Genetic landscape of pediatric movement disorders and management implications

Abstract

Objective: To identify underlying genetic causes in patients with pediatric movement disorders by genetic investigations.

Methods: All patients with a movement disorder seen in a single Pediatric Genetic Movement Disorder Clinic were included in this retrospective cohort study. We reviewed electronic patient charts for clinical, neuroimaging, biochemical, and molecular genetic features. DNA samples were used for targeted direct sequencing, targeted next-generation sequencing, or whole exome sequencing.

Results: There were 51 patients in the Pediatric Genetic Movement Disorder Clinic. Twenty-five patients had dystonia, 27 patients had ataxia, 7 patients had chorea-athetosis, 8 patients had tremor, and 7 patients had hyperkinetic movements. A genetic diagnosis was confirmed in 26 patients, including in 20 patients with ataxia and 6 patients with dystonia. Targeted next-generation sequencing panels confirmed a genetic diagnosis in 9 patients, and whole exome sequencing identified a genetic diagnosis in 14 patients.

Conclusions: We report a genetic diagnosis in 26 (51%) patients with pediatric movement disorders seen in a single Pediatric Genetic Movement Disorder Clinic. A genetic diagnosis provided either disease-specific treatment or effected management in 10 patients with a genetic diagnosis, highlighting the importance of early and specific diagnosis.

Figure 1. All patients with pediatric genetic movement disorders, their genetic diagnoses, and type of genetic investigations

Abbreviations: CMP = cardiomyopathy; EE = epileptic encephalopathy; GDD = global developmental delay; NCL = neuronal ceroid lipofuscinosis; TNGS = targeted next generation sequencing; WES = whole exome sequencing.

Figure 2. Specific brain MRI findings of 8 patients

(A) Brain MRI of patient 2 with Leigh disease shows increased T2 signal in the subthalamic nuclei and brain stem in axial image at the age of 3 years. (B) Brain MRI of patient 3 with PDHC deficiency shows dysgenesis of corpus callosum and in T1 sagittal image and dilated ventricles in T2 axial image at the age of 4 years. (C) Brain MRI of patient 5 with mitochondrial encephalopathy shows increased fluid-attenuated inversion recovery signal in bilateral putamen and left caudate head and body at the age of 6.5 years. (D) Brain MRI of patient 6 with PDHC E3 deficiency shows increased T2 signal in bilateral globus pallidi in axial image at the age of 3.5 years. (E) Brain MRI of patient 7 with neuronal ceroid lipofuscinosis type 2 shows increased T2 signal in cerebral white matter, cerebral atrophy and small thalami in axial image, and thin corpus callosum in T1 sagittal image at the age of 13 years. (F) Brain MRI of patient 8 with neuronal ceroid lipofuscinosis type 2 shows increased T2 white matter signal intensity and decreased T2 thalami signal intensity in axial image and cerebellar atrophy in T1 sagittal image at the age of 11 years. (G) Brain MRI of patient 9 with HMG CoA synthase 2 deficiency shows symmetrical increased signal intensity in putamen and caudate nucleus in T2 axial image at the age of 5 years. (H) Brain MRI of patient 20 with KCNA2-associated epileptic encephalopathy shows cerebellar atrophy in T1 sagittal image at the age of 10 years. Abbreviations: HMG = 3-hydroxy-3-methylglutaryl; PDHC = pyruvate dehydrogenase complex.

Figure 3. Algorithm for diagnostic workup in pediatric movement disorders