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Abnormal Neurological Development; early diagnosis and intervention

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​​​ ​​​​​​​​​​​​​​​​​​​​​​​Anddi logo​ANDDI aims at studying and developing early diagnostic tools and interventions for children with abnormal neurological development, many of whom have genetic diseases. This ambitious goal, which can result in an improvement of the lives of these children and their caretakers, can only be achieved in a multidisciplinary and comprehensive setting, covering all aspects of abnormal neurological development including etiology, pathogenesis, ​epigenetics, diagnostic applications, accurate phenotyping (pediatric and neurological examination, dysmorphology, neuroradiology, orthopedagogy), intervention (e.g., diet, medication) and follow-up.

In children with abnormal neurological development and developmental delay, most genes involved in the pathogenesis are still unknown. Consequently whole-exome NGS in this heterogeneous group of disorders offers enormous opportunities: (1) early diagnosis by ultrafast and innovative diagnostic platforms, (2) detection of thus far unknown causes of developmental delay (DD), (3) unraveling susceptibility and epigenetic factors and, (4) a better understanding of pathogenesis. All these factors contribute to the design of rational early personalized interventions and treatments.

Mission  

ANDDI’s aims to study early diagnosis and intervention in children with abnormal neurological development. Its mission is to conduct research that contributes to an improvement of the quality of life and the number of healthy years lived by those with impaired neurological development. The programme is committed to multidisciplinary approaches, covering all aspects of abnormal neurological development, including etiology, pathogenesis, epigenetics, diagnostics, phenotyping and intervention. In order to fulfill this mission, ANDDI explores better surveillance and the earliest possible individualized treatment strategies for children whose neurological development is threatened.

Programme Leaders   Principal Investigators   Description of the Programme  

ANDDI aims at studying and developing early diagnostic tools and interventions for children with abnormal neurological development, many of whom have genetic diseases.The programme comprises studies at 4 different levels:

  1. Improvement of diagnostic strategies in children with abnormal neurological development using different next generation sequencing techniques (NGS). The starting point of these studies are the phenotypically well-characterized patients of the GEO clinic (>800, clinical-exome NGS), children with epilepsy (>1000, genome-wide arrays and targeted NGS gene panel), movement disorders (targeted NGS gene panel) and ultrafast 48-hour whole genome sequencing for critically ill children. For a limited number of indications, the NGS platforms will be combined with metabolomics platforms at the division of Laboratory Medicine.
  2. Identification of novel genes involved in abnormal neurological development in selected patient groups (primary microcephaly, movement disorders, idiopathic hyperketotic hypoglycemia (IKH), and tic disorders) through sophisticated phenotyping using dysmorphology, neuroradiology, movement disorder recordings, and developmental and behavioral assessments adapted to the patient groups under study.
  3. Study of the effects of treatment and epigenetic influences in well-characterized patient cohorts, already available in the UMCG: CHARGE syndrome, Phelan-McDermid syndrome (intranasal insulin), PKU (epigenetic effects on the necessity of treatment), PKU and HTI (medical and dietary treatments).
  4. Implementation of new early prenatal diagnostic techniques for the identification of structural abnormalities of the fetal cerebrum and study of underlying causes and outcomes.

Research themes that are covered in ANDDI’s projects are: abnormal neurological development, motor control and movement disorders, perceptual and cognitive neuroscience, and imaging.

Relevance to Healthy Ageing  

There is vast accumulating evidence that the conditions present during early life, including the prenatal period, have lifelong consequences for the development and health status of an individual. Thus, early diagnosis and early treatment of impending abnormal neurological development in children may lead to a dramatic improvement of their quality of life and an increase in the number of their healthy years into adulthood, perhaps even into old age. Children with Phelan-McDermid syndrome illustrate this guiding principle. This syndrome is caused by a deletion of the SHANK3 gene and is characterized by severe behavioral and developmental problems. Studies that started in 2012, focusing on the underlying function and deletion of the gene involved, have identified a protein that interferes with the intracerebral insulin receptor, suggesting a positive effect of intranasallydministered insulin on the behavior and development ofthese patients, thus improving their long-term outcome.

Another example of research that aligns with the Healthy Ageing theme is the study of the effect of diet in (PKU) patients. Understanding the underlying causes for the differences in treatment necessity and age-related treatment effectiveness between PKU patients may result in more personalized lifestyle advice and thus better long-term well-being.

In summary, the primary strategic step to meet the above objectives was to position ANNDI’s research goals in line with the Healthy Ageing theme. In addition, ANDDI benefits from its networks – multidisciplinary teams that are well embedded in UMCG structures with researchers who have already been very successful on their own. Finally, the opportunity to improve and personalize diagnostics and treatment, including new treatment modalities for a group of extremely vulnerable young patients, contributes to the societal acceptance and validation of the research. The latter, i.e., the social relevance of our research, puts our program in a good strategic position in terms of funding and in terms of the continuity of our research.

Scientific and Societal output