Emerging Monogenic Complex Hyperkinetic Disorders

Abstract

Purpose of ReviewHyperkinetic movement disorders can manifest alone or as part of complex phenotypes. In the era of next-generation sequencing (NGS), the list of monogenic complex movement disorders is rapidly growing. This review will explore the main features of these newly identified conditions.Recent FindingsMutations in ADCY5 and PDE10A have been identified as important causes of childhood-onset dyskinesias and KMT2B mutations as one of the most frequent causes of complex dystonia in children. The delineation of the phenotypic spectrum associated with mutations in ATP1A3, FOXG1, GNAO1, GRIN1, FRRS1L, and TBC1D24 is revealing an expanding genetic overlap between epileptic encephalopathies, developmental delay/intellectual disability, and hyperkinetic movement disorders,.SummaryThanks to NGS, the etiology of several complex hyperkinetic movement disorders has been elucidated. Importantly, NGS is changing the way clinicians diagnose these complex conditions. Shared molecular pathways, involved in early stages of brain development and normal synaptic transmission, underlie basal ganglia dysfunction, epilepsy, and other neurodevelopmental disorders.

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

“… 27 , 28 Neurodevelopmental impairment, epilepsy, and movement disorders also frequently co-exist. 29 , 30 Rare variants in genes that encode a number of presynaptic proteins involved in Ca 2+ -regulated neurotransmitter release have been identified in individuals affected by a spectrum of neurological disorders. These include the following: 1. variants in SNAP25 (MIM: 60322) isoforms SNAP25a and SNAP25b; these variants have been identified in association with ID, seizures, and myasthenia 31 , 32 2. variants in SYT1 (MIM: 185605 ), which encodes the Ca 2+ -sensor synaptotagmin-1 required for evoked synchronous fusion; these variants are found in individuals with NDDs and hyperkinetic movements 33 , 34 3. variants in genes encoding the RIM interactor PNKD or the SNAP25 and synaptotagmin-1 interactor PRRT2; these variants have been identified in different forms of dyskinesias and seizures (MIM: 128200 ; MIM: 60575) 35 , 36 4. variants in UNC13A (MIM: 609894 ), encoding the synaptic regulator Munc13-1; these variants have been linked to an NDD with involuntary movements 37 5. variants in STXBP1 (MIM: 602926 ), encoding Munc18-1; these variants cause NDDs with epilepsy and autistic features 38 …”

Loss of Frrs1l disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities

“…In some patients, these clinical symptoms are accompanied by neurodegeneration in the cortex and cerebellum. Several families have now been diagnosed with this devastating condition, arguing for the inclusion of this gene in the diagnostic screening for epilepsy and dyskinetic disorders (Carecchio and Mencacci, 2017).…”

An Ontology Systems Approach on Human Brain Expression and Metaproteomics

“…Deficiencies in voltage-gated ion channels and synapses have been related to several mental and movement disorders (Baldessarini, 1996 ; Yogeeswari et al, 2004 ; Sullivan et al, 2012 ; Imbrici et al, 2013 ; Vitaliti et al, 2014 ; Mourre et al, 2017 ; Reig-Viader et al, in press ; Roeper, 2017 ). For example, epilepsy (Devergnas et al, 2012 ; Carecchio and Mencacci, 2017 ) and PD (Mourre et al, 2017 ) are associated with the basal ganglia, while ataxia has been observed with ion channel dysfunction in the cerebellum (Waszkielewicz et al, 2013 ).…”