High diagnostic yield by whole exome sequencing in a cohort of patients with movement disorders and/or progressive spasticity – possible targeted treatment implications and a way to precison medicine

Abstract

Background: Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movement and hypokinetic disorders with reduction in the degree of movement. Spasticity, though not being defined as a movement disorder, is a type of motor disorder occasionally admixed with movement disorders. Previous investigation on the underlying genetic causes of movement disorders in paediatric cohorts is not found in Asian countries. The objective of our study is to investigate the genetic causes of a cohort of Hong Kong paediatric patients with movement disorders and/ or progressive spasticity by whole exome sequencing and review the potential treatment implications. Methods: We studied a cohort of 30 patients who have paediatric-onset movement disorders and/ or progressive spasticity with unrevealing etiologies after extensive neurometabolic investigations including lumbar puncture. Patients highly suspected to have neurometabolic diseases such as mitochondrial diseases were excluded as a different disease category. Whole exome sequencing was performed in local settings of our department and oversea laboratory (Genome Diagnostics Nijmegen). Rare variants with population frequency ≤ 1% were interrogated for pathogenicity based on the ACMG guideline. In addition, we have reviewed some recent studies which shed light to the use of targeted therapies against the genetic defects associated with the disorders. Results: Genetic variants have been identified in 13 patients (43%) in our cohort. Five patients presented with dystonia were identified with variants in the VPS13D, CTNNB1, PURA and KMT2B genes. Three cases of ataxia were found to have variants in KCNC3, KCND3 and SLC2A1 associated with spinocerebellar ataxia 13, 19/22 and glucose transporter type 1 deficiency respectively. Three patients with progressive spasticity with or without admixed with movement disorders have variants in SPAST and SPG11 leading to spastic paraplegia 4 and 11 respectively. A patient with an initial diagnosis of dystonic cerebral palsy was identified with a GNAO1 variant associated with GNAO1 encephalopathy. Another patient with infantile-onset parkinsonism features, spasticity, episodic attacks of worsening of rigidity and tremor was identified with an ATP1A3 variant leading to a widening of the ATP1A3-related neurological phenotypic spectrum. Recent studies demonstrated some effective therapies against these genetic defects: 1) potassium channel activators for potassium channels (KCNC3) mutations; 2) L-dopa treatment to SPG11 associated neurotransmitter abnormalities and CTNNB1/beta-catenin deficient dystonia; 3) ketogenic diet as the first line treatment for SLC2A1 mutations; 4) globus pallidus interna deep brain stimulation (GPi-DBS) for KMT2B dystonia, with significant improvement in our patient; 5) Tetrabenazine as effective drug for GNAO1 encephalopathy; 6) ATP supplementation for ATP1A3- related neurological disorders. Interestingly, dissection of phenotype-genotype correlation in GNAO1 encephalopathy suggested that different mutations affecting the protein in different ways implicate different treatment strategies. Conclusion ; High diagnostic yield by whole exome sequencing has been shown in our patient cohort. Identification of the genetic etiologies may allow a more effective clinical management using targeted therapies and suggests potential development of precision medicine according to the particular variants identified in movement disorders and/ or progressive spasticity.