Phenotypic heterogeneity in genetic and acquired pediatric cerebellar disorders. Specific focus on ataxias caused by variants in the ITPR1 and KIF1C genes
Thesis event information
Date and time of the thesis defence
Place of the thesis defence
Leena Palotie Auditorium (101A), Aapistie 5A
Topic of the dissertation
Phenotypic heterogeneity in genetic and acquired pediatric cerebellar disorders. Specific focus on ataxias caused by variants in the ITPR1 and KIF1C genes
Doctoral candidate
Licentiate of Medicine Katariina Granath
Faculty and unit
University of Oulu Graduate School, Faculty of Medicine, Research Unit of Clinical Medicine
Subject of study
Pediatric neurology
Opponent
Professor Leena Haataja, University of Helsinki and Helsinki University Hospital
Custos
Professor Johanna Uusimaa, University of Oulu and Oulu University Hospital
Pediatric cerebellar disorders and their heterogeneity
Pediatric cerebellar disorders are a diverse group of rare diseases that involve either functional problems or structural abnormalities of the cerebellum. A typical symptom of these disorders is ataxia, which means difficulty coordinating voluntary movements. Other common symptoms may include problems with balance, abnormal eye movements, and unclear speech. Patients may also experience additional movement disorders, developmental delay, or associated conditions such as epilepsy and intellectual disability.
The cause of the disease can be genetic or acquired, but in many cases, the exact cause remains unknown. Key tools in diagnosing these conditions include genetic testing and brain MRI scans. There are many different genes that can cause cerebellar disorders, and some of them are still unknown. Even among patients with the same genetic mutation, symptoms can vary greatly, which challenges diagnostic efforts.
This study aimed to investigate the epidemiology, etiologies, and clinical and neuroradiological features of pediatric cerebellar disorders in Northern Finland between 1970 and 2022. The study was based on patients treated at Oulu University Hospital. Phenotypes caused by known disease genes were compared with previously published cases with matching etiologies. A variant of unknown significance in the KIF1C gene was studied using cell models. International research networks were created to study variants in the ITPR1 gene.
The cohort included 107 individuals, with an incidence of 21.9 per 100,000 live births. A defined etiology was identified in 59 patients, including monogenic (66%), chromosomal (12%), and non-genetic etiologies (22%). The most common finding in brain imaging studies was cerebellar atrophy, but this only correlated with the progression of patient’s symptoms in less than half of the cases.
The most common clinical features were ataxia, developmental delay, epileptic seizures, hypotonia, and abnormal findings in brain MRI. The pathogenicity of the KIF1C variant was confirmed by revealing abnormal intracellular localization of the protein, along with changes in RNA and protein levels, utilizing multidisciplinary team model. The international dataset on ITPR1 gene variants included 46 patients and helped in delineating geno-phenotype correlations. ITPR1 variants were annotated to the most common transcript, and the clustering of disease-causing mutations to the key functional areas of the protein was revealed. The findings of this research expand the clinical spectrum of pediatric cerebellar disorders and provide valuable information for professionals working with these conditions.
The cause of the disease can be genetic or acquired, but in many cases, the exact cause remains unknown. Key tools in diagnosing these conditions include genetic testing and brain MRI scans. There are many different genes that can cause cerebellar disorders, and some of them are still unknown. Even among patients with the same genetic mutation, symptoms can vary greatly, which challenges diagnostic efforts.
This study aimed to investigate the epidemiology, etiologies, and clinical and neuroradiological features of pediatric cerebellar disorders in Northern Finland between 1970 and 2022. The study was based on patients treated at Oulu University Hospital. Phenotypes caused by known disease genes were compared with previously published cases with matching etiologies. A variant of unknown significance in the KIF1C gene was studied using cell models. International research networks were created to study variants in the ITPR1 gene.
The cohort included 107 individuals, with an incidence of 21.9 per 100,000 live births. A defined etiology was identified in 59 patients, including monogenic (66%), chromosomal (12%), and non-genetic etiologies (22%). The most common finding in brain imaging studies was cerebellar atrophy, but this only correlated with the progression of patient’s symptoms in less than half of the cases.
The most common clinical features were ataxia, developmental delay, epileptic seizures, hypotonia, and abnormal findings in brain MRI. The pathogenicity of the KIF1C variant was confirmed by revealing abnormal intracellular localization of the protein, along with changes in RNA and protein levels, utilizing multidisciplinary team model. The international dataset on ITPR1 gene variants included 46 patients and helped in delineating geno-phenotype correlations. ITPR1 variants were annotated to the most common transcript, and the clustering of disease-causing mutations to the key functional areas of the protein was revealed. The findings of this research expand the clinical spectrum of pediatric cerebellar disorders and provide valuable information for professionals working with these conditions.
Last updated: 11.9.2025