RESEARCH ARTICLE The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders Belén Pérez-Dueñas, MD, PhD,1,2,3* Kathleen Gorman, MD,4,5 Anna Marcé-Grau, PhD,1 Juan D. Ortigoza-Escobar, MD, PhD,6 Alfons Macaya, MD, PhD,1,2,3 Federica R. Danti, MD,7 Katy Barwick, PhD,4 Apostolos Papandreou, MD,4,5 Joanne Ng, MD, PhD,8 Esther Meyer, PhD,4 Shekeeb S. Mohammad, FRACP, PhD,9 Martin Smith, MD, PhD,10 Francesco Muntoni, MD, PhD,4,5 Pinki Munot, MD,5 Johanna Uusimaa, MD, PhD,11 Päivi Vieira, MD, PhD,11 Eammon Sheridan, MD,12 Renzo Guerrini, MD, FRCP,13 Jan Cobben, MD, PhD,14 Sanem Yilmaz, MD,15 Elisa De Grandis, MD, PhD,16 Russell C. Dale, MD, PhD,17 Roser Pons, MD, PhD,18 Kathryn J. Peall, MD, PhD,19 Vincenzo Leuzzi, MD, PhD,7 and Manju A. Kurian, MD, PhD4,5* Department of Pediatric Neurology, Vall d’Hebron Hospital Universitary and Vall d’Hebro n Research Institute (VHIR)., Barcelona, Spain 1 2 Department of Pediatrics, Obstetrics, Gynecology, Preventative Medicine and Public Health, Universitat Autònoma de Barcelona, Barcelona, Spain 3 Center for Biomedical Network Research on Rare Diseases (CIBERER) CB06/07/0063, Barcelona, Spain 4 Developmental Neurosciences Programme, Great Ormond Street–Institute of Child Health, University College London, London, United Kingdom 5 Dubowitz neuromuscular Center, Great Ormond Street Hospital for Children, London, United Kingdom 6 Department of Pediatric Neurology, Sant Joan de Déu Hospital, Barcelona, Spain 7 Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy 8 Gene Transfer Technology Group, Institute for Women’s Health, University College London, London, United Kingdom 9 Kids Neuroscience Centre and Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Westmead, New South Wales, Australia 10 Department of Pediatric Neurology, John Radcliffe Hospital, Oxford, United Kingdom 11 PEDEGO Research Unit, Department of Children and Adolescents, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland 12 School of Medicine, St James’s University Hospital, University of Leeds, Leeds, United Kingdom 13 Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital, University of Florence, Florence, Italy 14 North West Thames Regional Genetic Service, Northwick Park Hospital, London, United Kingdom 15 _ Department of Pediatrics, Division of Child Neurology, Ege University Medical Faculty, Izmir, Turkey 16 Child Neuropsychiatry Unit, Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Children’s Sciences, University of Genoa, Genoa, Italy 17 Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia 18 First Department of Pediatrics, Agia Sofia Children’s Hospital, National and Kapodistrian University of Athens, Athens, Greece 19 Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom A B S T R A C T : Background and Objective: The objec- Methods: Patients were recruited from 14 international tive of this study was to better delineate the genetic centers. Participating clinicians completed standardized landscape and key clinical characteristics of complex, proformas capturing demographic, clinical, and genetic early-onset, monogenic hyperkinetic movement disorders. data. Two pediatric movement disorder experts reviewed -This - - -is- -an- - open - - - - -access - - - - - -article - - - - -under - - - - the - - - terms - - - - -of- -the- - -Creative - - - - - - Commons - - - - - - - - - - - - - - - -Relevant - - - - - - -conflicts - - - - - - - -of- -interest/financial - - - - - - - - - - - - - disclosures: - - - - - - - - - - -Nothing - - - - - -to- -report. ------- Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Full financial disclosures and author roles may be found in the online version of this article. *Correspondence to: Dr. Belén Pérez-Dueñas, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Received: 22 April 2021; Revised: 19 June 2022; Accepted: 29 Barcelona Hospital Campus, Passeig Vall d’Hebro n 119, 08035 Barce- June 2022 lona, Spain; E-mail: belen.perez@vhir.org Prof. Manju A. Kurian, Developmental Neurosciences Programme, Published online in Wiley Online Library Great Ormond Street–Institute of Child Health, University College Lon- (wileyonlinelibrary.com). DOI: 10.1002/mds.29182 don, Great Ormond Street London WC1N 3JH, London, UK; E-mail: manju.kurian@ucl.ac.uk Movement Disorders, 2022 1 P É R E Z - D U E Ñ A S E T A L available video footage, classifying hyperkinetic move- neurodevelopment (1.5  2.9 vs. 4.7  3.8 years; ments according to published criteria. P < 0.001). Effective disease-specific therapies included Results: One hundred forty patients with pathogenic vari- dopaminergic agents for neurotransmitters disorders, ants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, ketogenic diet for glucose transporter deficiency, and FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, deep brain stimulation for SGCE-, KMT2B-, and PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) GNAO1-related hyperkinesia. were identified. In the majority, hyperkinetic movements Conclusions: This study highlights the complex pheno- were generalized (77%), with most patients (69%) man- types observed in children with genetic hyperkinetic ifesting combined motor semiologies. Parkinsonism- movement disorders that can lead to diagnostic diffi- dystonia was characteristic of primary neurotransmitter culty. We provide a comprehensive analysis of motor disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); semiology to guide physicians in the genetic investiga- chorea predominated in ADCY5-, ATP1A3-, FOXG1-, tion of these patients, to facilitate early diagnosis, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related precision medicine treatments, and genetic counseling. disorders; and stereotypies were a prominent feature in © 2022 The Authors. Movement Disorders published FOXG1- and GNAO1-related disease. Those with gener- by Wiley Periodicals LLC on behalf of International alized hyperkinetic movements had an earlier disease Parkinson and Movement Disorder Society onset than those with focal/segmental distribution (2.5  0.3 vs. 4.7  0.7 years; P = 0.007). Patients with Key Words: dystonia; chorea; myoclonus; infantile par- developmental delay also presented with hyperkinetic kinsonism; hyperkinetic movement disorders movements earlier than those with normal Hyperkinetic movement disorders (HMDs) encompass or extensive structural abnormalities of the basal gang- a broad spectrum of complex diseases, frequently associ- lia. Through this work, we provide a comprehensive ated with motor disability. Hyperkinesia is characterized analysis of motor semiology, as well as detailed infor- by involuntary, excessive movements or abnormal mus- mation about associated key neurological and systemic cle activity during active movement.1 A number of differ- features, to better guide and interpret genetic investiga- ent hyperkinetic phenotypes are described, including tions, thereby facilitating accurate diagnosis, prognosti- dystonia, chorea, athetosis, myoclonus, tremor, tics, and cation, and future genetic counseling. stereotypies. Accurate terminology is essential to facili- tate diagnosis, therapeutic choices, and communication between professionals. Patients and Methods Despite recent major advances in molecular genetics, Study Design children presenting with suspected genetic HMDs often Nineteen international tertiary pediatric movement remain a diagnostic challenge. Many of them have a com- disorder centers were invited to participate in the study, bined hyperkinetic motor semiology that can be difficult of which 14 contributed patients (Supplementary Data to accurately categorize, even for the experienced move- in Appendix S1). ment disorder specialist. Associated comorbidities, such as developmental delay and other neurological or systemic Ethical Approval and Consent features, frequently coexist, causing complex HMD phe- notypes that are difficult to recognize. Appropriate ethical approvals were in place at all The differential diagnosis is often broad, given the participating centers (Supplementary Data in phenotypic overlap with hypoxic-ischemic encephalop- Appendix S1). Written informed consent was obtained athy, autoimmune diseases, infection, stroke, and meta- for publication of video footage. bolic disorders. For many complex genetic HMDs, there are currently no disease biomarkers or radiologi- Study Inclusion Criteria cal clues to aid the diagnostic odyssey. In addition, with Individual patient criteria included: (1) patient’s age growing genetic heterogeneity and phenotypic pleiot- at motor symptom onset <18 years; (2) video footage of ropy, it has become increasingly difficult to predict entire body (head, neck, trunk, and limbs) available for genotype from clinical phenotype. Nonetheless, in this expert clinical review; and (3) confirmation of genetic genomic era, the importance of accurate and detailed etiology as defined by American College of Medical endophenotyping to assist correct interpretation of Genetics and Genomics guidelines.2For each genetic dis- genomic variants cannot be underestimated. order, the reported literature confirms that (1) HMD is In this study, we aim to better characterize the genetic the main motor feature with either one (pure HMD landscape of complex childhood HMDs, with a focus phenotype) or more (combined HMD phenotype) of on disorders without either blood and urine biomarkers the following movement phenotypes: dystonia, chorea, 2 Movement Disorders, 2022 C H I L D H O O D H Y P E R K I N E T I C M O V E M E N T D I S O R D E R S athetosis, myoclonus, or tremor; (2) HMD is not purely Results paroxysmal; (3) HMD is commonly associated with other neurological, neuropsychiatric, or systemic com- Retrospective data analysis was undertaken on orbidities; (4) there are no highly predictive blood or 140 patients with complex genetic HMD (Table S1 in urine biomarkers for the gene in question; and (5) there Appendix S1). The mean age of HMD onset was is no major basal ganglia structural abnormality 2.8 (range 0–17) years. Mean patient age at last clinical (or only subtle findings) on neuroimaging for the gene assessment was 13.3 (range 0.5–68) years. Male/female in question. ratio was relatively equal (66:74). A total of 96/140 (68.6%) patients have been previously reported in the Data Acquisition literature. Video footage was obtained during clinic appointments, as part of routine clinical care, and was considered to be Molecular Genetic Findings representative of the HMD by the treating clinician. Only Seventeen different genetic etiologies were identified videos showing footage of the entire body were selected (Table S1 in Appendix S1). Forty-two patients had biallelic for review. Videos were reviewed by two child neurolo- variants in eight genes, including those causing recessive gists with expertise in movement disorders (B.P.-D. and neurotransmitter defects (DDC, DHPR, PTPS, SLC6A3, M.A.K.). The observed HMD semiology was classified SPR, and TH) and PDE10A- and MICU1-related disease. according to published consensus guidelines.1 The body The remaining 98 patients had autosomal dominant vari- distribution was recorded as focal, segmental, or general- ants in nine genes (ADCY5, ATP1A3, FOXG1, GCH1, ized. Other coexisting non-HMDs, such as parkinsonism GNAO1, KMT2B, NKX2.1, SGCE, SLC2A1) that were and ataxia, were also recorded. either inherited or had occurred de novo. Within the Clinical data were collected through an anonymized cohort, all parents harboring the same ATP1A3, NKX2.1, standardized proforma to record age at assessment, sex, or SLC2A1 variant as their affected child were also symp- ethnicity, consanguinity, other affected family members, tomatic. In contrast, incomplete penetrance was observed causative gene and mutation, mode of inheritance, and for ADCY5-, KMT2B-, GCH1-, and SGCE-related gene-related phenotype. We also gathered data regard- HMDs. Although the majority (126/140) of patients had ing age at HMD onset, disease evolution, paroxysmal intragenic variants, microdeletions encompassing the caus- or fluctuating HMD symptoms, triggers, other neuro- ative gene were identified on aCGH in 14 patients with logical or systemic features, and response to treatment. FOXG1-, KMT2B-, NKX2.1-, and SGCE-related HMDs. The functional impact of HMD on daily living activities Variants in a broad range of genes were identified, (DLAs) was scored (Supplementary Data in with key neuronal roles, including regulation of tran- Appendix S1). scription, neuronal differentiation, synaptic transmis- sion, postsynaptic G protein–cAMP signaling, ion flux, dopamine homeostasis, glucose transport, and mainte- Genetic Analysis nance of the dystrophin–glycoprotein complex (Fig. 1). All patients had been previously diagnosed with path- ogenic or likely pathogenic variants in genes reported HMD Classification and Body Distribution to be associated with complex HMD genes, using stan- dard American College of Medical Genetics and Geno- Figures 2 and 3 illustrate two diagrams with the dif- mics guidelines.2 Genetic diagnoses were made by ferent combinations of movement disorders linked to (1) array comparative genomic hybridization (aCGH) each genetic defect (Fig. 2) and the age at onset, key (n = 14), (2) targeted diagnostic or research Sanger hyperkinetic motor semiology, and key associated neu- sequencing of single genes (n = 85), (3) diagnostic mul- rological and systemic features identified in our series tiple gene panels (n = 18), (4) research whole-exome (Fig. 3). The majority of patients (96/140, 68.6%) had sequencing (n = 19), and (5) research whole-genome two or more coexisting HMDs (two HMDs, n = 68; sequencing (n = 4) (Table S1 in Appendix S1). three HMDs, n = 27; four HMDs, n = 1) (Video S1). Dystonia was the most frequently reported HMD (n = 125), followed by chorea-ballism (n = 50), myoc- Statistical Analysis lonus (n = 45), tremor (n = 23), and stereotypies The SPSS v.24.0 (IBM Corp., Armonk, N.Y., USA) (n = 18) (Tables 1 and 2). Tics were identified in one statistical package was used to calculate means, stan- patient. Patients with HMDs also showed other dard deviations, and ranges. Based on small sample coexisting non-HMDs, such as parkinsonism (n = 29) size, the Mann–Whitney U test was chosen to compare and ataxia (n = 9). Pure HMD phenotypes were continuous variables (ie, age at disease onset) between observed in 35 patients (pure dystonia, n = 25; pure different phenotypic groups. Differences were reported chorea, n = 5; pure myoclonus, n = 5) (Tables 1 as significant when P < 0.05. and 2). Movement Disorders, 2022 3 P É R E Z - D U E Ñ A S E T A L 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 30 ,50 -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-50 -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] n n n n n n FIG. 2. Venn diagram that represents the different combinations of movement disorders that were linked to each genetic defect in our series. [Color fig- ure can be viewed at wileyonlinelibrary.com] The majority of patients (108/140, 77%) had a gener- with SGCE, SLC2A1, ADCY5, and atypical, later- alized HMD (Table 1, Fig. 2). Focal or segmental onset neurotransmitters disorders (GCH1, SLC6A3, HMD was observed in only 32/140 (23%) patients DDC, PTPS, and SPR). Patients with focal semiology 4 Movement Disorders, 2022 C H I L D H O O D H Y P E R K I N E T I C M O V E M E N T D I S O R D E R S 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] had significantly later onset of HMD than those with (n = 40), tremor (n = 20), and stereotypies (n = 17) generalized symptoms (4.7  0.7 vs. 2.5  0.3 years, (Fig. 2, Table 1). Overall, within the cohort, a number respectively; P = 0.001). of distinct dystonia phenotypes were evident, including pure dystonia, chorea-dystonia, myoclonus-dystonia, Abnormal Eye Movements and dystonia-parkinsonism (Video S2). Dystonia of the lower limbs was observed in 58 ambu- Oculogyric crises were commonly seen in all neurotrans- lant and 27 nonambulant patients. In the nonambulant mitter defects except autosomal dominant Segawa disease. group, bilateral dystonic postures included fixed/variable Eyelid myoclonus and ocular flutter were evident in DTDS leg flexion/extension, striatal toe, toe clawing, and (Dopamine Transporter Deficiency Syndrome). Ptosis (TH clenched feet. In the ambulant group, patients had gait and AADC (Aromatic L-amino acid decarboxylase) defi- dystonia with lower-limb posturing, toe-walking, striatal ciency) and oculomotor dyspraxia (TH deficiency) were toe, toe-clawing, and gait disturbance. All patients with also observed. Within the wider cohort, strabismus KMT2B-HMD had lower-limb symptoms at disease (FOXG1 and ATP1A3) and nystagmus (MICU1) were onset, leading to a purely dystonic gait. Lower-limb dysto- also reported. Tonic upgaze associated with severe retro- nia was also observed in 21/61 patients with neurotrans- collis was observed in one patient with KMT2B-dystonia. mitter defects and in 10/30 SGCE patients, the latter associated with myoclonic jerks in three patients. In the Hyperkinetic Facial Movements remaining patients, gait dystonia was associated with cho- Facial hyperkinesia was observed in 80 patients, affecting rea (ATP1A3, GNAO1, and NKX2.1) and ataxia the upper (n = 31) and/or lower face (n = 66). Forehead (ATP1A3, NKX2.1, and SLC2A1). wrinkling, excessive blinking, facial grimacing, perioral mus- Upper-limb dystonia was observed in 98/140 patients, cle twitching, lip pursing, jaw opening or clenching, and with fixed/variable dystonic posturing of the arms, hand tongue thrusting, dyskinesia, or impersistence were fisting, superimposed coarse dystonic tremor, and action- observed. Facial hyperkinesia was more frequent in children induced writer’s cramp. with FOXG1-, ADCY5-, NKX2.1-, and GNAO1-related Cervical dystonia was evident in 50 patients (neuro- HMD, as well as AADC deficiency and DTDS. transmitter defects, SGCE, KMT2B, FOXG1, ATP1A3, ADCY5, and SLC2A1). Dystonia Pure dystonia was observed in 25 patients (Fig. 2). Chorea For the remainder, dystonia was always combined with Generalized chorea was observed in 50 patients other HMDs, namely, chorea (n = 40), myoclonus (Fig. 2). Pure chorea was seen in only five patients with Movement Disorders, 2022 5 6 TABLE 1 Age at onset, motor semiology, body distribution, and effective treatments for complex genetic HMDs identified in our cohort Distribution of the Average age at Average age at No. of patients with HMDs and Gene (no. of onset of HMDs last assessment HMDs according to No. of patients with coexistence with Effective treatment patients) (range), y (range), y consensus guidelines facial HMDs ataxia/parkinsonism for HMDs ADCY5 (n = 4) 1.3 6.7 Dystonia (4) Facial dyskinesia (perioral) Generalized chorea Yes – Transient and partial (0.5–2.5) (3–11) Chorea (3) (3) (F, T, L) (3) improvement with valproate P É R E Z - D U E Ñ A S Movement Disorders, 2022 Tongue impersistence (3) Focal: CC (1) (1), acetazolamide (1), carbamazepine (1) E T ATP1A3 (n = 6) 0.3 12 Dystonia (6) Facial dyskinesias (4) Generalized (F, T, L) Yes – Flunarizine (4), (0.08–4) (8–30) Chorea (5) OM dystonia (1) in all topiramate (1), and diazepam A L Myoclonus (3) Ataxia (3) (1) decreased paroxysmal Ballismus (1) Parkinsonism (1) episodes and improved development in one patient FOXG1 (n = 17) 0.6 11 Chorea (16) Facial dyskinesia Generalized (F, T, L) Yes – Levodopa reduced (0–1) (3–25) Dystonia (16) (grimacing/lip pursing) in all hyperkinesia and increased Stereotypies (14) (12) Parkinsonism (1) dexterity in four patients Myoclonus (2) Jaw dystonia and tongue protrusion (12) GNAO1 (n = 7) 2.3 5.4 Chorea (7) Perioral dyskinesia (5) Generalized (F, T, L) Yes – Tetrabenazine (2) and (0.3–8.9) (0.6–14) Dystonia (5) Eye blinking (1) in all DBS (1) improved Ballismus (3) movement disorder Stereotypies (3) Myoclonus (1) KMT2B (n = 17) 8.1 20 Dystonia (17) Orolingual dystonia (2) Generalized (F, T, L) Yes – DBS inserted in nine (1–43) (8–60) Tremor (3) in all patients with considerable Myoclonus (2) benefit MICU1 (n = 2) 2.5 14–20 Chorea (2) Facial dyskinesias (1) Generalized (F, T, L) None mentioned (2–3) Tremor (2) in both Sensory/paroxysmal ataxia (2) NKX2.1 (n = 8) 3 12 Chorea (8) Tongue impersistence (4) Generalized (F, T, L) Yes – Levodopa had a transient (1–7) (4–18) Dystonia (4) Facial dyskinesia (2) in all and partial improvement in Myoclonus (2) OM dystonia (1) Ataxia (2) chorea and gait (1) PDE10A (n = 2) 0.3 7.5 Chorea (2) OM dystonia (2) Generalized (F, T, L) No (7–8) Dystonia (2) in both SGCE (n = 30) 4 25 Myoclonus-dystonia (25) Excessive blinking (7) Generalized (9) Yes – DBS significantly (1.3–11) (2–68) Myoclonus (5) Chin jerks (6) Focal/segmental (21) improved dystonia and myoclonus (3) (Continues) TABLE 1 Continued Distribution of the Average age at Average age at No. of patients with HMDs and Gene (no. of onset of HMDs last assessment HMDs according to No. of patients with coexistence with Effective treatment patients) (range), y (range), y consensus guidelines facial HMDs ataxia/parkinsonism for HMDs Areas involved: CC (22), ULs (26), axial (24), LLs (12) SLC2A1 (n = 4) 2.9 7.7 Dystonia (3) Facial dyskinesia (2) Generalized (2) Yes – Ketogenic diet improved (1.5–5) (4–14) Chorea (1) Ataxia (2) motor performance and Myoclonus (1) Focal: ULs (1), CC (1) paroxysmal episodes (4) Tremor (1) Neurotransmitters defects DDC (n = 9) 0.27 9.2 Dystonia (9) Facial dyskinesias (5) Generalized (F, T, L) Yes – Dopamine agonists (9) (0–0.75) (0.6–32) Myoclonus (2) OM dystonia (3) (7) and MAOIs (3) improved Chorea/Ballismus (2) Eye rolling (2) Segmental: ULs (1) oculogyric crisis and motor Tremor (1) Parkinsonism (4) function in all patients DHPR (n = 4) 0.8 3 Dystonia (4) Facial dyskinesia of jaw Generalized (F, T, L) Yes – Levodopa, 5-HT, (0–2) (0.5–10) Kinetic tremor (1) and tongue (2) in all patients vitamin B6 MAOI – partial Parkinsonism (2) relief of motor symptoms in C H I L D H O O D all GCH (n = 6) 6 12.8 Dystonia (6) Facial dyskinesia (1) Generalized (F, T, L) Yes – Levodopa led to (2–15) (4–41) Dystonic tremor (1) (5) significant and lasting Focal: LLs (3) improvement in all Parkinsonism (1) PTPS (n = 4) 4.2 9.8 Dystonia (4) OM dystonia (3) Generalized (F, T, L) Yes – Tetrahydrobiopterin (4), (0.1–16) (0.6–32) Tremor (2) Down gaze deviation (1) (3) levodopa (3), 5-HT (2), Segmental (UL, CC) MAOIs (2) improved motor (1) function H Y P E R K I N E T I C Parkinsonism (2) SLC6A3 (n = 10) 4.2 10 Dystonia (10) Ocular flutter (4) Generalized (F, T, L) Yes – Ropinirole (3) and (0.04–11) (2–28) Rest tremor (7) Eyelid myoclonus (3) (8) pramipexole (1) caused mild Chorea (3) Facial grimacing (4) Focal (CC) (2) and transient improvement Ballismus (1) OM dystonia (3) Parkinsonism (8) in motor symptoms SPR (n = 4) 10.3 1.5 Dystonia (4) Facial and tongue Generalized (F, T, L) Yes – Levodopa stopped M O V E M E N T (0.5–15) (0–5) Tremor (2) dyskinesia (2) (3) oculogyric crisis and led to Focal dystonia (CC progressive improvement in and OGCs) (1) motor development in all Parkinsonism (2) patients Movement Disorders, 2022 (Continues) 7 D I S O R D E R S P É R E Z - D U E Ñ A S E T A L GNAO1- and NKX2.1-related HMD, while in the remainder, chorea was associated with other HMDs progressive improvement in oculogyric crisis and led to (dystonia, n = 36; stereotypies, n = 16; myoclonus, neurodevelopment in all Yes – Levodopa stopped n = 9; ballismus, n = 4; tremor, n = 2; tics, n = 1). Effective treatment Chorea was the predominant HMD in ADCY5- (n = 4), ATP1A3- (n = 5), FOXG1- (n = 16), all areas of GNAO1- (n = 7), MICU1- (n = 2), NKX2.1- (n = 8), for HMDs and PDE10A-related (n = 2) disease. Chorea was also patients a prominent HMD in seven children with neurotrans- mitter defects (DDC, TH, SLC6A3), commonly in tan- dem with dystonia (n = 5), ballismus (n = 2), myoclonus (n = 1), coarse tremor (n = 3), and stereoty- Age at onset and age at last assessment are reported in years. Distribution of the movement disorder: face (F), trunk (T), limbs (L), upper limbs (UL), lower limbs (LL), and craniocervical (CC). ataxia/parkinsonism Generalized (F, T, L) HMD, hyperkinetic movement disorder; OM, oromandibular; DBS, deep brain stimulation; MAOI, monoamine oxidase inhibitor; Oculogyric crisis (OGCs)5-hydroxytryptophan (5-HT). Distribution of the pies (n = 1) (Video S3). coexistence with Parkinsonism (7) Myoclonus HMDs and Myoclonus was observed in 45 patients (Fig. 2). Pure in all myoclonus was observed in only five patients with SGCE-related HMD, while in the other cases, myoclo- nus coexisted with dystonia (n = 40), chorea (n = 9), and tremor (n = 1) (Video S4). No. of patients with Tremor Facial and tongue dyskinesias (3) facial HMDs Tremor was observed in 23 patients, most commonly in those with neurotransmitter diseases, but also in KMT2B-, MICU1-, and SLC2A1-related diseases (Fig. 2). Tremor was observed in combination with dys- tonia (n = 20), parkinsonism (n = 13), ataxia (n = 3), chorea (n = 2), and myoclonus (n = 2). In patients with consensus guidelines neurotransmitters defects, a coarse generalized resting No. of patients with HMDs according to tremor was observed in nine infants with parkinsonism- dystonia (Video S5). Focal neck and upper limb tremor Myoclonus (3) were observed in seven patients with neurotransmitter Ballismus (1) Dystonia (7) Tremor (3) Chorea (2) defects (DHPR, GCH1, PTPS, SLC6A3, and SPR). Prominent head tremor was also identified in one child with Glut1 deficiency and in a patient with KMT2B- dystonia with retrocollis. last assessment Average age at (0.5–13) Stereotypies (range), y 3.7 Fourteen patients with FOXG1-related HMDs displayed complex motor stereotypies of the upper limbs (repetitive mouthing of hands/objects, midline hand wringing, grasp- ing of clothes), lower limbs (pedalling/pulling), body rocking, bruxism, and nail biting. Three children with onset of HMDs Average age at GNAO1-related HMDs also showed self-injurious stereo- (0.2–1) 0.4 (range), y typic behavior (lip and nail biting, hair pulling) and repeti- tive nonpurposeful distal finger movements. Other Neurological and Systemic Features TABLE 1 Continued Developmental delay was evident in 69/140 (49%) Gene (no. of patients, being severe in 36 patients with neurotrans- TH (n = 7) mitter defects (SLC6A3, TH, DHPR, DDC) and in patients) GNAO1-, FOXG1-, and ATP1A3-related HMDs. Patients with developmental delay had an earlier age of HMD onset than those with normal neurodevelopment 8 Movement Disorders, 2022 C H I L D H O O D H Y P E R K I N E T I C M O V E M E N T D I S O R D E R S TABLE 2 Prevalence of different movement phenotypes in complex genetic hyperkinetic movement disorders Genes Chorea Dystonia Myoclonus Tremor Parkinsonism Ataxia Stereotypies ADCY5 ATP1A3 FOXG1 GNAO1 KMT2B MICU1 NKX2.1 PDE10A SGCE SLC2A1 Neurotransmitter defects DDC DHPR GCH PTPS SLC6A3 SPR TH 0–24% 25–49% 50–74% 75–100% Color shading indicates the percentage of patients with this movement disorder. (1.5  2.9 vs. 4.7  3.8; P < 0.001). Epileptic seizures Fifty-one patients were able to walk independently, but were reported in 32/140 (23%) patients and more com- their gait was slow and/or frequently associated with bal- monly in those with FOXG1, SLC2A1, GNAO1, ance difficulties and falling. Patients with GNAO1, DDC, ATP1A3, and DHPR variants. Microcephaly was iden- PDE10A, SLC6A3, and FOXG1 mutations had the tified in 23/140 (16%) patients with FOXG1, GNAO1, highest average scores for gait impairment (2.9, 2.5, 2.5, SLC2A1, SGCE, and MICU1 variants and some neuro- 2.3, and 2.3, respectively), followed by those with KMT2B transmitters disorders (TH, PTPS, DDC, SPR). Other and ATP1A3 (1.5), TH and PTPS (1.3), GCH1, MICU1, associated neurological features included psychiatric and NKX2.1 (1), SLC2A1 (0.6), and ADCY5, DHPR, problems (49/140 patients with anxiety, mood disor- and SPR (0.5) variants. Patients with SGCE mutations ders, emotional lability, aggressive behavior, attention had the lowest average gait impairment score (0.36). deficit hyperactivity disorder, autism spectrum disorder, Speech impairment was recorded in 73/112 (65%) obsessive–compulsive disorder, panic disorder, specific patients older than 3 years. The most affected groups phobia), hypotonia (37/140), pyramidal signs (17/140), (>75% of the cases) were those with ATP1A3-, as well as systemic features (46/140 patients, ie, failure FOXG1-, GNAO1-, KMT2B-, and PDE10A-related to thrive, short stature, dysmorphic features, autonomic HMDs and all patients with neurotransmitter defects dysfunction, gastrointestinal dysfunction, hypothyroid- with the exception of GCH1 deficiency (Table S3 in ism, respiratory distress) (Table S2 in Appendix S1). Appendix S1). Speech difficulties included dysarthria (all HMD genes), language delay (infantile-onset DDC- , ATP1A3-, FOXG1-, GNAO1-, PDE10A-, SLC6A3-, Functional Impairment of HMDs and Impact and TH-related HMDs), bradylalia (neurotransmitters on DLAs defects), and dysphonia (KMT2B). Ninety-five of 124 patients (77%) had gait impairment. Patients with genetic HMDs also had difficulties with Forty-four were either nonambulant or able to walk eating/swallowing (n = 54), as well as DLAs requiring only supported by another individual or assistive device. fine motor control (n = 67) (Table S3 in Appendix S1). Movement Disorders, 2022 9 P É R E Z - D U E Ñ A S E T A L Paroxysmal Fluctuation HMDs but did not show significant improvement in Oculogyric crises, triggered by hunger, illness, and one 10-year-old boy with a severe PDE10A-related fatigue, were recorded in 25/46 (54%) children with HMD after 2-year follow-up (Table 1, Table S2 in DDC-, DHPR-, PTPS-, SLC6A3-, SPR-, and TH-related Appendix S1). HMDs. These children also had periodic dystonic attacks that were often associated with orolingual dyski- nesia. Diurnal fluctuation of motor symptoms (associ- Discussion ated with sleep benefit) was also described in this group. Gait difficulties, poor balance, and frequent falls trig- Through this multicenter study, we have delineated gered by fatigue and prolonged exercise (with partial the genetic landscape of complex HMDs, where diag- relief of symptoms after sleep) were seen in five of eight nostic difficulty is frequently encountered, given the patients with GCH1 defects (Table S4 in Appendix S1). paucity of reliable blood/urine biomarkers, often non- In ATP1A3 patients, paroxysmal paralysis, dystonia, specific neuroimaging, and broad differential diagnosis. ataxia, and dysphagia were commonly reported. Identi- Complex HMD disorders are commonly misdiagnosed, fied triggers were extremes of temperature, bathing, emo- for example, as “dyskinetic” or “dystonic” forms of tional stress, or fatigue. Paroxysmal exacerbation of acquired cerebral palsy.3,4 Accurate clinical diagnosis is baseline choreoathetosis was reported in two children essential for prompt instigation of gene-specific treat- with ADCY5 variants, triggered by drowsiness and sleep ments, disease prognostication, and genetic counseling. in one. Episodes of acute ataxia, quadriplegia, and Despite the individual rarity of these conditions, we dystonic posturing were described in all four children were able to characterize a large cohort of patients with with Glut1 deficiency after exercise, fatigue, prolonged HMDs of broad clinical and genetic heterogeneity. As a fasting, and febrile illness. Patients with GNAO1 muta- result, we provide a comprehensive analysis of motor tions showed exacerbation of hyperkinetic movements semiology and associated clinical features in pediatric with intercurrent infection, heightened emotion, and pur- complex HMDs, together with video recorded material, poseful movements. Periods of severe exacerbation were that will be valuable for both diagnostic and educa- characterized by relentless hyperkinesia, often necessitat- tional purposes. ing admission to the intensive care unit. Dystonic crises Our study highlights the increasing diagnostic value were also reported in patients with KMT2B-related dis- of multigene panels and whole-exome/genome sequenc- ease (n = 2) and SLC6A3-related disorders (n = 4), most ing, which led to a diagnosis in almost one third of the commonly triggered by intercurrent illness. cohort. The identification of several microdeletions encompassing disease-causing genes (FOXG1, KMT2B, NKX2.1, SGCE) also highlights the diagnostic utility of Treatment and Disease Course aCGH for complex HMD.5,6 Variants in a broad range Thirty-four of 45 patients with neurotransmitters of genes were identified, with different but inter- defects showed varying degrees of clinical improvement connected cellular functions (Fig. 1). Genes involved in with dopaminergic agents (levodopa [L-dopa], dopamine primary neurotransmitter disorders affect dopamine agonists, monoamine oxidase inhibitors). Of the synthesis (DDC, DHPR, PTPS, SPR, and TH) and remaining 11 patients, 1 patient with DHPR deficiency dopamine transport (SLC6A3). Mutations in GNAO1 developed a pharmacoresistent epileptic encephalopathy and other G protein subunits (GNAL), adenylyl cyclase with progressive neurological deterioration (despite ade- (ADCY5), and cyclic nucleotide phosphodiesterase quate dopaminergic treatment), and 10 patients with (PDE10A) disrupt the postsynaptic G protein–cAMP DTDS showed a progressive neurodegenerative disease pathway axis and may impair neuromodulation or course with minimal response to drug intervention. Pro- transduction of transmembrane signaling, presynaptic gression of hyperkinetic movements was commonly seen autoinhibitory effects, and altered neuronal excitability. as part of disease evolution in patients with GNAO1 Other HMD genes code for neuronal proteins with key (7/7) and KMT2B (15/17) variants and less frequently in biological roles, including Na+/K+-ATPase transport, patients with FOXG1- (6/17), ATP1A3- (2/6), ADCY5- osmoregulation, and excitability (ATP1A3), transcrip- (2/4), and SGCE-related (3/30) disorders. Effective thera- tional repressors involved in the promotion of neuro- pies included the ketogenic diet (SLC2A1; n = 4), genesis and cortical neuronal differentiation (FOXG1), flunarizine (ATP1A3; n = 4), and tetrabenazine transcription factors essential for striatal development (GNAO1; n = 2). Some patients with HMDs also (NKX2-1), dystrophin–glycoprotein complex that links responded partially or transiently to L-dopa, benzodiaze- the actin cytoskeleton to the extracellular matrix pines, trihexyphenidyl, carbamazepine, acetazolamide, (SGCE), regulation of mitochondrial Ca2+ uptake and and topiramate. Deep brain stimulation (DBS) of the synaptic transmission (MICU1), glucose transport internal globus pallidus was effective in 13 patients with (SLC2A1), and posttranscriptional regulation of gene drug-resistant SGCE-, KMT2B-, and GNAO1-related expression (KMT2B). 10 Movement Disorders, 2022 C H I L D H O O D H Y P E R K I N E T I C M O V E M E N T D I S O R D E R S From a clinical perspective, pure HMD phenotypes variants. The co-occurrence of epilepsy and hyperki- (defined as those with a single manifesting HMD phe- netic phenotypes in genetic syndromes is increasingly notype) were exceptional in our cohort of patients. We recognized.23 Underlying mechanisms are not entirely observed a pure dystonic motor semiology in patients clear but may be a consequence of the gene defect, as with KMT2B- and neurotransmitter disorder–related well as epigenetic phenomena, environmental factors, HMDs, leading to gait difficulties in early childhood.6,7 or the effect of motor evolution in the developing Also, a minority of patients with NKX2-1 defects brain.24 showed a pure chorea phenotype. In contrast, most Many complex genetic HMDs are also associated patients had a combination of two or more HMDs, or a with disease-specific paroxysmal exacerbations. complex movement disorder with both hyperkinetic and Oculogyric crises appeared to be exclusive to patients hypokinetic features, commonly known as dystonia-plus with neurotransmitters defects.3,22 Plegic attacks were syndromes. In some children with parkinsonism-dystonia identified in patients with ATP1A3 variants and Glut1 caused by biogenic amine defects, hypokinesia and deficiency.13,17 More recently, acute hemiplegia has bradykinesia may be severe and predominate over the also been reported in patients with ADCY5 variants.25 HMD phenotype.3,8 Within our series, status dystonicus was seen in patients Chorea was the second most frequently identified with GNAO1, KMT2B, and SLC6A3 mutations.6,14,26 HMD, evident in >50% patients with ADCY5, Some paroxysmal episodes were caused by specific ATP1A3, FOXG1, NKX2.1, SLC2A1, GNAO1, and triggers. Exercise-induced HMDs were seen in Segawa PDE10A variants.9-15 Chorea was mostly present in disease27 and Glut1 deficiency syndrome.28 Diurnal combination with dystonia and sometimes myoclonus. fluctuation, with improvement after sleep, was recorded Myoclonus was characteristic of SGCE patients,16 but in all neurotransmitter defects.3,22 As previously also observed in ATP1A3 disease,17 NKX2.1,13,18 reported, paroxysmal chorea during sleep and on FOXG1,11 GNAO1,14 KMT2B,6 SLC2A1, and some wakening was seen in ADCY5-related disease.9 We also neurotransmitters defects,19,20 usually in combination identified several other triggers in our cohort, including with chorea and dystonia. Myoclonus-dystonia has also fever, intercurrent illness, fatigue, emotional stress, been reported in children with ADCY5 and GCH21 temperature, purposeful movements, and fasting. defects, but this combination was not observed in our Complex genetic HMDs also significantly impact on cohort of patients. As previously reported, stereotypies DLAs. More than half of the cohort showed gait and were a key disease feature in FOXG1 and GNAO1 speech impairment, and a significant proportion also patients, always in combination with other HMDs.11,14 showed difficulties in eating, hygiene, and dressing. It is Abnormal ocular, facial, and oromandibular move- likely that for some conditions (FOXG1, GNAO1), ments were also important clues for diagnosis: eyelid intellectual disability also contributed to functional myoclonus, ocular flutter, and oculogyric crises were impairment.11,14 Gait impairment was a common find- exclusively observed in neurotransmitter diseases.22 ing in our cohort, with half of the patients (GNAO1, Forehead wrinkling, facial grimacing, perioral muscle DDC, PDE10A, SLC6A3, and FOXG1 defects) either twitching, jaw dystonia, and tongue dyskinesias were unable to walk at all or requiring assistance for ambu- frequently seen in children with generalized cho- lation. In contrast, a mildly impaired but independent reodystonia phenotypes because of ADCY5, NKX2.1, gait pattern was commonly observed in patients with GNAO1, and ATP1A3 mutations.9,10,12,14 drug-responsive neurotransmitters defects (GCH1, In our cohort, the majority had a generalized pattern DHPR, SPR, TH, and PTPS), nonprogressive chorea of HMDs. Only a few patients showed a focal or seg- (NKX2.1, ADCY5), Glut1 syndrome (SLC2A1), and mental distribution, predominantly affecting the upper myoclonus-dystonia (SGCE). limbs and neck, with significantly later onset of the Standard investigations, including blood/urine tests HMD. Genetic defects presenting in the first year of life and neuroimaging, are unyielding for the genetic defects were more likely to lead to both a generalized HMD included in our study. Rarely, subtle neuroimaging pat- pattern and also developmental delay, as observed in terns can be present, including corpus callosum abnor- patients with neurotransmitter defects (with the excep- malities and brain atrophy in GNAO1 and FOXG1 tion of dominant GCH1-related disease) and those with defects,11,29 and subtle T2 low signal intensity within the ATP1A3, FOXG1, GNAO1, SLC2A1, and PDE10A globus pallidus in KMT2B-dystonia.6 Interestingly, variants.10,11,13-15 Furthermore, in NKX2.1-related patients with heterozygous mutations in PDE10A show HMDs, patients had delayed motor development and bilateral striatal necrosis, while those included in our early hypotonia in infancy.12,18 In addition to develop- study with biallelic variants have normal structural mag- mental delay, many patients in the cohort had other netic resonance imaging despite having low levels of neurological and systemic features. Epilepsy was pre- PDE10A protein in the striatum.15 Our study highlights sent in one quarter of our cohort, especially in patients the merit of undertaking cerebrospinal fluid glucose and with FOXG1, GNAO1, ATP1A3, and SLC2A1 neurotransmitters, particularly to aid diagnosis of Glut1 Movement Disorders, 2022 11 P É R E Z - D U E Ñ A S E T A L deficiency and neurotransmitter defects (Fig. 2). In considering complex genetic HMDs, although our delib- patients with suspected disorders of monoamine metabo- erate aim was to focus on better delineating complex lism, urine sepiapterin or blood prolactin levels can also HMD disorders where the HMD was the main pheno- be measured; however, they are neither universally avail- type without highly predictive blood, urine, or radiologi- able nor sensitive/specific for diagnostic purposes. cal biomarkers. Finally, it is important to emphasize that Although not disease specific, hypothyroidism was evi- the motor features identified in our cohort are derived dent in NKX2.1 disease12 and increased creatine kinase from a very small subset of individuals with each genetic levels in patients with MICU1 defects.30 defect; therefore, the spectrum of movement disorders Genetic characterization of patients with complex analyzed in this study does not fully represent the breath HMDs may facilitate selection of appropriate therapies. of HMDs that may be associated with a particular gene. Many patients with neurotransmitter defects in our series In conclusion, detailed clinical assessment and careful showed a significant and sustained improvement with classification of the HMD semiology is key to diagnos- dopaminergic agents.22 However, our study confirms that ing complex genetic HMDs. If neuroimaging, blood, both AADC deficiency and DTDS remain challenging, and urine neurometabolic testing are unyielding, cere- where novel treatment strategies, such as gene therapy, brospinal fluid analysis and targeted neurogenetic inves- may have a role.31 Ketogenic diet improved motor perfor- tigations should be promptly undertaken. In the future, mance and paroxysmal episodes in four of five patients better understanding of the underlying disease mecha- with Glut1 deficiency.28 More recently, triheptanoin has nisms will no doubt facilitate the development of preci- been shown to dramatically reduce paroxysmal motor sion treatment strategies for these disorders. disorders and epileptic discharges in patients with Glut1 deficiency in open-label pilot studies,32 but these results Acknowledgments: This work was supported by an NIHR Professor- were not confirmed in a randomized, blinded, placebo- ship (to M.A.K.). M.A.K. has received funding from the Sir Jules Thorn controlled clinical trial, suggesting that triheptanoin is of Award for Biomedical Research and Wellcome Trust. B.P.-D. was supported by Instituto de Salud Carlos III, PI 18/01319 and PI21/00248, limited therapeutic use.33 and has received funding from Beca José Castillejos (CAS14/00328). Recently, the Rare Movement Disorders Study Group K.J.P. was supported by an MRC Clinician–Scientist Fellowship (511015) and was supported by the Dystonia Medical Research Foundation and of the International Parkinson and Movement Disorder Fight for Sight. S.S.M. has received funding from the Winston Churchill Society designed an online survey to identify worldwide Memorial trust and Cerebral Palsy Alliance. barriers for the genetic diagnosis of movement disor- ders. They found limited access to genetic testing in all countries compared with Europe and North America. Data Availability Statement Given these findings, it is important to emphasize that Data available on request due to privacy/ethical patients with early-onset dystonia of unknown etiology restrictions should receive a trial with L-dopa to exclude a possible defect in dopamine metabolism, regardless of the avail- ability of genetic testing.34 References DBS remains important for patients with medically 1. Sanger TD, Chen D, Fehlings DL, et al. Definition and classification intractable dystonia, and the contribution of genetic testing of hyperkinetic movements in childhood. Mov Disord 2010;25: 1538–1549. to outcome from DBS is increasingly recognized.35 In our 2. Richards S, Aziz N, Bale S, et al. 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Papandreou A, Danti FR, McTague A, et al. The expanding spec- trum of movement disorders in genetic epilepsies. Dev Med Child Neurol 2019;62:178–191. 24. Lin JP, Nardocci N. Recognizing the common origins of dystonia Supporting Data and the development of human movement: a manifesto of unmet needs in isolated childhood dystonias. Front Neurol 2016;7:226 Additional Supporting Information may be found in 25. Westenberger A, Max C, Brüggemann N, et al. Alternating hemiplegia the online version of this article at the publisher’s of childhood as a new presentation of adenylate cyclase 5-mutation- associated disease: a report of two cases. J Pediatr 2017;181:306–308. web-site. Movement Disorders, 2022 13 SGML and CITI Use Only DO NOT PRINT Author Roles B.P.-D. and M.A.K. conceived, organized, and executed the project. They also drafted the manuscript. K.G., J.D.O.-E., A.M., A.M.-G., F.R.D., K.B., and E.M. assisted in data analysis and contributed to writing sections of the manuscript. A.P., J.N., S.S.M., M.S., F.M., P.M., J.U., P.V., E.S., R.G., J.C., S.Y., E.D.G., R.C.D., R.P., K.J.P., and V.L. provided clinical data for the project and reviewed and critiqued the manuscript. Financial Disclosures