Background
People with rare genetic syndromes have a significantly increased risk of developing a mental disorder over the course of their lives – yet their access to specialized psychiatric diagnosis and treatment within the German healthcare system is structurally impeded. This is particularly true for Prader-Willi syndrome (PWS), a disorder caused by defects in genomic imprinting in the 15q11.2-q13 chromosomal region with a prevalence of approximately 1 in 10,000 to 1 in 30,000: In addition to muscle hypotonia, hyperphagia with consequent obesity, hypogonadism, and short stature, it is primarily psychological symptoms and behavioral abnormalities – mood disorders, psychotic episodes, temper outbursts, obsessive-compulsive symptoms, skin picking, and pronounced sleep-wake disturbances – that determine the quality of life and opportunities for social participation of those affected and their families.
A central focus of our research group is the clinical characterization of mental disorders in adults with PWS. Diagnosis is complicated in individuals with intellectual disabilities, as the standard ICD criteria are not directly applicable and symptom presentation can be atypical. We are therefore investigating which standardized and syndrome-specific assessment tools enable valid data collection and how the prevalence, symptom profile, and course of mental disorders manifest across the lifespan – particularly in later adulthood, a period that is becoming increasingly important due to the significantly increased life expectancy of people with PWS but is scarcely represented in the current body of research.
A second focus is the genotype-phenotype relationship. The three genetic subtypes of PWS – paternal 15q11-q13 deletion, maternal uniparental disomy 15, and imprinting defects – differ significantly in their psychiatric risk profiles. The studies available to date are based predominantly on small case numbers and incomplete genetic subtyping. We characterize the genotype-phenotype relationship using genetic and molecular methods. Building on this, we clinically offer genetic subtyping to patients in our specialized clinic and systematically link this to standardized psychopathological assessment.
A third area of focus is psychopharmacotherapy and drug safety. To date, there are no evidence-based treatment recommendations for mental disorders in PWS; experience shows that dosage ranges, efficacy, and side effect profiles differ significantly from those of the general population. We therefore systematically document treatment courses and adverse drug reactions and are working to develop consensus-based treatment recommendations.
Methodologically, our research group combines clinical and health services research with molecular biological analyses – including epigenetic, proteomic, and metabolomic approaches. The molecular biology work is conducted in close collaboration with the “ Molecular Neurosciences” research group (led by Prof. Dr. rer. nat. Peter Claus), whose methodological spectrum ranges from methylation-specific qPCR to Sanger, NGS, and nanopore sequencing, as well as stem cell-based in vitro neural models.
Overarching Goals
Our research aims to improve evidence-based psychiatric care for people with Prader-Willi syndrome and other rare genetic syndromes, while also understanding the neurobiological mechanisms underlying the development of psychiatric symptoms in these disorders.
The central goals of our work are:
- Establishing a standardized psychiatric diagnostic approach for rare genetic syndromes that has been validated for individuals with intellectual disabilities
- Systematic, prospective documentation of the prevalence, type, clinical presentation, and course of mental health disorders in PWS across the entire adult lifespan
- Differentiating the psychiatric phenotype among the genetic subtypes of PWS
- Developing and agreeing upon evidence-based recommendations for psychopharmacotherapy in PWS, with special consideration of drug safety
- Identification of molecular biological and epigenetic markers as risk and predictive factors for mental disorders in PWS
- Establishment of early detection approaches to prevent severe and chronic disease progression
- Analysis of care structures, needs, and barriers in psychiatric care for people with intellectual disabilities and translation of findings into clinical practice
- Application of the concepts developed for PWS to other rare syndromic disorders
Selection of current projects
PSY-PWS is the central project of our research group and forms the data foundation for the majority of our other research projects. It is a single-center, prospective observational study in the form of a patient registry maintained at the Department of Psychiatry, Social Psychiatry, and Psychotherapy at MHH.
The study includes adult patients with genetically confirmed Prader-Willi syndrome who are receiving treatment at our specialized clinic. Since this is a registry, the study has no set duration; we anticipate treating approximately 50 patients per year.
Data collected includes a structured psychiatric assessment using psychometric tests developed specifically for individuals with intellectual disabilities (including PAS-ADD, ABC, VFE-ER, Hyperphagia Questionnaire, and DOTES), the genetic subtype, treatment courses including adverse drug reactions, as well as blood and serum samples for molecular biological analyses. Follow-up visits will take place at three, six, and twelve months, as well as at shorter intervals if clinically necessary.
Primary endpoint: Assessment and characterization of the prevalence and presentation of mental disorders, as well as their treatment course.
Secondary endpoints: Evaluation of established and new diagnostic quality standards for intellectual disability; differences in prevalence, symptom profile, and treatment course between genetic subtypes; systematic recording of adverse drug reactions; molecular biological risk factor analysis focusing on neurotrophic factors (FGF2, BDNF, VEGF, GDNF) at the expression and methylation levels.
Project Leader: Christian Eberlein, M.D.
Project team members: Maximilian Jakob, Angelina Jechalke, Gesa Ordon
Molecular Biology Project Leader: Dr. rer. nat. Alexandra Burkert
The three genetic subtypes of PWS differ not only genetically but also clinically: A significantly increased risk of schizophrenia-spectrum disorders has been described for maternal uniparental disomy, whereas other behavioral phenotypes are predominant in cases of paternal deletion. However, the current evidence is based on small cohorts, some of which have not been fully subtyped.
Based on data from the PSY-PWS registry, we characterize the psychiatric phenotype stratified by genotype and link the clinical data to epigenetic analyses of candidate target regions. Preliminary work by our group has already demonstrated hypomethylation of distinct promoter regions of the oxytocin receptor gene in PWS and PWS-associated psychosis, as well as hypomethylation of the dopamine transporter promoter in association with hyperphagic behavior. These findings are currently being validated in an expanded cohort using Nanopore-based sequencing methods and supplemented with additional target regions.
The analyses are being conducted in collaboration with the Molecular Neuroscience Research Group (Prof. Dr. Peter Claus), which is applying experimental approaches from research on monogenic diseases to Prader-Willi syndrome.
Project Leader: Dr. med. Christian Eberlein
Project team members: Maximilian Jakob, Angelina Jechalke, Gesa Ordon
Collaboration: Prof. Dr. rer. nat. Peter Claus, Dr. rer. nat. Alexandra Burkert (methylation-specific qPCR, Sanger and Nanopore sequencing), Dr. med. Kirsten Jahn, PhD (epigenetic analysis, in vitro neuronal models), Dipl.-Biol. Vanessa Buchholz
PD Dr. med. Maximilian Deest, Dr. med. Jelte Wieting
To date, there are no guideline-based recommendations for the treatment of mental disorders in people with Prader-Willi syndrome. Treatment is therefore largely off-label and based on case-by-case experience, even though both the response to treatment and the side effect profile can differ significantly from those of the general population – for example, with regard to metabolic side effects, sedative effects, or paradoxical reactions.
Our research group is pursuing a three-pronged approach here:
- Registry-based efficacy and safety analyses: Evaluation of treatment courses, dosage ranges, and adverse drug reactions systematically recorded in the PSY-PWS registry. Preliminary work by our group on the treatment of impulsivity episodes with aripiprazole has already provided initial evidence of a favorable benefit-risk ratio.
- Link to drug safety research: Utilization of the structures established at the clinic for recording adverse drug reactions in psychiatry.
- International Consensus Building: Preparation of an international Delphi study to establish consensus on treatment recommendations for psychopharmacotherapy in PWS, with the participation of clinical experts from European and non-European PWS centers.
Project Leader: Christian Eberlein, M.D.
Project team members: Maximilian Jakob, Angelina Jechalke, Gesa Ordon
People with intellectual disabilities and comorbid mental illness are particularly dependent on specialized treatment services, which are only available sporadically within the German healthcare system. In a previous study, we were able to systematically document the characteristics, needs, and barriers to psychiatric care for people with PWS.
Building on this, we are examining care pathways, housing and support arrangements, the transition from pediatric to adult care, and the legal framework governing treatment—including issues related to guardianship and capacity to consent. A particular focus is on the interface between outpatient specialized psychiatric treatment and integration support services.
Project Leader: Dr. med. Christian Eberlein
Project Team: Maximilian Jakob, Angelina Jechalke, Gesa Ordon
Clinic
Special Clinic “Mental Health in Rare Syndromic Disorders”
For several years, the Department of Psychiatry, Social Psychiatry, and Psychotherapy at MHH has offered specialized outpatient treatment for adults with mental health conditions associated with rare genetic syndromes and intellectual disabilities, making it one of the few psychiatric departments nationwide to provide comprehensive psychiatric care for this patient group. The primary focus is on Prader-Willi syndrome.
The services include detailed syndrome-specific diagnostics, pharmacotherapy, and follow-up care; counseling for family members and legal guardians; and professional support for staff at residential and care facilities. Treatment is provided both at the institute’s outpatient clinic on-site and through home visits to specialized residential facilities in northern Germany. The outpatient clinic also serves as the clinical foundation for the PSY-PWS Registry.
Contact / Schedule an appointment through our institute outpatient clinic: Mental Health in Rare Syndromic Disorders
☎ 0511 532 - 3167
9.00 - 12.00 p.m.
Notable Scientific Collaborations
- Molecular Neuroscience Working Group, Department of Psychiatry, Social Psychiatry, and Psychotherapy (Prof. Dr. rer. nat. Peter Claus) – epigenetic and multidimensional analyses; close methodological alignment with the department’s concept of neurobiological social psychiatry, as well as the application of experimental concepts from research on monogenic disorders to Prader-Willi syndrome
- Drug Safety in Psychiatry – AMSP (PD Dr. med. Sermin Toto)
- Institute of Human Genetics, MHH (Prof. Dr. med. Nataliya Di Donato, Dr. med. Bernd Auber, MBA)
- PWS Specialized Centers: Diakovere Annastift, Bruno-Valentin-Institut MZEB
- Prader-Willi Syndrome Association Germany e. V.
- International Prader-Willi Syndrome Organization
Research Group Members
Research Group Leadership
Dr. Christian Eberlein, M.D.
Senior Physician at the Department of Psychiatry, Social Psychiatry, and Psychotherapy
Board-Certified Specialist in Psychiatry and Psychotherapy
Director of the Special Clinic “Mental Health in Rare Syndromic Disorders”
Phone: +49 511 532 3167
Fax: +49 511 532 3168
Email: eberlein.christian@mh-hannover.de
Research Focus:
- Research into the neurobiological basis of mental disorders in people with Prader-Willi syndrome
- Clinical and health services research on the nature, prevalence, and symptoms of mental disorders, as well as on pharmacological and non-pharmacological treatment options for PWS
- Mental disorders in other rare syndromic conditions
Excellence at a Glance (Memberships):
German Society for Psychiatry and Psychotherapy, Psychosomatics, and Neurology (DGPPN)
Working Group for Neuropsychopharmacology and Pharmacopsychiatry (AGNP)
German Balint Society (DBG)
PWSVD – Prader-Willi Syndrome Association of Germany (PWSVD)
International Prader-Willi Syndrome Organization (IPWSO) Mental Health Network (IMHN)
Publications: PubMed
Other Members
Maximilian Jakob (Email: Jakob.Maximilian@mh-hannover.de)
Angelina Jechalke (Email: Jechalke.Angelina@mh-hannover.de)
Gesa Ordon (Email: Ordon.Gesa@mh-hannover.de)
Selected Publications
- Eberlein CK, Jakob M, Jechalke A, Ordon G. Psychiatric Challenges in Prader-Willi Syndrome. Nervenarzt. 2026;97(4):339–344. DOI
- Wieting J, Herrmann T, Deest-Gaubatz S, Eberlein CK, Bleich S, Frieling H, Deest M. Psychiatric care for people with Prader-Willi syndrome—characteristics, needs, and barriers. J Appl Res Intellect Disabil. 2024;37(4):e13266. DOI
- Wieting J, Jahn K, Eberlein CK, Bleich S, Frieling H, Deest M. Hypomethylation of the dopamine transporter (DAT) gene promoter is associated with hyperphagia-related behavior in Prader-Willi syndrome: a case-control study. Behav Brain Res. 2023;450:114494. DOI
- Deest M, Wieting J, Jakob MM, Deest-Gaubatz S, Groh A, Seifert J, Toto S, Bleich S, Frieling H, Eberlein CK. Aripiprazole treatment for temper outbursts in Prader-Willi syndrome. Orphanet J Rare Dis. 2022;17(1):324. DOI
- Wieting J, Jahn K, Buchholz V, Lichtinghagen R, Deest-Gaubatz S, Bleich S, Eberlein CK, Deest M, Frieling H. Alteration of serum leptin and LEP/LEPR promoter methylation in Prader-Willi syndrome. Psychoneuroendocrinology. 2022;143:105857. DOI
- Heseding HM, Jahn K, Eberlein CK, Wieting J, Maier HB, Proskynitopoulos PJ, Glahn A, Bleich S, Frieling H, Deest M. Distinct promoter regions of the oxytocin receptor gene are hypomethylated in Prader-Willi syndrome and in Prader-Willi syndrome-associated psychosis. Transl Psychiatry. 2022;12(1):246. DOI