The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders

Abstract

Background and objective: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders.

Methods: Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria.

Results: One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders; and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P < 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia.

Conclusions: This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: chorea; dystonia; hyperkinetic movement disorders; infantile parkinsonism; myoclonus.

FIG 1

Proposed disease pathways involved in genetic hyperkinetic movement disorders (HMDs) of childhood onset: schematic representation of neuronal synapse and key proteins postulated to be involved in motor control. Yellow star: mechanism in dystonia not fully elucidated for this gene, postulated mechanism, or function not known; red circle: gene reported in association with complex genetic HMDs in this article; pink circle: gene not reported in this article; green circle: dopamine; gray circles: DAG, cAMP, and AMP as indicated in figure. Akt, protein kinase B; AMP, adenosine 3′,5′‐monophosphate; AR, aldose reductase; β‐arr, β‐arrestin; BH4, tetrahydrobiopterin; cAMP, cyclic AMP; CREB, cAMP‐response element binding; DAG, diacylglycerol; DAT, dopamine transporter; DNHTP, 7,8‐dihydroneopterin triphosphate; GLUT1, glucose transporter 1; GNAQ, guanine nucleotide‐binding protein G(q); GSK‐3, glycogen synthase kinase 3; GTP, guanosine‐5′‐triphosphate; IP₃, inositol 1,4,5‐triphosphate; MAPK, mitogen‐activated protein kinase; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PP2A, protein phosphatase 2; PTP, 6‐pyruvoyl tetrahydropterin; SP, sepiapterin reductase; VMAT2, vesicular monoamine transporter 2. [Color figure can be viewed at wileyonlinelibrary.com]

FIG 2

Venn diagram that represents the different combinations of movement disorders that were linked to each genetic defect in our series. [Color figure can be viewed at wileyonlinelibrary.com]

FIG 3

Flow diagram with the age at onset, key hyperkinetic motor semiology, and key associated neurological and systemic features identified in our series. We also include biochemical and radiological biomarkers that are valuable for the differential genetic diagnosis. CSF, cerebrospinal fluid; Dev, developmental; HMD, hyperkinetic movement disorder; MRI, magnetic resonance imaging; SWI, susceptibility weighted imaging. [Color figure can be viewed at wileyonlinelibrary.com]