Phenotypic Heterogeneity in Genetic and Acquired Pediatric Cerebellar Disorders

Abstract

Background: The genetic landscape of pediatric cerebellar disorders (PCDs) in Finland is undefined.

Objectives: The objective was to define epidemiological, clinical, neuroradiological, and genetic characteristics of PCDs in Northern Finland.

Methods: A longitudinal population-based cohort study of children with a movement disorder or a cerebellar malformation (diagnosis ≤16 years; study period 1970-2022) was performed in the tertiary catchment area of the Oulu University Hospital, Finland. The genotype-to-phenotype associations were compared with 1007 published cases with matching monogenic etiologies.

Results: A total of 107 patients were included (cumulative incidence 21.9 per 100,000 live births). A defined genetic or non-genetic etiology was identified for 59 patients. These etiologies were monogenic (66%), chromosomal (12%), or non-genetic (22%). Ataxia was the most common movement disorder. Friedreich's ataxia was uncommon, whereas ataxias belonging to the Finnish Disease Heritage were overrepresented. Forty-eight cases remained undefined. The diagnostic yield (ie, pathogenic or likely pathogenic variants) of next-generation sequencing (NGS) in ataxia was 65%. Common features were ataxia, developmental delay, seizures, hypotonia, and abnormality in brain MRI, whereas hearing loss, sensory neuropathy, and microcephalia were associated with fewer etiologies.

Conclusions: PCDs are a heterogeneous disease group with a high proportion of genetic etiologies. Age of onset and certain clinical findings may help distinguish between different disease entities. The diagnostic yield of NGS has increased over time. Our dataset will support clinicians to recognize PCDs, their co-morbidities, and genetic etiologies. Further data on epidemiology, shared disease mechanisms, and the natural history of PCDs will be critical for the development of treatment approaches. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: ataxia; cerebellum; neurogenetics; neuroimaging; pediatric.

FIG. 1

Location and composition of the PEDIATAX cohort. (A) The Oulu University Hospital is the only tertiary care center specialized in child neurology in Northern Finland (dark violet). (B) Establishment of the PEDIATAX cohort. (C) Etiologies for PCDs and number of patients in each group. One patient has been included in two categories. (D) Proportions of PCDs, adapted from O'Malley et al. SLC2A1* = The GLUT1 deficiency syndrome caused by variants in the SLC2A1 gene can be classified as both a metabolic disease and a pediatric neurotransmitter disease. CT, computed tomography; ICD, International Classification of Diseases; MRI, magnetic resonance imaging; PCD, pediatric cerebellar disorder; VUS, variant of unknown significance. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 2

Age at onset in genetically confirmed PCDs (A) and a heatmap of genotype‐to‐phenotype correlations (B) in previously published cases (n = 1007). The proportion of patients with the indicated age of onset or phenotype per genotype is present as dark violet (0) to light yellow (1.0). PCD, pediatric cerebellar disorder. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 3

Examples of neuroradiological findings in the PEDIATAX cohort. (A) Microduplication 15q13.3 (1 year 7 months): Symmetrical periventricular and deep white matter signal changes (arrows) in axial T2 (high signal in 1, 2) and coronal T1 flair (low signal in 3, 4) images. (B) SPAST gene: At 3 years and 9 months (5–7) MRI was considered normal. At 18 years, MRI shows progressive cerebral and cerebellar atrophy (arrows, 8, 9), slight ventricular enlargement, and thinner corpus callosum (arrowhead 10). (C) Maple syrup urine disease, BCKDHB gene: During infection at 1 year and 10 months globus pallidus, cerebral peduncles and dorsal brainstem showed bilateral abnormal high T2 signal (arrows, 11, 12) and diffusion restriction (arrows 13, 14) suspicious of metabolic etiology. During infection at 10 years and 3 months MRI showed only slight T2 signal increase (arrow, 16) and slight diffusion restriction (arrow, 18) around the cerebral aqueduct and the earlier findings had normalized (15–18). (D) Microdeletion Xp11.4 (9 months): Severe pontocerebellar hypoplasia with a typical dragon fly sign (arrows) in coronal images (19, 20). Both cerebellar hemispheres and vermis are hypoplastic. Marked pontine hypoplasia (star) is demonstrated in the sagittal plane (21). (E) Cerebral palsy: At 5 months brain MRI was considered normal in a child with diagnosis of cerebral palsy (22–24). At 2 years and 6 months there were signs of Wallerian degeneration in the corticospinal tracts and atrophy and increased T2 signal bilaterally in thalami and nuclei lentiformis (arrows 25, 26) and around the posterior horns of lateral ventricles. In addition, corpus callosum was thinner than normally (arrowhead 27). The findings persisted at 17 years (28–30).