Genetic causes of cerebral palsy.

Genetic causes of cerebral palsyAbstractCerebral palsy (CP) is a clinical descriptive term that defines a heterogeneous group of non-progressive, neurodevelopmental disorders of motor impairment, which co-occur with a wide range of medical conditions such as epilepsy, autism, mental disorder, etc. It is the most frequent cause of motor impairment in children with an important impact on quality of life. It's prevalence ranges between 1.5 and 2.5 in 1000 live births. The causes of cerebral palsy are quite variable. Known causes are preterm birth, congenital (brain) abnormalities, intrauterine infection, thrombophilia etc. It was thought that asphyxia at birth was the most frequent cause of cerebral palsy. However, large population-based studies have shown that it is a causative factor in only 10% of CP patients. Recent studies demonstrate an important contribution of genetic factors in the etiology of CP. However, the genetic causes are heterogeneous and the mechanisms of action of these genes related to CP pathology are largely unknown. Genetic investigations in CP patients in Belgium were limited until recently. In this research project, we make a gene panel for CP that can be diagnostic in a cost-effective manner. Furthermore, we want to gain insight into the pathophysiology of CP and associated pathways, which can lead to better insight into the condition itself, early intervention and development of treatment and therapeutic interventions in the future. We performed diagnostic genetic studies in CP-patients that are followed at the Pediatric Neurology department of the University Hospital of Antwerp using (1) SNP-array to exclude chromosomal anomalies and (2) a whole exome sequencing (WES) based gene panel consisting of 200 genes associated with CP and CP-mimics. When no genetic diagnosis can be made in diagnostic setting, WES data are further studied in research setting. The found genetic variants are saved in a custom-made database that allows us to make genotype-phenotype correlations. This research strategy has led to the identification of de novo variants in the KIF1A gene in a relatively large proportion of our CP-population (6/100). These variants are localized in the KIF1A motor domain and can't be found in control databases. In silico prediction programs classify the variants as (probably) pathogenic. KIF1A is a kinesin motor protein, that is responsible for cargo transport along microtubule tracts. It is for example responsible for the transportation of ATG9, a key component in the autophagy pathway. It was demonstrated in C. Elegans that ATG9 regulates autophagy-induction at the synapse. We believe that pathogenic KIF1A-variants inhibit the induction of autophagy. The same mechanism has been described in the AP4-deficiency syndrome, one of the first identified genetic causes of cerebral palsy, caused by a mutation in a subunit of the AP4-complex. AP4 is involved in the transportation of ATG9A.Other mutations in autophagy genes have been described in association with neurological symptoms such as developmental delay, intellectual disability, spasticity, hypotonia, ataxia, epilepsy etc. The clinical characteristics seen in these gene mutations resemble those of CP. It is therefore thought that the presence of genetic variants that dysregulate autophagy, cause a reduced neuroprotective capacity against environmental factors such as hypoxic ischemia or inflammation. Because of this, an increased vulnerability for the development of cerebral palsy occurs. This hypothesis will be further investigated in our research project. Furthermore, we will analyze our population for new genetic variants that can cause cerebral palsy or cerebral palsy mimics. Key wordsCerebral palsy, Single Nucleotide Polymorphism-array, Whole exome sequencing

Keywords:CLINICAL RESEARCH, CEREBRAL PALSY, GENETICS

Disciplines:Developmental neuroscience, Paediatrics and neonatology not elsewhere classified