created_at":"2025-09-17 08:39:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":78751,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOlfactory function in Sniffin’ Sticks test\u003c/strong\u003e \u003cstrong\u003eA)\u003c/strong\u003e Comparison of olfactory sensitivity in subjects with 22q11.2DS and controls. Highest number of dilutions is given for most diluted odor that was still detected. 22q11.2DS subjects showed lower sensitivity (F1,105 = 36.109, p \u0026lt; .001, partial eta² = .256). \u003cstrong\u003eB)\u003c/strong\u003eComparison of olfactory discrimination in subjects with 22q11.2DS and controls. Number of correct discriminations of the target odor from triplets is given. 22q11.2DS subjects showed lower sensitivity (F1,109 = 51.248, p \u0026lt; .001, partial eta² = .320). Created with GraphPad Prism\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7518391/v1/65099958ddd296454c5d7c66.png"},{"id":91511161,"identity":"f32a337e-dab1-4378-81be-6d107f26a326","added_by":"auto","created_at":"2025-09-17 08:47:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":792697,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7518391/v1/906c1d0f-4d58-408d-9508-58f555945cca.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Biomarkers in young individuals with 22q11.2 deletion syndrome, a population at high risk for dopaminergic neuropsychiatric disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003e22q11.2 deletion syndrome (22q11.2DS) is one of the most common genetic disorders associated to a wide range of somatic diseases and abnormalities. It is also one of the strongest risk factors for Parkinson\u0026rsquo;s disease (PD), schizophrenia (SCZ) and attention deficit hyperactivity disorder (ADHD) (Butcher, Kiehl et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2013\u003c/span\u003e, Hoeffding, Trabjerg et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). In all three conditions, dopaminergic dysfunction has been implied to contribute to the underlying pathophysiological mechanisms (Poewe, Seppi et al. \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2017\u003c/span\u003e, Cai, Xing et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Due to haploinsufficiency of the gene encoding the catecholamine-o-methyltransferase (COMT), an enzyme responsible for inactivating and removing dopamine (DA) from the synaptic cleft, individuals with 22q11.2DS display increased synaptic DA concentrations (Boot, Booij et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2008\u003c/span\u003e) and therefore a certain disposition for disorders associated with abnormalities in the dopaminergic system. Two promising candidate biomarkers for these disorders - PD, SCZ and ADHD - are olfactory function as well as increased size of the echogenic area of the substantia nigra (SN+) assessed via transcranial sonography (TCS).\u003c/p\u003e\u003cp\u003eIncreased concentration of synaptic DA would be expected to lead to inhibited neurotransmission of interneurons in the olfactory bulb resulting in reduced sensory performance (Schecklmann, Schwenck et al. \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Several studies of relatively small sample size have already documented deficits in olfactory function in children and adults with 22q11.2DS (Moberg, Turetsky et al. \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). However, the Sniffin\u0026rsquo; sticks olfaction test has not been used consistently in previous studies, even though it has been shown to be most reliable in patients with increased inattentiveness, a symptom that would be expected in patients with 22q11.2DS with high comorbidity of ADHD (Hugh, Siu et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Of two existing studies using this method in children, only in one small pilot study carried out by our working group age-matched controls were included (Romanos, Schecklmann et al. \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2011\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eSN\u0026thinsp;+\u0026thinsp;is an established biomarker for patients with PD, present even before the onset of motor symptoms (Berg, Roggendorf et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2002\u003c/span\u003e). In adults with 22q11.2DS without PD, SN\u0026thinsp;+\u0026thinsp;has been demonstrated to be present in one study (Butcher, Marras et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). However, replication and data on the temporal development of SN\u0026thinsp;+\u0026thinsp;are missing. It was hypothesized that in 22q11.2DS, olfactory dysfunction and SN\u0026thinsp;+\u0026thinsp;can constitute early markers of disease disposition even before the appearance of any neuropsychiatric symptoms. Furthermore, it was expected that comorbid ADHD symptoms, IQ and comorbid ear-nose-throat (ENT) anomalies correlate with olfactory dysfunction as well as subclinical early signs of SCZ and PD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eParticipants\u003c/h2\u003e\u003cp\u003eAll participants in the 22q11.2DS group had a genetically confirmed diagnosis of the syndrome. Healthy controls were matched for age\u0026thinsp;\u0026plusmn;\u0026thinsp;1 year and sex. Patients were recruited via the specialized 22q11.2DS outpatient facility at the Center for Mental Health at the University Hospital of W\u0026uuml;rzburg and the self-help association \u0026ldquo;Wir sind 22Q e.V.\u0026rdquo; Healthy controls were recruited via another ongoing study at the Center for Mental Health and staff. N\u0026thinsp;=\u0026thinsp;70 probands per group (22q11.2DS and controls) were enrolled in total. Assessment of olfactory function was performed on N\u0026thinsp;=\u0026thinsp;60 of the participants per group. TCS was performed on N\u0026thinsp;=\u0026thinsp;50 of the participants per group.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePsychometric assessment\u003c/h3\u003e\n\u003cp\u003eCognitive ability in all participants with 22q11.2DS and in a subsample of controls was assessed with a recognized and well-established procedure selected according to the linguistic and aging needs. The Wechsler test was applied appropriate for age and verbal ability: a) the Wechsler Intelligence Scale for Children - Fifth Edition (WISC-V) (D \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2017\u003c/span\u003e) for age 7;3\u0026ndash;16;11, or b) the Wechsler Preschool and Primary Scale of Intelligence - Third Edition (WPPSI-III) (D \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) for age 3;0\u0026ndash;7;2, or c) the Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV) (D \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2012\u003c/span\u003e) from the age of 17, or d) the Wechsler Nonverbal Scale of Ability (WNV) (Wechsler D \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) for age 4;0\u0026ndash;21.\u003c/p\u003e\u003cp\u003eFor general psychopathology the parent and the self-report form of the Child Behaviour Checklist (Doepfner M \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) was used. ADHD symptoms were assessed with the VSK (Koglin U \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2016\u003c/span\u003e) for preschool children and with the FBB-ADHS (D\u0026ouml;pfner M \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2017\u003c/span\u003e) and DISYPS-II (Manfred D\u0026ouml;pfner \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2008\u003c/span\u003e) in school children and adolescents. Participants over the age of 18 completed the Adult ADHD Self-Report Scale (WHO, 2003). 22q11.2DS patients over 18 years were assessed with the Eppendorfer Schizophrenie-Inventar (ESI) (Ma\u0026szlig; \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2001\u003c/span\u003e) for symptoms of psychosis and Unified Parkinson\u0026rsquo;s Disease Rating Scale (MDS-UPDRS) for motor and non-motor symptoms of PD (International Parkinson and Movement Disorder Society, 2008).\u003c/p\u003e\n\u003ch3\u003eAssessment of olfactory function\u003c/h3\u003e\n\u003cp\u003eOlfactory function was assessed with the Sniffin' Sticks test from Burghart Messtechnik GmbH (Wedel, Germany). Odors are presented via felt pens (14 cm long, 1.3 cm diameter) containing a pad soaked with an odorant in propylene glycol solvent. To present the odors, the cap of the pen is removed and the tip of the pen is moved past both nostrils of the participant for about 3 seconds at a distance of 2 cm (Hummel, Kobal et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). The assessment was performed as described elsewhere with olfactory sensitivity defined as number of dilutions of last odor correctly identified and olfactory discrimination as number of correctly discriminated odors (Hummel, Kobal et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2007\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eAssessment of Substantia Nigra echogenicity by transcranial sonography\u003c/h3\u003e\n\u003cp\u003eTCS exams were performed with a 2.5-MHz phased array transducer (model PA240, Esaote) on the MyLab GoldTM25 (Esaote S.p.A., Genua, Italy) ultrasound machine following the consensus guidelines (Walter and Skoloudik \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). Bilateral images were obtained through the temporal acoustic bone window at a penetration depth of 14\u0026ndash;16 cm with a dynamic range of 45 dB. Videos of the entire scanning period were recorded. Subsequently the software MyLab Desk (Esaote) was used to extract images of the mesencephalic plane and assess the structures of interest. The outer circumference of the ipsilateral SN was circled in 2x magnification on the left and the right side and used the maximal area of the SN (SNmax) in mm\u0026sup2; for analysis (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). All evaluations were performed by two experienced independent raters blind to the subjects\u0026rsquo; clinical status.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eData were analysed with SPSS 25 (IBM). The significance level was set to \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. For SNmax, olfactory sensitivity and olfactory discrimination scores, separate analyses of covariance were performed with group and sex as between-subject factors and age as covariate. To compare the 22q11.2DS subgroups with and without ENT abnormalities, t-tests were used. To assess the relationship between IQ and SNmax, olfactory sensitivity and olfactory discrimination scores and psychometric assessment, correlations were calculated.\u003c/p\u003e\u003cp\u003eInterrater reliability for SNmax was assessed with the intraclass correlation coefficient. In case of good agreement, the average SNmax of the assessments of both raters was analysed.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eSample characteristics\u003c/h2\u003e\u003cp\u003eFor details regarding clinical characteristics, see also Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical characteristics of the samples for assessment of olfactory function/ echogenicity of the substantia nigra. *TCS: transcranial sonography, **22q11.2DS: deletion syndrome 22q11.2,\u003csup\u003e1\u003c/sup\u003e anxiety disorder, \u003csup\u003e2\u003c/sup\u003e affective disorder, \u003csup\u003e3\u003c/sup\u003e developmental disorder, \u003csup\u003e4\u003c/sup\u003eautism spectrum disorder, \u003csup\u003e5\u003c/sup\u003e disorder of intellectual development, \u003csup\u003e6\u003c/sup\u003e psychosis.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eOlfaction sample\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eTCS* sample\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGroup\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e22q11.2DS**\u003c/b\u003e(N\u0026thinsp;=\u0026thinsp;60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eControls\u003c/b\u003e (N\u0026thinsp;=\u0026thinsp;60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e22q11.2DS\u003c/b\u003e (N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eControls (\u003c/b\u003eN\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17.27\u0026thinsp;\u0026plusmn;\u0026thinsp;8.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17.3\u0026thinsp;\u0026plusmn;\u0026thinsp;8.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16.02\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e15.76\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex (m/f)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37/23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e37/23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30/20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e30/20\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiagnoses (N)\u003c/p\u003e\u003cp\u003eANX\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAFD\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eDDD\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eASD\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eDID\u003csup\u003e5\u003c/sup\u003e\u003c/p\u003e\u003cp\u003ePSY\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003cp\u003e12\u003c/p\u003e\u003cp\u003e16\u003c/p\u003e\u003cp\u003e5\u003c/p\u003e\u003cp\u003e12\u003c/p\u003e\u003cp\u003e9\u003c/p\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8\u003c/p\u003e\u003cp\u003e7\u003c/p\u003e\u003cp\u003e12\u003c/p\u003e\u003cp\u003e6\u003c/p\u003e\u003cp\u003e8\u003c/p\u003e\u003cp\u003e8\u003c/p\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003enone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIQ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e78.73\u0026thinsp;\u0026plusmn;\u0026thinsp;13.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e105.76\u0026thinsp;\u0026plusmn;\u0026thinsp;12.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e78.38\u0026thinsp;\u0026plusmn;\u0026thinsp;13 16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e110.42\u0026thinsp;\u0026plusmn;\u0026thinsp;15 61\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eOlfaction sample\u003c/span\u003e: The olfaction sample comprised N\u0026thinsp;=\u0026thinsp;60 patients with 22q11.2DS (n\u0026thinsp;=\u0026thinsp;37 males, m\u0026thinsp;=\u0026thinsp;17.3\u0026thinsp;\u0026plusmn;\u0026thinsp;8.72 years, age range 6\u0026ndash;44) and N\u0026thinsp;=\u0026thinsp;60 healthy controls (m\u0026thinsp;=\u0026thinsp;17.27\u0026thinsp;\u0026plusmn;\u0026thinsp;8.64 years) matched for age\u0026thinsp;\u0026plusmn;\u0026thinsp;1 year and sex. Mean IQ was lower in the 22q11.2DS group (m\u0026thinsp;=\u0026thinsp;78.73\u0026thinsp;\u0026plusmn;\u0026thinsp;13.48) than in the control group (m\u0026thinsp;=\u0026thinsp;105.76\u0026thinsp;\u0026plusmn;\u0026thinsp;12.9), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eTCS sample\u003c/span\u003e: The TCS sample comprised N\u0026thinsp;=\u0026thinsp;50 patients with 22q11.2DS (n\u0026thinsp;=\u0026thinsp;30 males, m\u0026thinsp;=\u0026thinsp;16.02\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8 years, age range 4\u0026ndash;44) and N\u0026thinsp;=\u0026thinsp;50 healthy controls (m\u0026thinsp;=\u0026thinsp;15.76\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6 years) matched for age (\u0026plusmn;\u0026thinsp;1 year) and sex. Mean IQ was lower in the 22q11.2DS group (m\u0026thinsp;=\u0026thinsp;78.38\u0026thinsp;\u0026plusmn;\u0026thinsp;13 16) compared to controls (m\u0026thinsp;=\u0026thinsp;110.42\u0026thinsp;\u0026plusmn;\u0026thinsp;15 61), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eOlfactory assessment\u003c/h3\u003e\n\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eOlfactory sensitivity\u003c/span\u003e: A significant effect for group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea) was observed, with 22q11.2DS subjects presenting with lower sensitivity scores (m\u0026thinsp;=\u0026thinsp;5.91\u0026thinsp;\u0026plusmn;\u0026thinsp;3.25) compared to controls (m\u0026thinsp;=\u0026thinsp;9.48\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9) in the total sample (F\u003csub\u003e1,105\u003c/sub\u003e = 36.109, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001, partial eta\u0026sup2; = .256). Furthermore a significant age effect was observed, with older subject showing higher sensitivity scores (F\u003csub\u003e1,105\u003c/sub\u003e = 4.987, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.028, partial eta\u0026sup2; = .045). Moreover, positive correlation of olfactory sensitivity with IQ (r\u0026thinsp;=\u0026thinsp;.342, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001) was calculated. Within the 22q11.2DS sample, the subgroup with ENT abnormalities had comparable sensitivity scores to 22q11.2DS subjects without ENT abnormalities, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.914. There was no correlation with ADHD scores in psychometric assessment, all \u003cem\u003ep\u003c/em\u003es\u0026thinsp;\u0026gt;\u0026thinsp;.305.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eOlfactory discrimination\u003c/span\u003e: A significant effect for group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb) was observed, with 22q11.2DS subjects showing with lower discrimination scores (m\u0026thinsp;=\u0026thinsp;8.77\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6) compared to controls (m\u0026thinsp;=\u0026thinsp;12.12\u0026thinsp;\u0026plusmn;\u0026thinsp;2.59) in the total sample (F\u003csub\u003e1,109\u003c/sub\u003e = 51.248, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001, partial eta\u0026sup2; = .320). Additionally a significant age effect was found, with older subjects showing better discrimination abilities (F\u003csub\u003e1,109\u003c/sub\u003e = 9.172, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.003, partial eta\u0026sup2; = .078). There was a positive correlation of olfactory discrimination scores with IQ (r\u0026thinsp;=\u0026thinsp;.513 \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001). Within the 22q11.2DS sample, significantly lower discrimination scores were seen in the subgroup with ENT abnormalities (m\u0026thinsp;=\u0026thinsp;8.00\u0026thinsp;\u0026plusmn;\u0026thinsp;2.17) compared to 22q11.2DS subjects without ENT abnormalities (m\u0026thinsp;=\u0026thinsp;9.91\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.009. There was no correlation of discrimination scores with ADHD scores (all \u003cem\u003ep\u003c/em\u003es\u0026thinsp;\u0026gt;\u0026thinsp;.581).\u003c/p\u003e\u003cp\u003eIn the 22q11.2DS sample, no relationships between olfactory functioning (sensitivity, discrimination) and symptoms of PD or SCZ in psychometric assessment were found.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eTranscranial sonography\u003c/h2\u003e\u003cp\u003eThe intraclass correlation coefficient showed excellent agreement between the two blind rater assessing the SN (ICC\u0026thinsp;=\u0026thinsp;0.863; CI 0.795\u0026ndash;0.908) (Cicchetti \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e1994\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn the total sample, no main effects for group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.167), age (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.469), or sex (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.815) were observed regarding SNmax. The interaction between group and sex also did not reach statistical significance (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.769). There was no correlation between SNmax area and ADHD or SCZ scores, all \u003cem\u003ep\u003c/em\u003es\u0026thinsp;\u0026gt;\u0026thinsp;.421.\u003c/p\u003e\u003cp\u003eLooking at the child (4\u0026ndash;17 years) and adult (18\u0026thinsp;+\u0026thinsp;years) subsamples separately, there were trend-level effects for group in adults (F\u003csub\u003e1,32\u003c/sub\u003e = 3.514, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.07; m\u003csub\u003econtrols\u003c/sub\u003e = 16.33\u0026thinsp;\u0026plusmn;\u0026thinsp;10.39; m\u003csub\u003e22q11.2DS\u003c/sub\u003e = 11.25\u0026thinsp;\u0026plusmn;\u0026thinsp;7.10) and for sex (F\u003csub\u003e1,60\u003c/sub\u003e = 3,120, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.82; m\u003csub\u003emales\u003c/sub\u003e = 14.03\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2 m\u003csub\u003efemales\u003c/sub\u003e = 10.28\u0026thinsp;\u0026plusmn;\u0026thinsp;6.76) in children.\u003c/p\u003e\u003cp\u003eIn the 22q11.2DS sample, a negative correlation between SNmax and PD symptoms was calculated (MDS-UPDRS motor domain: r=-.738, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.023; non-motor domain: r=-.742, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.022).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study the previous finding of reduced olfactory sensitivity and olfactory discrimination in 22q11.2DS was replicated. However, the hypothesis could not be confirmed that SN + is present in the relatively young sample with 22q11.2DS and there was no correlation of PD, SCZ or ADHD symptoms with olfactory dysfunction. SNmax in 22q11.2DS correlated negatively with the motor domain of PD symptoms, but not with ADHD or SCZ symptoms. Consistent with previous findings, the impairment in olfactory sensitivity in 22q11.2DS was not related to ENT abnormalities (Moberg, Turetsky et al. \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Of note ENT abnormalities in the 22q11.2DS group were found associated with worse olfactory discrimination. Many of the previous studies only controlled for velopharyngeal insufficiency, while we also included frequent ENT-infections, chronic effusions of the tympanic cavitas and general otorhinolaryngologic problems. Interestingly, smoking was shown to explain for part of the difference in olfaction before (Butcher, Marras et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). The ENT-component as part of the airways may still be underestimated, even if it is unlikely to explain for the overall rate of olfactory deficits. It may be most likely that ENT- and neuronal alterations combine in 22q11.2DS to enhance olfactory dysfunction of olfactory discrimination.\u003c/p\u003e\u003cp\u003eFurthermore, a moderating effect of age and IQ on olfactory function was found. Regarding age, this is in line with previous reports of an age effect in children in the Sniffin’ sticks test (Hugh, Siu et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Regarding IQ, it is conceivable that the simultaneous occurrence of lower IQ and olfactory deficits could be due to brain organic alterations affecting both functions. In addition, there is evidence that reduced olfactory function may also be associated with cognitive decline (Dintica, Marseglia et al. \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Cognitive decline has been described as occurring phenomenon over the lifespan in 22q11.2DS, especially preceding the outbreak of psychosis (Vorstman, Breetvelt et al. 2015). It is interesting that olfactory dysfunction was more severe in those patients who had lower IQ scores at the time of our study. Longitudinal data including assessment of the IQ at several time points are needed to investigate further whether there is correlation with the outbreak of PD and SCZ in this subgroup.\u003c/p\u003e\u003cp\u003eOur examined 22q11.2DS patients are at a statistically increased risk for the development of early-onset PD with an outbreak in comparatively few years. We have found hyposmia in our patients, but no correlation with symptoms of PD. We did not find SN + in our 22q11.2DS sample.\u003c/p\u003e\u003cp\u003eThe only study that previously found SN + in patients with 22q11.2DS was carried out in a smaller sample with significantly older patients than in the present study (Butcher, Marras et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Interestingly, in idiopathic PD, there is discussion in the field whether SN + already occurs as an early sign before onset of core symptoms or not (Berg \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). The present study rather points to the side that SN+, at least in very young persons, can only be used for detection of prodromal stages of PD in a limited way. Otherwise, it could be argued, the present sample at risk for the development of PD, would presumably be affected by early changes in SN. So far, there are only scarce reports on post-mortems of 22q11.2DS patients who developed PD (Butcher, Kiehl et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2013\u003c/span\u003e) warranting further investigations to differentiate early-onset PD seen in 22q11.2DS compared to idiopathic PD. One might speculate that reduced olfactory function in 22q11.2DS is a result of increased dopamine concentration with consecutive increased inhibition of olfactory transmission \u003cem\u003eper se\u003c/em\u003e and SN + may only appear later in life as part of a neurodegenerative process.\u003c/p\u003e\u003cp\u003eIn one previous study SN + was observed in children with ADHD (Romanos, Weise et al. \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). However, in the present sample only clinically subthreshold ADHD symptoms were present, which may explain the deviating results. We found olfactory dysfunction (olfactory sensitivity and discrimination) in our sample independent of the presence of ADHD symptoms (inattention and/or hyperactivity/impulsivity). This was true for both children and adults. Interestingly, in a study investigating the inattentive subtype, which is diagnosed more frequently in 22q11.2DS (Niarchou, Martin et al. \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), instead of the combined subtype of ADHD, reduced olfactory function (odor identification) was found before (Gansler, Fucetola et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e1998\u003c/span\u003e). None of the subjects in our sample had a medication history for methylphenidate. Previous studies have shown a normalization of olfactory function in ADHD patients under continuous medication with methylphenidate (Romanos, Renner et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). In contrast, since methylphenidate acts mainly by providing dopamine in the synaptic cleft, it might be possible that olfactory function in 22q11.2DS might be further reduced by the medication. Systematic surveys are needed here to investigate this possible side effect of methylphenidate in 22q11.2DS.\u003c/p\u003e\u003cp\u003eIn a subsample, we investigated the correlation of SCZ symptoms with olfactory dysfunction or SN + and found no significant moderating effect.\u003c/p\u003e\u003cp\u003eRegarding olfaction, it seems that the genetic risk factor 22q11.2DS leads to a profile like that found in adults at ultra-high risk for developing SCZ (severe schizotypal symptoms plus first degree relative of SCZ patient), who show consistent olfactory dysfunction (Brewer, Wood et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2003\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn adolescent first degree relatives of SCZ patients an age and IQ effect on olfaction was found before, which is in agreement with the presumably developmental age effects found also in our study. Prodromal disorganisation correlated with olfactory deficits in this group, so it may be interesting to investigate this in 22q11.2DS in future (Keshavan, Vora et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2009\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe present study is subject to several limitations. Different age-adapted ADHD questionnaires were used in children and adults requiring separate analyses of the relationship between ADHD symptoms and olfaction/ echogenicity of SN in both age groups, thus reducing statistical power. Correlations with severity of symptoms of PD, SCZ and ADHD could only be performed in a subsample of the patients.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTo our knowledge, in the present study the largest cohort of subjects with 22q11.2DS to date was investigated with respect to olfactory function and to echogenicity of the SN. In this young cohort, while replicating reduced olfactory function, no increased SN echogenicity was measured, warranting further investigations on the temporal dynamics of this potential risk marker for the development of early-onset PD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the families who participated in this study and the self-help association \u0026ldquo;Wir sind 22Q e.V.\u0026rdquo; for their continued support. This work was partially supported by the \u0026bull;UNION-CVD-CSP Deutsche Forschungsgemeinschaft (DFG) Clinician Scientist program, project no. 413657723.\u003c/p\u003e\u003cp\u003e\u003cem\u003eHuman Ethics and Consent to Participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInformed Consent\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFreely given informed consent was obtained prior to data collection for all participants or their legal guardian.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthics Approval\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study received appropriate ethics committee approval from the leading Ethics Committee (Ethics Committee of the Faculty of Medicine, W\u0026uuml;rzburg University, 45/17-sc, 12/23). The study including questionnaires and methodology was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All participants gave their informed consent and assent prior to their inclusion in the study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding Declaration\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis work was partially supported by the \u0026bull;UNION-CVD-CSP Deutsche Forschungsgemeinschaft Clinician Scientist program, project no. 413657723.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting Interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eR.T. and M.R. received grant research support from BfArM. M.R. received a research grant from Kids-Safe, Innovation Committee of the German Federal Joint Committee (G-BA grant number 01NVF16021). J.G. received research grants from the Bavarian State Ministry of Labour and Social Welfare, Family Affairs and Women (StMAS), and the Federal Ministry of Education and Research (BMBF). She receives royalties from Hogrefe for the publication of a treatment manual. F.R. and C.S. supported activities of the 22q11.2 patient organization \u0026ldquo;Wir sind 22Q\u0026rdquo; and were compensated for travel expenses and lodging. F.R. has received funding as part of the \u0026bull;UNION-CVD-CSP DFG Clinician Scientist program, project no. 413657723. Z.F., J.H., C.S. and T.S. report no potential conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eClinical Trial Number: not applicable\u003c/em\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBerg, D. (2011). \"Hyperechogenicity of the substantia nigra: pitfalls in assessment and specificity for Parkinson's disease.\" J Neural Transm (Vienna) 118(3): 453\u0026ndash;461.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBerg, D., W. Roggendorf, U. Schroder, R. Klein, T. Tatschner, P. Benz, O. Tucha, M. Preier, K. W. Lange, K. Reiners, M. Gerlach and G. 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(1994). \"Guidelines, criteria, and rules of thumb for evaluating normed and standardized assessment instruments in psychology.\" Psychological Assessment 6(4): 284\u0026ndash;290.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eD, W. (2012). \"Wechsler Adult Intelligence Scale \u0026ndash; Fourth Edition.\" G\u0026ouml;ttingen: Hogrefe.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eD, W. (2017). \"Wechsler Intelligence Scale for Children \u0026ndash; Fifth Edition.\" G\u0026ouml;ttingen: Hogrefe.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eD, W. (2018). \"Wechsler Preschool and Primary Scale of Intelligence \u0026ndash; Fourth Edition.\" G\u0026ouml;ttingen: Hogrefe.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDintica, C. S., A. Marseglia, D. Rizzuto, R. Wang, J. Seubert, K. Arfanakis, D. A. Bennett and W. 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Makary (1998). \"Are there cognitive subtypes in adult attention deficit/hyperactivity disorder?\" J Nerv Ment Dis 186(12): 776\u0026ndash;781.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHoeffding, L. K., B. B. Trabjerg, L. Olsen, W. Mazin, T. Sparso, A. Vangkilde, P. B. Mortensen, C. B. Pedersen and T. Werge (2017). \"Risk of Psychiatric Disorders Among Individuals With the 22q11.2 Deletion or Duplication: A Danish Nationwide, Register-Based Study.\" JAMA Psychiatry 74(3): 282\u0026ndash;290.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHolweck, J. (2021). Putative Biomarker neuropsychiatrischer Entwicklungskomorbidit\u0026auml;ten beim Deletionssyndrom 22q11.2, Julius-Maximilians-Universit\u0026auml;t W\u0026uuml;rzburg.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHugh, S. C., J. Siu, T. Hummel, V. Forte, P. Campisi, B. C. Papsin and E. J. Propst (2015). \"Olfactory testing in children using objective tools: comparison of Sniffin' Sticks and University of Pennsylvania Smell Identification Test (UPSIT).\" J Otolaryngol Head Neck Surg 44(1): 10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHummel, T., G. Kobal, H. Gudziol and A. Mackay-Sim (2007). \"Normative data for the \"Sniffin' Sticks\" including tests of odor identification, odor discrimination, and olfactory thresholds: an upgrade based on a group of more than 3,000 subjects.\" Eur Arch Otorhinolaryngol 264(3): 237\u0026ndash;243.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKeshavan, M. S., A. Vora, D. Montrose, V. A. Diwadkar and J. Sweeney (2009). \"Olfactory identification in young relatives at risk for schizophrenia.\" Acta Neuropsychiatr 21(3): 121\u0026ndash;124.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKoglin U, P. F. (2016). \"Verhaltensskalen f\u0026uuml;r das Kindergartenalter.\" G\u0026ouml;ttingen: Hogrefe.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eManfred D\u0026ouml;pfner, A. G.-D., Gerd Lehmkuhl (2008). \"Diagnostik-System f\u0026uuml;r psychische St\u0026ouml;rungen nach ICD-10 und DSM-IV f\u0026uuml;r Kinder und Jugendliche - II.\"\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMa\u0026szlig;, R. (2001). \"Eppendorfer Schizophrenie-Inventar.\"\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMoberg, P. J., B. I. Turetsky, E. A. Moberg, C. G. Kohler, S. X. Tang, R. C. Gur, R. E. Gur and D. R. Roalf (2020). \"Meta-analysis of olfactory dysfunction in 22q11.2 deletion syndrome.\" Psychiatry Res 285: 112783.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNiarchou, M., J. Martin, A. Thapar, M. J. Owen and M. B. van den Bree (2015). \"The clinical presentation of attention deficit-hyperactivity disorder (ADHD) in children with 22q11.2 deletion syndrome.\" Am J Med Genet B Neuropsychiatr Genet 168(8): 730\u0026ndash;738.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePoewe, W., K. Seppi, C. M. Tanner, G. M. Halliday, P. Brundin, J. Volkmann, A. E. Schrag and A. E. Lang (2017). \"Parkinson disease.\" Nat Rev Dis Primers 3: 17013.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRomanos, M., T. J. Renner, M. Schecklmann, B. Hummel, M. Roos, C. von Mering, P. Pauli, H. Reichmann, A. Warnke and M. Gerlach (2008). \"Improved odor sensitivity in attention-deficit/hyperactivity disorder.\" Biol Psychiatry 64(11): 938\u0026ndash;940.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRomanos, M., M. Schecklmann, K. Kraus, A. J. Fallgatter, A. Warnke, K.-P. Lesch and M. Gerlach (2011). \"Olfactory deficits in deletion syndrome 22q11.2.\" Schizophrenia Research 129(2): 220\u0026ndash;221.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRomanos, M., D. Weise, M. Schliesser, M. Schecklmann, J. Loffler, A. Warnke, M. Gerlach, J. Classen and C. Mehler-Wex (2010). \"Structural abnormality of the substantia nigra in children with attention-deficit hyperactivity disorder.\" J Psychiatry Neurosci 35(1): 55\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchecklmann, M., C. Schwenck, R. Taurines, C. Freitag, A. Warnke, M. Gerlach and M. Romanos (2013). \"A systematic review on olfaction in child and adolescent psychiatric disorders.\" J Neural Transm (Vienna) 120(1): 121\u0026ndash;130.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVorstman, J. A., E. J. Breetvelt, S. N. Duijff, S. Eliez, M. Schneider, M. Jalbrzikowski, M. Armando, S. Vicari, V. Shashi, S. R. Hooper, E. W. Chow, W. L. Fung, N. J. Butcher, D. A. Young, D. M. McDonald-McGinn, A. Vogels, T. van Amelsvoort, D. Gothelf, R. Weinberger, A. Weizman, P. W. Klaassen, S. Koops, W. R. Kates, K. M. Antshel, T. J. Simon, O. Y. Ousley, A. Swillen, R. E. Gur, C. E. Bearden, R. S. Kahn, A. S. Bassett, B. International Consortium on and S. Behavior in 22q11.2 Deletion (2015). \"Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome.\" JAMA Psychiatry 72(4): 377\u0026ndash;385.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWalter, U. and D. Skoloudik (2014). \"Transcranial sonography (TCS) of brain parenchyma in movement disorders: quality standards, diagnostic applications and novel technologies.\" Ultraschall Med 35(4): 322\u0026ndash;331.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWechsler D, N. J. (2014). \"Wechsler Nonverbal Scale of Ability.\" G\u0026ouml;ttingen: Hogrefe.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Journal of Rare Diseases](https://link.springer.com/journal/44162)","snPcode":"44162","submissionUrl":"https://submission.nature.com/new-submission/44162/3","title":"Journal of Rare Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"22q11 Deletion Syndrome, DiGeorge Syndrome, biomarker, olfaction, transcranial sonography, dopamine","lastPublishedDoi":"10.21203/rs.3.rs-7518391/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7518391/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eIndividuals with 22q11.2 deletion syndrome (22q11.2DS) show a wide range of somatic features. The syndrome also leads to increased risk of neuropsychiatric disorders including schizophrenia, attention deficit hyperactivity disorder and early-onset Parkinson\u0026rsquo;s disease, presumably mediated by alterations in dopaminergic neurotransmission. Potential biomarkers of these conditions are an increased size of the echogenic area of the substantia nigra (SN+) and reduced olfactory function. The aim of the study was to test potential biomarkers for the mentioned neuropsychiatric disorders in patients with 22q11.2DS.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eOlfactory function (sensitivity and discrimination) was assessed with the Sniffin\u0026rsquo; Sticks test. The maximal size of the echogenic area of the SN (SNmax in mm\u0026sup2;) was evaluated by two blind raters. Findings of patients with 22q11.2DS and controls were compared in analyses of covariance.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe sample for assessment of olfactory function comprised N\u0026thinsp;=\u0026thinsp;60 patients (n\u0026thinsp;=\u0026thinsp;37 males, m\u0026thinsp;=\u0026thinsp;17.3\u0026thinsp;\u0026plusmn;\u0026thinsp;8.8 years) and N\u0026thinsp;=\u0026thinsp;60 controls. The sample for assessment of SN echogenicity comprised N\u0026thinsp;=\u0026thinsp;50 patients (n\u0026thinsp;=\u0026thinsp;30 males, m\u0026thinsp;=\u0026thinsp;16.02\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8 years) and N\u0026thinsp;=\u0026thinsp;50 controls. The group with 22q11.2DS showed impaired olfactory sensitivity (F\u003csub\u003e1,105\u003c/sub\u003e = 36.109, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001, partial eta\u0026sup2; = .256) and discrimination (F\u003csub\u003e1,109\u003c/sub\u003e = 51.248, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001, partial eta\u0026sup2; = .320) compared to controls. No significant group differences could be observed with regard to the SNmax (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.167).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eIn this young sample previous findings were replicated demonstrating reduced olfactory function in 22q11.2DS, whereas no significant changes in SN were detected.\u003c/p\u003e","manuscriptTitle":"Biomarkers in young individuals with 22q11.2 deletion syndrome, a population at high risk for dopaminergic neuropsychiatric disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-17 08:39:05","doi":"10.21203/rs.3.rs-7518391/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-09T20:46:46+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-05T23:57:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3667001574276370035263229602682938604","date":"2025-11-14T18:36:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-27T20:52:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"286928491111185260404121169240155359661","date":"2025-10-13T09:30:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-09T11:41:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-09T04:41:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-09T04:40:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Rare Diseases","date":"2025-09-02T13:37:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Journal of Rare Diseases](https://link.springer.com/journal/44162)","snPcode":"44162","submissionUrl":"https://submission.nature.com/new-submission/44162/3","title":"Journal of Rare Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fc633052-bbb7-4c33-aaa7-4212a98ffaec","owner":[],"postedDate":"September 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-04-28T07:53:20+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-17 08:39:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7518391","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7518391","identity":"rs-7518391","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}