Genetic landscape of pediatric movement disorders and management implications

Abstract

ObjectiveTo identify underlying genetic causes in patients with pediatric movement disorders by genetic investigations.MethodsAll 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.ResultsThere 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.ConclusionsWe 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.

Exome Sequencing in Paediatric Patients with Movement Disorders with Treatment Possibilities

“…Diagnostic rates were relatively higher in cohorts with only paediatric patients and with the use of WES. Comparing with studies using targeted NGS approach with a diagnostic rate range from 11-28%, our study and Cordeiro et al (19) with WES has a higher diagnostic rate of 32% and 51% respectively. Further looking into the diagnoses, two (2/10, 20%) and six (6/26, 23%) in our cohort and Cordeiro et al's cohort can be made by WES only.…”

“…Most of the previous studies in MDs patient cohorts had not investigated the therapeutic potentials based on the genetic diagnosis. Only the study of Cordeiro et al (19) suggested that 38% of their patients with genetic diagnoses had treatment implications (Table 3). With the growth of new treatment strategies emerging in recent years, genetic testing becomes even more crucial to direct genotype-targeted therapies in MDs.…”

Genetic background of ataxia in children younger than 5 years in Finland

“…3 Our diagnostic yield was at the same level as other smaller exome sequencing studies of symptom-based pediatric ataxia (46%-80%). 7,8,23 The percentage of genetically diagnosed patients that were found to have a de novo variant underlying their disease in previous studies varied. In the first such published study, 7 in a cohort of 28 families (6 consanguineous), 9% had a pathogenic de novo variant.…”

“…Our study revealed a remarkably higher de novo rate of 45% in patients with previously molecularly undiagnosed childhoodonset ataxia. Other reports include a 25% de novo rate in a study that investigated congenital ataxia in consanguineous families 8 and another study 23 that found a 42% de novo rate in a pediatric movement disorder cohort including patients with ataxia.…”

A Proposed Diagnostic Algorithm for Inborn Errors of Metabolism Presenting With Movements Disorders

“…Based on the distinct pathway involved, IEMs can be categorized as described by the nosology of Ferreira et al into the following groups (1): (1) Disorders of nitrogen-containing compounds, (2) Disorders of vitamins, cofactors, metals, and minerals, (3) Disorders of carbohydrates, (4) Mitochondrial disorders of energy metabolism, (5) Disorders of lipids, (6) Disorders of Tetrapyrroles, (7) Storage disorders, (8) Disorders of peroxisome and oxalate, and (9) Congenital disorders of glycosylation. This accurate and updated nosology will be applied in this review, in which a total of 231 IEMs presenting with MD will be included.…”