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Abstract

Genetic epilepsies and developmental and epileptic encephalopathies are commonly associated with concomitant movement disorders, which can mimic seizures and/or create additional disability. Appropriate diagnosis is critical to proper management. A broad range of movement disorder phenomenologies occur among patients with genetic epilepsy, including dystonia, chorea, ataxia, myoclonus, stereotypy, tics, and Parkinsonism. For some genes, clear relationships exist between genotype and movement disorder phenotype, while in other situations, the relationship is more complex. Diagnosis of movement disorders involves elements of history, physical examination, video review, and neurophysiology. Assessment of associated impairment, distress, and/or safety concerns is important for considering risks/benefits of treatment. Movement disorders may range from severe and dangerous, requiring pharmacologic or neuromodulatory treatments such as deep brain stimulation, to relatively benign, with only reassurance and continued observation required. Appropriate treatments differ based on phenomenology and etiology, with some genes associated with tailored treatments which can provide dramatic benefit.

Keywords

epilepsy movement disorders genetics

Introduction

Genetic epilepsies, frequently childhood onset, are often associated with additional neurodevelopmental symptoms beyond seizures. Concurrent movement disorders are common among patients with genetic epilepsy, particularly among those with developmental and epileptic encephalopathies (DEEs).¹ Distinguishing between seizure and movement disorder in these patients is important to optimize treatment and prevent unnecessary side effects.

Several genes are associated with both epilepsy and movement disorders, with some patients presenting with epilepsy, some patients presenting with movement disorder, and some patients with both. This phenotypic variability relates to genotype in some cases and is more complex in others.

Both the clinical presentation and the underlying etiology may influence the appropriate treatment of movement disorders associated with epilepsy. Certain disorders have etiology-specific treatment, such as the ketogenic diet in GLUT1 deficiency syndrome. In other situations, impact on life and phenomenology guide treatment decisions.

In this narrative review with several genes as case examples, we will describe common movement disorder phenomenologies, list commonly reported epilepsy and movement disorder phenotypes associated with genetic epilepsy by gene, consider the importance of genotype–phenotype associations, and review considerations for diagnosis and treatment.

Clinical Characteristics

Movement disorders are typically characterized by phenomenology, as this can inform understanding of localization and etiology and guide treatment options. Broadly speaking, movement disorder phenomenologies can be characterized as hyperkinetic, ataxic, or hypokinetic. Hyperkinetic phenomenologies are further differentiated by suppressibility, stereotyped versus patterned, posturing versus random characteristics of movement, and influence of voluntary movement on severity of movements. Movement disorders may be continuous or paroxysmal, with paroxysms frequently, but not always, associated with provoking factors, such as in the case of kinesiogenic and/or exertional dyskinesias.

Definitions and descriptions of phenomenology of hyperkinetic or ataxic movements in the pediatric population including dystonia, chorea, athetosis, myoclonus, tremor, tics, stereotypy, and ataxia have been developed and detailed elsewhere.^2–4 We will review key features, helpful for differentiating these phenomenologies on exam, here.

Dystonia involves sustained or intermittent and/or jerky contractions, which can involve twisting or posturing, co-contraction of agonist–antagonist muscles. Dystonia is more variable than spasticity, and is typically worsened by voluntary movement and/or emotion.

Chorea involves ongoing random discrete involuntary movements which are often described as “dance-like” while athetosis involves more slow writhing movements. Both are associated with motor impersistence and typically worsen with voluntary movement and/or emotion.

Myoclonus involves brief lightning-like jerks due to sudden muscle contraction which are often repeated but non-rhythmic.

Tremor is a rhythmic oscillatory movement about a null-point.

Tics and stereotypies are brief, suppressible, stereotyped movements. Tics are typically associated with an urge, which young and/or nonverbal children may not be able to describe, and may be briefly suppressible. Stereotypies are repetitive movements that are often associated with excitement or emotion. Stereotypies generally begin before age three and maintain the same pattern over time while tics usually begin at later ages with a waxing and waning pattern that involves shifts in the patterned movement or sound observed.

Ataxia, a disorder of coordination rather than excessive involuntary movement, involves inability to generate an expected voluntary movement trajectory, not attributed to weakness or involuntary muscle activity. Ataxia is frequently associated with wide-based gait and/or difficulty with tandem gait, dysmetria of limbs and eyes, and oculomotor apraxia.

Parkinsonism, relatively infrequent in the pediatric population, involves resting tremor, bradykinesia (slowness of movements with decrement in amplitude of movement over time), rigidity (increased tone without velocity dependence of spasticity), and postural instability, when described in adults. Many of these features are also described in the pediatric population.⁵

These terms have been used to characterize phenomenology of movement disorders commonly reported in patients with genetic epileptic disorders, reported in association with genes and epilepsy phenotype in Table 1. Additional movement disorder phenomenology terminology in this chart includes dyskinesia, a general term often used when overlap between dystonia, chorea, and/or athetosis occurs, ballismus, with involves large-amplitude choreiform movements, and paroxysmal tonic upgaze, a brief dystonic involuntary eye movement.

Table 1.

List of Genes Commonly Reported in Association With Both Epilepsy and Movement Disorders.

Gene	Epilepsy phenotype	Movement disorder phenomenology
15q11 (Angelman syndrome)^6–9	IESS, GE with myoclonic and atypical absence seizures	Myoclonus Dystonia Stereotypy Tremor
ACBD6¹⁰	GE	Dystonia Tremor Parkinsonism
ALDH5A1 (succinic semialdehyde dehydrogenase deficiency)^6,11	GE, Myoclonic seizures	Ataxia Dystonia Chorea Hypokinesia
ARX^12–15	IESS, Myoclonic Seizures	Dystonia, including status dystonicus¹⁶ Chorea Myoclonus
ASL (arginosuccinic aciduria)^17,18	Generalized Epilepsy, Focal Epilepsy, Atypical absence seizures	Ataxia Dystonia Tremor Movement disorders often onset in second or third decade of life
ATP1A3^6,19,20 Associated with Alternating Hemiplegia of Childhood	GE, Focal Epilepsy, Absence Seizures	Dystonia (paroxysmal or continuous)
CACNA1A^21,22	EI-DEE, Absence Seizures	Episodic Ataxia Paroxysmal tonic upgaze Ataxia
CACNA1B²³	EI-DEE, GE	Myoclonus Dystonia Chorea
CACNA1E^24,25	EI-DEE, IESS, GE	Dystonia Chorea Myoclonus
CAD²⁶	EI-DEE, DEE, Focal seizures	Ataxia Tremor
DHDDS^6,27–31	DEE, Epilepsy with Eyelid Myoclonus	Tremor Myoclonus Ataxia including oculomotor apraxia Parkinsonism Dystonia
ECHS1^32,33	Epilepsy	Dystonia (can be paroxysmal exertional) Ataxia
FBXO28^34,35	DEE, IESS, Progressive Myoclonic Epilepsy	Dystonia Chorea Myoclonus
FOXG1^6,36–39	IESS, GE	Chorea Dystonia Stereotypy
FRRS1L^40,41	IESS, LGS	Chorea
GABRA1^42,43	EI-DEE, IESS, EMAtS	Ataxia Dystonia Myoclonus
GABRB2⁴⁴	GEFS+, EIMFS, IESS, GE, LGS	Chorea Dystonia Ataxia
GABRB3^45,46	GEFS+, IESS, EMAtS, DEE	“Dyskinesia” Dystonia Ataxia
GAMT^47,48	Febrile seizures, GE	Chorea/Athetosis Ataxia
GNAO1^6,49–54	EI-DEE or later onset milder focal and generalized seizures	Chorea Dystonia Ballismus Ataxia Myoclonus Tremor
GNB1^6,55	GE	Dystonia (can be paroxysmal) Myoclonus Chorea
GOSR2^56,57	Progressive myoclonic epilepsy	Ataxia Myoclonus Dystonia
GRIA3^58–61	IESS, DEE	Chorea Myoclonus Dystonia Stereotypy
GRIN1^62,63	IESS, EMAtS, DEE	Chorea Dystonia
GRIN2B⁶⁴	Febrile seizures, SeLECTS, DEE	Chorea Dystonia
HIBCH^6,33	DEE	Ataxia Dystonia, often paroxysmal
KCNA1^65–67	DEE, Focal Epilepsy	Episodic ataxia Paroxysmal kinesiogenic dyskinesia
KCNMA1^68,69	GE	Paroxysmal dyskinesia Ataxia Myoclonus
MECP2 (Rett Syndrome)^6,70,71	GE	Stereotypy Dystonia Ataxia Hypokinesia/Parkinsonism
MECP2 duplication syndrome^6,72,73	GE with multiple seizure types	Ataxia Stereotypy Chorea
NGLY1^74–76	EMAtS, DEE, IESS	Chorea Dystonia Myoclonus Tremor
NUS1^30,77	GE, EMAtS	Myoclonic tremor Ataxia including oculomotor apraxia Parkinsonism Stereotypy
PCDH12⁷⁸	Early Onset Epilepsy	Dystonia Ataxia
PIGN⁷⁹	DEE, ID + E	Chorea Ataxia Dystonia Myoclonus
PRICKLE1^6,80	Progressive myoclonic epilepsy	Ataxia Myoclonus Stererotypy
PRRT2^6,81	SeLFNE	Paroxysmal kinesiogenic dyskinesia
PURA^6,82,83	IESS, DEE, LGS	Chorea Dystonia Stereotypy
RHOBTB2^84–86	DEE	Dystonia ChoreaAtaxia
SCN1A^87–91	GEFS+, DS	Ataxia Chorea/orofacial dyskinesia Dystonia Myoclonus Tremor Parkinsonism Eyelid stereotypy⁹²
SCN2A^93–96	SeLFNE, DEE, EIMFS, IESS, ASD with seizures	Dystonia Complex stereotypy
SCN8A^6,97–100	SeLFNE, DEE, NDDwGE	Ataxia Dystonia (can be paroxysmal) Myoclonus (partial LOF variant)¹⁰¹
SLC13A5^102,103	GE, Focal Epilepsy	Dystonia Chorea Ataxia
SLC2A1 (Glut1 deficiency)^6,104–106	Early Onset Absence Epilepsy, EMAtS, GE	Episodic ataxia Paroxysmal exertional dystonia Dystonia Chorea
ST3GAL5 (GM2 synthase deficiency)^107,108	Infantile Onset Epilepsy	Chorea Dystonia Stereotypy
STXBP1^109,110	IESS, EI-DEE, DEE	Tremor (myoclonic) Myoclonus Dystonia Stereotypy
UBA5¹¹¹	GE	Dystonia
VAMP2¹¹²	GE, IESS	Chorea Dystonia Stereotypy
WARS2^6,113	GE	Parkinsonism Tremor Dystonia Chorea Myoclonus
WDR45^6,114,115	DEE	Dystonia Parkinsonism Movement Disorders onset in adulthood
WWOX¹¹⁶	EI-DEE, IESS, EIMFS	Dystonia Parkinsonism
YIF1B^117,118	GE	Dystonia Chorea
ZNF142¹¹⁹	GE	Tremor Dystonia Ataxia

Abbreviations: SeLFNE, self-limited familial neonatal epilepsy; IESS, infantile epileptic spasms syndrome; GEFS+, genetic epilepsy with febrile seizures plus; EIMFS, epilepsy of infancy with migrating focal seizures; DS, Dravet syndrome; EI-DEE, early infantile developmental and epileptic encephalopathy; NDDwGE, neurodevelopmental disorder with generalized epilepsy; EMAtS, epilepsy with myoclonic atonic (and tonic) seizures; GE, generalized epilepsy; LGS, Lennox–Gastaut syndrome; ID + E, intellectual disability and epilepsy.

Movement disorders can frequently be disabling, given their common interference with voluntary movement, potential for discomfort, and in severe cases, potential for injury and/or rhabdomyolysis. However, it is worth noting that movement disorders can also frequently be noticeable without being impairing or distressing. This is particularly the case for stereotypy and often for tics, but can be true of any phenomenology. Therefore, clinical evaluation of movement disorders requires both identification of phenomenology and evaluation of associated disability and distress, if any.

Genotype–Phenotype Associations

Given the clinical heterogeneity in many disorders with concomitant movement disorders and epilepsy, attention to genotype–phenotype correlations may inform clinical treatment. Increasingly, specific phenotypic patterns are related to specific variants which can have implications for treatment choices and prognostication.

For example, in SCN8A, both epilepsy and movement disorder phenotypes are associated with the genotype and functional impact. Gain-of-function (GoF) variants are frequently associated with a severe epilepsy phenotype with focal-onset seizures in infancy, while loss-of-function (LoF) variants are associated with intellectual disability without epilepsy as well as epilepsy manifest as generalized, primarily absence, seizures with onset after infancy.^120–122 While movement disorders can occur in both GoF and LoF variants, chronic ataxia and myoclonus are particularly described in LOF variants.^98,101 Sodium-channel blockers, particularly useful in SCN8A-related GoF disorders, are not generally effective with SCN8A LoF variants.¹²³

GNAO1-related disorders are exemplary of the clinical implications and complexity in this area. Since the first description in 2013, about 200 variants have been associated with a spectrum of movement disorders and epileptic encephalopathy, as well as variable overlap. Nearly half of the reported variants are in a handful of “hot spots,” or recurrent variants, and correlate to a particular phenotype.¹²⁴ For example, the most commonly reported variants at the p.R209 residue typically display a severe movement disorder with dystonia, chorea and hyperkinetic crises with a milder, non-DEE epilepsy. In contrast, variants in the p.G40 residue commonly have DEE with a milder movement disorder. While initially a dichotomous mechanism was proposed in which GoF variants were associated with movement disorders and LoF associated with epileptic encephalopathies based on a cAMP assay of downstream GTPase activity variants,⁵⁰ this did not fully explain the clinical heterogeneity. A third hot spot, p.G203R typically manifests as DEE and a movement disorder with hyperkinetic crises. Recently, milder later-onset dystonia, including inherited cases, have been associated with novel GNAO1 variants and presumed to be due to haploinsufficiency.¹²⁵ The full understanding of this heterogeneity in g-protein signaling remains incompletely understood.

Other examples of disorders in which genotype influences movement disorder phenotype include SCN1A, where GoF mutations are more likely to be associated with movement disorders,⁸⁷ KCNMA1, where GoF mutations often present with paroxysmal dyskinesia while LoF variants often are associated with other phenemonologies,⁶⁹ MECP2-related disorder (Rett syndrome) where truncating mutations are associated with more severe dystonia and rigid-akinetic syndrome,⁷⁰ and GRIA3 where GoF variants are more likely to be associated with movement disorders, and earlier onset of epilepsy.⁶⁰

By studying these correlations, clinicians can better predict disease progression, identify at-risk individuals, and tailor interventions to the unique needs of each patient, advancing personalized medicine and improving outcomes.

Diagnosis

Distinguishing movement disorders and seizures often presents a challenge in patients with epilepsy and DEEs, particularly when there is overlap in both the phenomenology and underlying genetic cause. Since genetic variants co-segregate in families presenting with diverse epilepsies and movement disorders with significant phenotypic hetereogenity,¹²⁶ we cannot rely on genotype alone to differentiate seizures from movement disorders. This distinction is important: misclassification of seizures and movements impacts patient care and may affect clinical trial outcomes.¹²⁷ Treatment for seizures and movement disorders are often vastly different.

The first step in evaluating motor symptoms in a patient with genetic epilepsy involves a history and neurologic examination, which in many cases is sufficient to identify features of specific movement disorder phenomenologies as detailed above. Assessing the influence of voluntary movement on the involuntary movement can help distinguish between movement disorders and seizure, such as with exacerbation of the involuntary movement in the case of dystonia or chorea and suppressibility with tics or stereotypy. Some paroxysmal disorders may be provoked in clinic for direct observation, such as using excitement to provoke a stereotypy or sudden movement after a prolonged rest to provoke paroxysmal kinesiogenic dyskinesia. Video recording the examination can allow for more careful evaluation for these features. However, a lack of diagnostic clarity may occur when paroxysmal movements (a) may not be observed during a clinical encounter and (b) may have a clear onset/offset which raises concern for an epileptic etiology. Some phenomenologies, such a myoclonus, could have an epileptic etiology and require further evaluation, and some movement disorder presentations may raise concern about atypical features, such as an apparent tic or stereotypy which does not appear to be suppressible.

In these situations, video EEG is the gold standard for distinguishing epileptic from non-epileptic events including movement disorders. It should be noted that there are many other etiologies of paroxysmal non-epileptic events apart from movement disorder. Many of these are specifically described in genetic epilepsies and DEEs, including neuro-irritability related to internal or external stimuli, autonomic dysfunction, severe behavioral disturbances, and catatonia.¹²⁸ Therefore, the absence of epileptic findings on EEG is not sufficient to diagnose movement disorder as the etiology of a paroxysmal event.

Further complicating EEG interpretation is the observation that only 21% of focal aware (formerly “simple partial”) seizures have ictal EEG change on scalp EEG.¹²⁹ Synchronized cortical activity from a minimum of 6 cm² and, more typically 20 cm², is required to produce a spike on scalp EEG.¹³⁰ Therefore, a “negative” ictal scalp EEG does not exclude seizures. This highlights the importance of also considering history and physical examination in distinguishing seizures from movement disorders and other types of spells. Videos of events, now commonplace with smartphones, are also fairly accurate when viewed by trained experts.¹³¹

Additional neurophysiologic evaluations, such as surface electromyography (EMG), can be helpful for distinguishing movement disorder phenomenologies, sometimes in combination with surface EEG. In the case of surface EMG, electrodes are placed on muscles involved in the abnormal movements, ideally including agonist/antagonist muscle pairs on both sides of the body to allow for evaluation of synchrony between limbs and coherence between agonist/antagonist muscles. Methods for acquiring and evaluating this data are well detailed by Hallett et al¹³² Surface EMG synchronized with video can allow for objective evaluation of exacerbation and/or suppression of involuntary movements with voluntary movement or other stimuli. It can also be a useful adjunct in distinguishing between phenomenologies and localizing the neuroanatomical origin of myoclonus.

Considering the special case of myoclonus, distinguishing origin of the myoclonus is challenging and frequently requires adjunctive neurophysiologic studies. For epileptic myoclonus, this is typically (but not always) associated with spikes or polyspikes on scalp EEG, synchronized with short burst duration (<50 ms) surface EMG activity. Epilepsia partialis continua is an exception as it can be EEG-negative given highly focal origin and involves burst duration which is often longer than 50 ms. Particularly in DEEs, careful consideration of epileptic myoclonus is indicated for patients with semi-rhythmic myoclonus which can clinically resemble tremor.⁶

Non-epileptic cortical myoclonus may be diagnosed by identifying a cortical potential prior to myoclonus onset using jerk-locked back-averaging of the EEG. Subcortical origins of myoclonus, such as thalamus-basal ganglia, reticular, propriospinal, spinal, or peripheral, carry their own neurophysiologic signature whose identification can help guide treatment choices.⁷

While less studied than myoclonus, other types of movement disorders can be distinguished by neurophysiologic features, such as via surface EMG. For example, dystonia involves prolonged bursts of muscle activity which may be tonic, phasic, or rhythmic and abnormal activation of agonist/antagonist muscles (co-contraction) or contralateral muscles (overflow).¹³³

Finally, it should be noted that as patients with genetic epilepsies can have concurrent movement disorders and seizures, the identification of a movement disorder does not exclude the potential for seizure and vice-versa, as many patients will have both, potentially presenting at different ages.

Treatment

Treatment of movement disorders in DEEs is often guided by phenomenology, but in some circumstances, treatment can be more precision-based when there are known interventions for a specific disorder or genotype. Not all movement disorders require treatment; less than half of patients in a recently-described cohort required treatment for their movement symptoms.¹ For many movement disorders, the risks and potential side effects of treatment may outweigh the benefits, and each family may have different preferences and values regarding the risks and benefits of treatment. Pharmacotherapy can be considered when the movements cause distress or interrupt function, or if there is potential for harm from the movements. Stereotypies, for example, are generally not harmful and so do not typically require treatment. In rare circumstances where stereotypies pose risk of injury or are otherwise disruptive, behavioral treatment is the first-line approach,¹³⁴ but may be of limited utility for individuals with DEE due to associated developmental delay or cognitive impairment. Some additional movement phenotypes may also lack effective treatments. For example, there are no approved symptomatic therapies for ataxia, though 4-aminopyridine has shown benefit in spinocerebellar ataxia and KCNA1 cohorts.^135,136 Overall, these studies have small sample sizes and it is hard to generalize these results to other causes of ataxia.

Chorea, dystonia, and myoclonus are hyperkinetic movement disorders that are more likely to require treatment. Common pharmacologic agents used for dystonia include levodopa, anticholinergic agents such as trihexyphenidyl, benzodiazepines, baclofen, clonidine, or VMAT2 inhibitors such as tetrabenazine. Chemodenervation is also effective for treating dystonia, but best suited for focal dystonia or targeting a more problematic body region. Treatment options for chorea include dopamine blockade with typical or atypical antipsychotics, or dopamine depletion with VMAT2 inhibitors. For severe hyperkinesis, deep brain stimulation, particularly in individuals with GNAO1, has been helpful in preventing further hyperkinetic crises.¹³⁷ DBS has been used as rescue for status dystonicus with benefit for hyperkinetic movement disorders associated with other genetic epilepsies, including SCN2A, UBA5, and GNB1.^55,96,138 Non-epileptic myoclonus is often treated with anti-seizure medications similar to those used in myoclonic epilepsies; levetiracetam, valproate, and benzodiazepines are often implemented. However, efficacy may vary based on the localization of the myoclonus (cortical vs subcortical vs segmental).¹³⁹

Paroxysmal dyskinesias, although still consisting of dystonia, chorea, and ataxia in isolation or combination, may differ in their treatment compared to the more continuous movement phenotypes discussed above. Paroxysmal kinesigenic dyskinesia (PKD), often associated with variants in PRRT2, usually responds extremely well to very low doses of sodium channel blockers. Paroxysmal movement disorders in RHOBTB2 are also reported to respond to sodium channel blockers.⁸⁵ Paroxysmal exercise-induced dyskinesia (PED), which can be phenotypically differentiated from PKD in that more sustained exercise induces the abnormal movements rather than onset of exercise, is associated with GLUT1 deficiency syndrome and variants in SLC2A1. First-line treatment of PED associated with GLUT1 is with use of ketogenic diet. Paroxysmal non-kinesigenic dyskinesia (PNKD) episodes due to the N999S variant in KCNMA1 are often triggered by excitement (as in cataplexy) or tactile stimuli and exhibit a remarkable response to lisdexamfetamine.¹⁴⁰ In episodic ataxia due to variants in KCNA1 (EA1) or CACNA1A (EA2), episodes frequency or intensity can be reduced with carbonic anhydrase inhibitors such as acetazolamide.

Additionally, many inborn errors of metabolism are associated with both epilepsy and movement disorder. Dietary and/or gene therapies which address underlying metabolic deficient and/or toxic accumulations can also reduce movement disorder and epilepsy symptoms. Examples from genes listed in Table 1 include GAMT, where both epilepsy and movement disorders improve with creatine supplementation,⁴⁷ and CAD, which is treatable with uridine supplementation.²⁶

Discussion

The approach to the patient with concomitant epilepsy and movement disorder from a genetic disorder is challenging, but an evaluation that jointly considers phenomenology, impact, and etiology of a patient's movement disorder is essential to prevent inappropriate or unnecessary treatment and treat disabling symptoms in a tailored manner. Evaluation for movement disorders in genetic epilepsy should extend beyond consideration of movement disorder in the differential diagnosis for paroxysmal spells and include physical examination for continuous movement disorders such as dystonia or chorea which may impact functional abilities, comfort, and/or safety. In some situations, etiology-specific treatment targeted to underlying genetic diagnosis can impact both seizures and movement disorders. We provide a summary of our recommended approach to possible movement disorders in a patient with genetic epilepsy in Figure 1.

Figure 1.

Suggested approach to patient with genetic epilepsy to evaluate for possible concomitant movement disorder.

This review and the medical literature overall have several limitations regarding this broad topic. Descriptions of movement disorders associated with epilepsy as reported in the literature may skew towards more severe phenotypes. For example, we found that stereotypies were infrequently mentioned as movement disorders associated with genetic epilepsy, but when a cohort of patients with genetic DEEs were evaluated for movement disorder characterization, stereotypy was the most commonly identified phenomenology.¹ Poor ascertainment likely results in under-reporting of movement disorders in these patients. Additionally, inconsistent and overlapping terminology can create challenges in a broader understanding of this topic. Frequently, subjectivity is required for distinguishing movement disorder phenotypes and/or treatment response in clinical practice, which can also limit scholarly descriptions.

Conclusion

Movement disorders are commonly associated with genetic epilepsy and require proper identification and a tailored diagnostic and therapeutic approach is needed to provide best patient care.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research,authorship,and/or publication of this article.

Funding

The authors received no financial support for the research,authorship,and/or publication of this article.

ORCID iDs

Megan Abbott

Laura Tochen

John M. Schreiber

References

van der Veen

Tse

GTW

Ferretti

, et al. Movement disorders in patients with genetic developmental and epileptic encephalopathies. Neurology. 2023;101(19):e1884-e1892. doi:https://doi.org/10.1212/WNL.0000000000207808

Sanger

Chen

Fehlings

, et al. Definition and classification of hyperkinetic movements in childhood. Mov Disord. 2010;25(11):1538-1549. doi:https://doi.org/10.1002/mds.23088

Sanger

Delgado

Gaebler-Spira

Hallett

Mink

. Task force on childhood motor disorders. Classification and definition of disorders causing hypertonia in childhood. Pediatrics. 2003;111(1):e89-e97. doi:https://doi.org/10.1542/peds.111.1.e89

Sanger

Chen

Delgado

Gaebler-Spira

Hallett

Mink

. Taskforce on childhood motor disorders. Definition and classification of negative motor signs in childhood. Pediatrics. 2006;118(5):2159-2167. doi:https://doi.org/10.1542/peds.2005-3016

Parkinsonism in children: clinical classification and etiological spectrum—ClinicalKey. Accessed October 2, 2024. https://www-clinicalkey-com.proxy1.library.virginia.edu/#!/content/playContent/1-s2.0-S135380202030777X?returnurl=https:%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS135380202030777X%3Fshowall%3Dtrue&referrer=https:%2F%2Fpubmed.ncbi.nlm.nih.gov%2F

Mastrangelo

Galosi

Cesario

Renzi

Campea

Leuzzi

. Presenting patterns of genetically determined developmental encephalopathies with epilepsy and movement disorders: a single tertiary center retrospective cohort study. Front Neurol. 2022;13:855134. doi:https://doi.org/10.3389/fneur.2022.855134

Ferlazzo

Ascoli

Abate

, et al. Dystonia in angelman syndrome: a common, unrecognized clinical finding. J Neurol. 2021;268(6):2208-2212. doi:https://doi.org/10.1007/s00415-020-10395-4

Pollack

Grocott

Parkin

Larson

Thibert

. Myoclonus in angelman syndrome. Epilepsy Behav. 2018;82(6):170-174. doi:https://doi.org/10.1016/j.yebeh.2018.02.006

Samanta

. Epilepsy in Angelman syndrome: a scoping review. Brain Dev. 2021;43(1):32-44. doi:https://doi.org/10.1016/j.braindev.2020.08.014

10.

Kaiyrzhanov

Rad

Lin

, et al. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain. 2024;147(4):1436-1456. doi:https://doi.org/10.1093/brain/awad380

11.

Julia-Palacios

Kuseyri Hübschmann

Olivella

, et al. The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency. J Inherit Metab Dis. 2024;47(3):447-462. doi:https://doi.org/10.1002/jimd.12723

12.

Poirier

Eisermann

Caubel

, et al. Combination of infantile spasms, non-epileptic seizures and complex movement disorder: a new case of ARX-related epilepsy. Epilepsy Res. 2008;80(2-3):224-228. doi:https://doi.org/10.1016/j.eplepsyres.2008.03.019

13.

Akula

Quiroz

D’Gama

, et al. The spectrum of movement disorders in young children with ARX-related epilepsy-dyskinesia syndrome. Ann Clin Transl Neurol. 2024;11(6):1643-1647. doi:https://doi.org/10.1002/acn3.52055

14.

Rodgers

Calvert

Shoubridge

McGaughran

. A novel ARX loss of function variant in female monozygotic twins is associated with chorea. Eur J Med Genet. 2021;64(11):104315. doi:https://doi.org/10.1016/j.ejmg.2021.104315

15.

Sherr

. The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes. Curr Opin Pediatr. 2003;15(6):567-571. doi:https://doi.org/10.1097/00008480-200312000-00004

16.

Gorman

Cary

Gaffney

, et al. Status dystonicus due to missense variant in ARX: diagnosis and management. Eur J Paediatr Neurol. 2018;22(5):862-865. doi:https://doi.org/10.1016/j.ejpn.2018.04.015

17.

Gurung

Karamched

Perocheau

, et al. The incidence of movement disorder increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria. J Inherit Metab Dis. 2024;47(6):1213-1227. doi:https://doi.org/10.1002/jimd.12691

18.

Elkhateeb

Olivieri

Siri

, et al. Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: a retrospective international study. Epilepsia. 2023;64(6):1612-1626. doi:https://doi.org/10.1111/epi.17596

19.

Vezyroglou

Akilapa

Barwick

, et al. The phenotypic continuum of ATP1A3-related disorders. Neurology. 2022;99(14):e1511-e1526. doi:https://doi.org/10.1212/WNL.0000000000200927

20.

Cordani

Stagnaro

Pisciotta

, et al. Alternating hemiplegia of childhood: genotype–phenotype correlations in a cohort of 39 Italian patients. Front Neurol. 2021;12:658451. doi:https://doi.org/10.3389/fneur.2021.658451

21.

Le Roux

Barth

Gueden

, et al. CACNA1A-associated epilepsy: electroclinical findings and treatment response on seizures in 18 patients. Eur J Paediatr Neurol. 2021;33(5):75-85. doi:https://doi.org/10.1016/j.ejpn.2021.05.010

22.

Lipman

Fan

Shen

Chung

. Clinical and genetic characterization of CACNA1A-related disease. Clin Genet. 2022;102(4):288-295. doi:https://doi.org/10.1111/cge.14180

23.

Gorman

Meyer

Grozeva

, et al. Deciphering developmental disorders study, UK10 K consortium, NIHR BioResource, Millichap JJ, Carvill GL, Clayton-Smith J, Maher ER, Raymond FL, Kurian MA. Bi-allelic loss-of-function CACNA1B mutations in progressive epilepsy-dyskinesia. Am J Hum Genet. 2019;104(5):948-956. doi:https://doi.org/10.1016/j.ajhg.2019.03.005

24.

Di Micco

Affronte

Khinchi

, et al.

Seizure and movement disorder in CACNA1E developmental and epileptic encephalopathy: two sides of the same coin or same side of two different coins?

Epileptic Disord. 2024;26(4):520-526. doi:https://doi.org/10.1002/epd2.20242

25.

Helbig

Lauerer

Bahr

, et al. De novo pathogenic variants in CACNA1E cause developmental and epileptic encephalopathy with contractures, macrocephaly, and dyskinesias. Am J Hum Genet. 2018;103(5):666-678. doi:https://doi.org/10.1016/j.ajhg.2018.09.006

26.

Rymen

Lindhout

Spanou

, et al. Expanding the clinical and genetic spectrum of CAD deficiency: an epileptic encephalopathy treatable with uridine supplementation. Genet Med. 2020;22(10):1589-1597. doi:https://doi.org/10.1038/s41436-020-0933-z

27.

Galosi

Edani

Martinelli

, et al. De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus. Brain. 2022;145(1):208-223. doi:https://doi.org/10.1093/brain/awab299

28.

Mehta

Lal

. DHDDS mutation: a rare cause of refractory epilepsy and hyperkinetic movement disorder. JMD. 2023;16(1):107-109. doi:https://doi.org/10.14802/jmd.22154

29.

Piccolo

Amadori

Vari

, et al. Complex neurological phenotype associated with a De Novo DHDDS mutation in a boy with intellectual disability, refractory epilepsy, and movement disorder. J Pediatr Genet. 2021;10(3):236-238. doi:https://doi.org/10.1055/s-0040-1713159

30.

Williams

Waller

Qiu

, et al. DHDDS and NUS1: a converging pathway and common phenotype. Mov Disord Clin Pract. 2024;11(1):76-85. doi:https://doi.org/10.1002/mdc3.13920

31.

Wood

Montgomery

Devlin

. DHDDS related epilepsy—report of familial cases and review of the literature. Seizure. 2021;91(8):189-191. doi:https://doi.org/10.1016/j.seizure.2021.06.013

32.

Ozlu

Chelliah

Dahshi

, et al. ECHS1 deficiency and its biochemical and clinical phenotype. Am J Med Genet A. 2022;188(10):2908-2919. doi:https://doi.org/10.1002/ajmg.a.62895

33.

Marti-Sanchez

Baide-Mairena

Marcé-Grau

, et al. Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene. J Inherit Metab Dis. 2021;44(2):401-414. doi:https://doi.org/10.1002/jimd.12288

34.

FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability—Schneider—2021—Epilepsia—Wiley Online Library. Accessed September 24, 2024. https://onlinelibrary-wiley-com.proxy1.library.virginia.edu/doi/10.1111/epi.16784

35.

Krygier

Talaśka-Liczbik

Zawadzka

Mazurkiewicz-Bełdzińska

. Hyperkinetic movement disorder in FBXO28-related developmental and epileptic encephalopathy. Seizure. 2024;119:1-2. doi:https://doi.org/10.1016/j.seizure.2024.05.002

36.

Wong

Hsu

Weng

Tsai

Lee

. Cognition and evolution of movement disorders of FOXG1-related syndrome. Front Neurol. 2019;10:641. doi:https://doi.org/10.3389/fneur.2019.00641

37.

Cellini

Vignoli

Pisano

, et al. The hyperkinetic movement disorder of 1-related epileptic–dyskinetic encephalopathy. Dev Med Child Neurol. 2016;58(1):93-97. doi:https://doi.org/10.1111/dmcn.12894

38.

Papandreou

Schneider

Augustine

, et al. Delineation of the movement disorders associated with FOXG1 mutations. Neurology. 2016;86(19):1794-1800. doi:https://doi.org/10.1212/WNL.0000000000002585

39.

Seltzer

Ahmed

, et al. Epilepsy and outcome in FOXG1-related disorders. Epilepsia. 2014;55(8):1292-1300. doi:https://doi.org/10.1111/epi.12648

40.

Abdelmoumen

Jimenez

Valencia

, et al. Boricua founder variant in FRRS1L causes epileptic encephalopathy with hyperkinetic movements. J Child Neurol. 2021;36(2):93-98. doi:https://doi.org/10.1177/0883073820953001

41.

Madeo

Stewart

Sun

, et al. Loss-of-function mutations in FRRS1L lead to an epileptic-dyskinetic encephalopathy. Am J Hum Genet. 2016;98(6):1249-1255. doi:https://doi.org/10.1016/j.ajhg.2016.04.008

42.

Musto

Liao

VWY

Johannesen

, et al. GABRA1-related disorders: from genetic to functional pathways. Ann Neurol. 2024;95(1):27-41. doi:https://doi.org/10.1002/ana.26774

43.

Stamberger

Crosiers

Balagura

, et al. Natural history study of STXBP1-developmental and epileptic encephalopathy into adulthood. Neurology. 2022;99(3):e221-e233. doi:https://doi.org/10.1212/WNL.0000000000200715

44.

El Achkar

Harrer

Smith

, et al. GABRB2 working group. Characterization of the GABRB2-associated neurodevelopmental disorders. Ann Neurol. 2021;89(3):573-586. doi:https://doi.org/10.1002/ana.25985

45.

Møller

Wuttke

Helbig

, et al. Mutations in GABRB3. Neurology. 2017;88(5):483-492. doi:https://doi.org/10.1212/WNL.0000000000003565

46.

Burgess

Wang

McTague

, et al. The genetic landscape of epilepsy of infancy with migrating focal seizures. Ann Neurol. 2019;86(6):821-831. doi:https://doi.org/10.1002/ana.25619

47.

Mercimek-Mahmutoglu

Stoeckler-Ipsiroglu

Adami

, et al. GAMT deficiency. Neurology. 2006;67(3):480-484. doi:https://doi.org/10.1212/01.wnl.0000234852.43688.bf

48.

Yıldız

Ardıçlı

Göçmen

, et al. Electro-clinical features and long-term outcomes in guanidinoacetate methyltransferase (GAMT) deficiency. Eur J Paediatr Neurol. 2024;49(3):66-72. doi:https://doi.org/10.1016/j.ejpn.2024.02.006

49.

Schirinzi

Garone

Travaglini

, et al. Phenomenology and clinical course of movement disorder in GNAO1 variants: results from an analytical review. Parkinsonism Relat Disord. 2019;61(1):19-25. doi:https://doi.org/10.1016/j.parkreldis.2018.11.019

50.

Feng

Sjögren

Karaj

Shaw

Gezer

Neubig

. Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations. Neurology. 2017;89(8):762-770. doi:https://doi.org/10.1212/WNL.0000000000004262

51.

Thiel

Bamborschke

Janzarik

, et al. Genotype–phenotype correlation and treatment effects in young patients with GNAO1-associated disorders. J Neurol Neurosurg Psychiatry. 2023;94(10):806-815. doi:https://doi.org/10.1136/jnnp-2022-330261

52.

Ananth

Robichaux-Viehoever

Kim

, et al. Clinical course of six children with GNAO1 mutations causing a severe and distinctive movement disorder. Pediatr Neurol. 2016;59(2):81-84. doi:https://doi.org/10.1016/j.pediatrneurol.2016.02.018

53.

Axeen

Bell

Robichaux Viehoever

Schreiber

Sidiropoulos

Goodkin

. Results of the first GNAO1-related neurodevelopmental disorders caregiver survey. Pediatr Neurol. 2021;121(1):28-32. doi:https://doi.org/10.1016/j.pediatrneurol.2021.05.005

54.

Kelly

Park

Mihalek

, et al. Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region. Epilepsia. 2019;60(3):406-418. doi:https://doi.org/10.1111/epi.14653

55.

Jones

Morales-Briceño

Barwick

, et al. Myoclonus-dystonia caused by GNB1 mutation responsive to deep brain stimulation. Mov Disord. 2019;34(7):1079-1080. doi:https://doi.org/10.1002/mds.27708

56.

Hentrich

Parnes

Lotze

, et al. Novel genetic and phenotypic expansion in GOSR2-related progressive myoclonus epilepsy. Genes (Basel). 2023;14(10):1860. doi:https://doi.org/10.3390/genes14101860

57.

Polet

Anderson

Koens

, et al. A detailed description of the phenotypic spectrum of north sea progressive myoclonus epilepsy in a large cohort of seventeen patients. Parkinsonism Relat Disord. 2020;72:44-48. doi:https://doi.org/10.1016/j.parkreldis.2020.02.005

58.

Necpál

Winkelmann

Zech

Jech

. A de novo GRIA3 variant with complex hyperkinetic movement disorder in a girl with developmental delay and self-limited epilepsy. Parkinsonism Relat Disord. 2023;111:105437. doi:https://doi.org/10.1016/j.parkreldis.2023.105437

59.

Piard

Béreau

XiangWei

, et al. The c.2477G > A variant causes an exaggerated startle reflex, chorea, and multifocal myoclonus. Mov Disord. 2020;35(7):1224-1232. doi:https://doi.org/10.1002/mds.28058

60.

Rinaldi

Bayat

Zachariassen

, et al. Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes. Brain. 2024;147(5):1837-1855. doi:https://doi.org/10.1093/brain/awad403

61.

Trivisano

Santarone

Micalizzi

, et al. GRIA3 missense mutation is cause of an x-linked developmental and epileptic encephalopathy. Seizure. 2020;82(9):1-6. doi:https://doi.org/10.1016/j.seizure.2020.08.032

62.

Ohba

Shiina

Tohyama

, et al. GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders. Epilepsia. 2015;56(6):841-848. doi:https://doi.org/10.1111/epi.12987

63.

Lemke

Geider

Helbig

, et al. Delineating the GRIN1 phenotypic spectrum. Neurology. 2016;86(23):2171-2178. doi:https://doi.org/10.1212/WNL.0000000000002740

64.

Platzer

Yuan

Schütz

, et al. GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet. 2017;54(7):460-470. doi:https://doi.org/10.1136/jmedgenet-2016-104509

65.

Paulhus

Ammerman

Glasscock

. Clinical spectrum of KCNA1 mutations: new insights into episodic ataxia and epilepsy comorbidity. Int J Mol Sci. 2020;21(8):2802. doi:https://doi.org/10.3390/ijms21082802

66.

Tristán-Clavijo

Scholl

Macaya

, et al. Dominant-negative mutation p.Arg324Thr in KCNA1 impairs Kv1.1 channel function in episodic ataxia. Mov Disord. 2016;31(11):1743-1748. doi:https://doi.org/10.1002/mds.26737

67.

Yin

Lin

Cao

, et al. Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene. Hum Mol Genet. 2018;27(4):625-637. doi:https://doi.org/10.1093/hmg/ddx430

68.

Bautista

Yang

, et al. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nat Genet. 2005;37(7):733-738. doi:https://doi.org/10.1038/ng1585

69.

Miller

Moldenhauer

Keros

Meredith

. An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy. Channels (Austin). 2021; 15(1):447-464. doi:https://doi.org/10.1080/19336950.2021.1938852

70.

Temudo

Ramos

Dias

, et al. Movement disorders in Rett syndrome: an analysis of 60 patients with detected MECP2 mutation and correlation with mutation type. Mov Disord. 2008;23(10):1384-1390. doi:https://doi.org/10.1002/mds.22115

71.

Cardoza

Clarke

Wilcox

, et al. Epilepsy in Rett syndrome: association between phenotype and genotype, and implications for practice. Seizure. 2011;20(8):646-649. doi:https://doi.org/10.1016/j.seizure.2011.06.010

72.

Miguet

Faivre

Amiel

, et al. Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features. J Med Genet. 2018;55(6):jmedgenet-2017-104956. doi:https://doi.org/10.1136/jmedgenet-2017-104956

73.

Lotti

Geronzi

Grosso

. Electroencephalographic and epilepsy findings in mecp2 duplication syndrome. a family study. Brain Dev. 2019;41(5):456-459. doi:https://doi.org/10.1016/j.braindev.2018.12.008

74.

Enns

Shashi

Bainbridge

, et al. Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genet Med. 2014;16(10):751-758. doi:https://doi.org/10.1038/gim.2014.22

75.

Lam

Ferreira

Krasnewich

, et al. Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation. Genet Med. 2017;19(2):160-168. doi:https://doi.org/10.1038/gim.2016.75

76.

Levy

Frater

Gallentine

Phillips

Ruzhnikov

. Delineating the epilepsy phenotype of NGLY1 deficiency. J Inherit Metab Dis. 2022;45(3):571-583. doi:https://doi.org/10.1002/jimd.12494

77.

Riboldi

Monfrini

Stahl

Frucht

. NUS1 And epilepsy-myoclonus-ataxia syndrome: An under-recognized entity? Tremor Other Hyperkinet Mov (N Y). 2022;12:21. doi:https://doi.org/10.5334/tohm.696

78.

Fazeli

Bamborschke

Moawia

, et al. The phenotypic spectrum of PCDH12 associated disorders - five new cases and review of the literature. Eur J Paediatr Neurol. 2022;36(3):7-13. doi:https://doi.org/10.1016/j.ejpn.2021.10.011

79.

Bayat

de Valles-Ibáñez

Pendziwiat

, et al. PIGN encephalopathy: characterizing the epileptology. Epilepsia. 2022;63(4):974-991. doi:https://doi.org/10.1111/epi.17173

80.

Criscuolo

de Leva

Sorrentino

, et al. PRICKLE1 progressive myoclonus epilepsy in southern Italy. Mov Disord. 2010;25(15):2686-2687. doi:https://doi.org/10.1002/mds.23350

81.

Heron

Grinton

Kivity

, et al. PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet. 2012;90(1):152-160. doi:https://doi.org/10.1016/j.ajhg.2011.12.003

82.

Crippa

ACS

Bacheladenski

Rodrigues

DCB

Ferreira

Meira

Franklin

. Movement disorders in PURA syndrome: a video case series. Mov Disord Clin Pract. 2023;10(10):1542-1546. doi:https://doi.org/10.1002/mdc3.13804

83.

Johannesen

Gardella

Gjerulfsen

, et al. PURA study group. PURA-related developmental and epileptic encephalopathy: phenotypic and genotypic spectrum. Neurol Genet. 2021;7(6):e613. doi:https://doi.org/10.1212/NXG.0000000000000613

84.

Zagaglia

Steel

Krithika

, et al. RHOBTB2 mutations expand the phenotypic spectrum of alternating hemiplegia of childhood. Neurology. 2021;96(11):e1539-e1550. doi:https://doi.org/10.1212/WNL.0000000000011543

85.

de Pedro Baena

Sariego Jamardo

Castro

, et al. Exploring the spectrum of RHOBTB2 variants associated with developmental encephalopathy 64: a case series and literature review. Mov Disord Clin Pract. 2023;10(11):1671-1679. doi:https://doi.org/10.1002/mdc3.13880

86.

Langhammer

Maroofian

Badar

, et al. Genotype–phenotype correlations in RHOBTB2-associated neurodevelopmental disorders. Genet Med. 2023;25(8):100885. doi:https://doi.org/10.1016/j.gim.2023.100885

87.

Brunklaus

Brünger

Feng

, et al. The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications. Brain. 2022;145(11):3816-3831. doi:https://doi.org/10.1093/brain/awac210

88.

Sadleir

Mountier

Gill

, et al. Not all SCN1A epileptic encephalopathies are Dravet syndrome. Neurology. 2017;89(10):1035-1042. doi:https://doi.org/10.1212/WNL.0000000000004331

89.

Marco-Hernández

Caro-Llopis

Rubio Sánchez

, et al. Extending the phenotype related to SCN1A gene: arthrogryposis, movement disorders, and malformations of cortical development. J Child Neurol. 2022;37(5):340-350. doi:https://doi.org/10.1177/08830738211072694

90.

Clatot

Parthasarathy

Cohen

, et al. SCN1A gain-of-function mutation causing an early-onset epileptic encephalopathy. Epilepsia. 2023;64(5):1318-1330. doi:https://doi.org/10.1111/epi.17444

91.

Beck

Hull

Isom

. Beyond dravet syndrome: characterization of a novel, more severe SCN1A-linked epileptic encephalopathy. Epilepsy Curr. 2019;19(4):266-268. doi:https://doi.org/10.1177/1535759719858339

92.

De Palma L, Specchio N, Fusco L, et al. Early-onset eyelid stereotypies are a frequent and distinctive feature in Dravet syndrome. Seizure. 2021;89(1):66–70. doi:https://doi.org/10.1016/j.seizure.2021.07.001

93.

Reynolds

King

Gorman

. The phenotypic spectrum of SCN2A-related epilepsy. Eur J Paediatr Neurol. 2020;24(1):117-122. doi:https://doi.org/10.1016/j.ejpn.2019.12.016

94.

Alagia

Fecarotta

Romano

, et al. A novel splicing SCN2A mutation in an adolescent with low-functioning autism, acute dystonic movement disorder, and late-onset generalized epilepsy. Pediatric Neurology. 2023;138(1):58-61. doi:https://doi.org/10.1016/j.pediatrneurol.2022.10.011

95.

Howell

McMahon

Carvill

, et al. SCN2A encephalopathy. Neurology. 2015;85(11):958-966. doi:https://doi.org/10.1212/WNL.0000000000001926

96.

Mithani

Breitbart

Fasano

Gorodetsky

Ibrahim

. Deep brain stimulation for status dystonicus in a toddler with SCN2A-related disorder. Childs Nerv Syst. 2023;39(11):3033-3035. doi:https://doi.org/10.1007/s00381-023-06136-3

97.

Hammer

Xia

Schreiber

JM.

SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders. In: Adam

Feldman

Mirzaa

Pagon

Wallace

Amemiya

, eds. GeneReviews®. University of Washington, 2016. Accessed January 7, 2025. http://www.ncbi.nlm.nih.gov/books/NBK379665/

98.

Lyu

Boßelmann

Johannesen

, et al. Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia. EBioMedicine. 2023;98:104855. doi:https://doi.org/10.1016/j.ebiom.2023.104855

99.

Larsen

Carvill

Gardella

, et al. EuroEPINOMICS RES consortium CRP. The phenotypic spectrum of SCN8A encephalopathy. Neurology. 2015;84(5):480-489. doi:https://doi.org/10.1212/WNL.0000000000001211

100.

Johannesen

Gardella

Encinas

, et al. The spectrum of intermediate SCN8A-related epilepsy. Epilepsia. 2019;60(5):830-844. doi:https://doi.org/10.1111/epi.14705

101.

Wagnon

Mencacci

Barker

, et al. Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus. Hum Mutat. 2018;39(7):965-969. doi:https://doi.org/10.1002/humu.23547

102.

Yang

Spelbrink

Nye

Hsu

Porter

. Epilepsy and EEG phenotype of SLC13A5 citrate transporter disorder. Child Neurol Open. 2020;7:2329048X20931361. doi:https://doi.org/10.1177/2329048X20931361

103.

Spelbrink

Brown

Brimble

Blanco

Nye

Porter

. Characterizing a rare neurogenetic disease, SLC13A5 citrate transporter disorder, utilizing clinical data in a cloud-based medical record collection system. Front Genet. 2023;14:1109547. doi:https://doi.org/10.3389/fgene.2023.1109547

104.

Fajardo

Cirillo

. Understanding the spectrum of SLC2A1-associated disorders. Pediatr Neurol Briefs. 2017;31(2):4. doi:https://doi.org/10.15844/pedneurbriefs-31-2-1

105.

Leen

Klepper

Verbeek

, et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain. 2010;133(Pt 3):655-670. doi:https://doi.org/10.1093/brain/awp336

106.

Hully

Vuillaumier-Barrot

Le Bizec

, et al. From splitting GLUT1 deficiency syndromes to overlapping phenotypes. Eur J Med Genet. 2015;58(9):443-454. doi:https://doi.org/10.1016/j.ejmg.2015.06.007

107.

Heide

Jacquemont

Cheillan

, et al. GM3 synthase deficiency in non-Amish patients. Genet Med. 2022;24(2):492-498. doi:https://doi.org/10.1016/j.gim.2021.10.007

108.

Gordon-Lipkin

Cohen

Srivastava

Soares

Levey

Fatemi

. ST3GAL5-related disorders: a deficiency in ganglioside metabolism and a genetic cause of intellectual disability and choreoathetosis. J Child Neurol. 2018;33(13):825-831. doi:https://doi.org/10.1177/0883073818791099

109.

Spaull

Steel

Barwick

Prabhakar

Wakeling

Kurian

. STXBP1 stop-loss mutation associated with complex early onset movement disorder without epilepsy. Mov Disord Clin Pract. 2022;9(6):837-840. doi:https://doi.org/10.1002/mdc3.13509

110.

Xian

Parthasarathy

Ruggiero

, et al. Assessing the landscape of STXBP1-related disorders in 534 individuals. Brain. 2022;145(5):1668-1683. doi:https://doi.org/10.1093/brain/awab327

111.

Briere

Walker

High

, et al. A description of novel variants and review of phenotypic spectrum in UBA5-related early epileptic encephalopathy. Cold Spring Harb Mol Case Stud. 2021;7(3):a005827. doi:https://doi.org/10.1101/mcs.a005827

112.

Salpietro

Malintan

Llano-Rivas

, et al. Mutations in the neuronal vesicular SNARE VAMP2 affect synaptic membrane fusion and impair human neurodevelopment. Am J Hum Genet. 2019;104(4):721-730. doi:https://doi.org/10.1016/j.ajhg.2019.02.016

113.

Hübers

Huppertz

Wortmann

Kassubek

. Mutation of the WARS2 gene as the cause of a severe hyperkinetic movement disorder. Mov Disord Clin Pract. 2020;7(1):88-90. doi:https://doi.org/10.1002/mdc3.12855

114.

Saffari

Schröter

Garbade

, et al. Quantitative retrospective natural history modeling of WDR45-related developmental and epileptic encephalopathy – a systematic cross-sectional analysis of 160 published cases. Autophagy. 2022;18(7):1715-1727. doi:https://doi.org/10.1080/15548627.2021.1990671

115.

Abidi

Mignon-Ravix

Cacciagli

Girard

Milh

Villard

. Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient. Eur J Hum Genet. 2016;24(4):615-618. doi:https://doi.org/10.1038/ejhg.2015.159

116.

Oliver

Trivisano

Mandelstam

, et al. WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk. Epilepsia. 2023;64(5):1351-1367. doi:https://doi.org/10.1111/epi.17542

117.

AlMuhaizea

AlMass

AlHargan

, et al. Truncating mutations in YIF1B cause a progressive encephalopathy with various degrees of mixed movement disorder, microcephaly, and epilepsy. Acta Neuropathol. 2020;139(4):791-794. doi:https://doi.org/10.1007/s00401-020-02128-8

118.

Medico Salsench

Maroofian

Deng

, et al. Expanding the mutational landscape and clinical phenotype of the YIF1B related brain disorder. Brain. 2021;144(10):e85. doi:https://doi.org/10.1093/brain/awab297

119.

Christensen

Levy

Mohammadi

, et al. Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder. Clin Genet. 2022;102(2):98-109. doi:https://doi.org/10.1111/cge.14165

120.

Hack

Horning

Juroske Short

Schreiber

Watkins

Hammer

. Distinguishing loss-of-function and gain-of-function SCN8A variants using a random forest classification model trained on clinical features. Neurol Genet. 2023;9(3):e200060. doi:https://doi.org/10.1212/NXG.0000000000200060

121.

Schreiber

Tochen

Brown

, et al. A multi-disciplinary clinic for SCN8A-related epilepsy. Epilepsy Res. 2020;159:106261. doi:https://doi.org/10.1016/j.eplepsyres.2019.106261

122.

Johannesen

Liu

Koko

, et al. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications. Brain. 2022;145(9):2991-3009. doi:https://doi.org/10.1093/brain/awab321

123.

Conecker

Xia

Hecker

, et al. Global modified Delphi consensus on diagnosis, phenotypes, and treatment of SCN8A-related epilepsy and/or neurodevelopmental disorders. Epilepsia. 2024;65(8):2322-2338. doi:https://doi.org/10.1111/epi.17992

124.

Briere

Thiel

Sweetser

Koy

Axeen

GNAO1-related disorder. In: Adam

Feldman

Mirzaa

Pagon

Wallace

Amemiya

, eds. GeneReviews®. University of Washington, 2023. Accessed January 7, 2025. http://www.ncbi.nlm.nih.gov/books/NBK597155/

125.

Wirth

Garone

Kurian

, et al. Highlighting the dystonic phenotype related to GNAO1. Mov Disord. 2022;37(7):1547-1554. doi:https://doi.org/10.1002/mds.29074

126.

Marini

Conti

Mei

, et al. PRRT2 mMutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine. Neurology. 2012;79(21):2109-2114. doi:https://doi.org/10.1212/WNL.0b013e3182752ca2

127.

French

Friedman

. Appropriate selection of participants for clinical trials in epilepsy. Lancet Neurol. 2023;22(7):554-555. doi:https://doi.org/10.1016/S1474-4422(23)00202-8

128.

Moore

Amatya

Chu

Besterman

. Catatonia in autism and other neurodevelopmental disabilities: a state-of-the-art review. Npj Ment Health Res. 2022;1(1):12. doi:https://doi.org/10.1038/s44184-022-00012-9

129.

Devinsky

Kelley

Porter

Theodore

. Clinical and electroencephalographic features of simple partial seizures. Neurology. 1988;38(9):1347-1352. doi:https://doi.org/10.1212/wnl.38.9.1347

130.

Pacia

Ebersole

. Intracranial EEG substrates of scalp ictal patterns from temporal lobe foci. Epilepsia. 1997;38(6):642-654. doi:https://doi.org/10.1111/j.1528-1157.1997.tb01233.x

131.

Amin

Primiani

MacIver

Rivera-Cruz

Frontera

Benbadis

. Value of smartphone videos for diagnosis of seizures: Everyone owns half an epilepsy monitoring unit. Epilepsia. 2021;62(9):e135-e139. doi:https://doi.org/10.1111/epi.17001

132.

Hallett

DelRosso

Elble

, et al. Evaluation of movement and brain activity. Clin Neurophysiol. 2021;132(10):2608-2638. doi:https://doi.org/10.1016/j.clinph.2021.04.023

133.

Van Der Veen

Klamer

Elting

JWJ

Koelman

JHTM

Van Der Stouwe

AMM

Tijssen

MAJ

. The diagnostic value of clinical neurophysiology in hyperkinetic movement disorders: a systematic review. Parkinsonism Relat Disord. 2021;89:176-185. doi:https://doi.org/10.1016/j.parkreldis.2021.07.033

134.

Barry

Baird

Lascelles

Bunton

Hedderly

. Neurodevelopmental movement disorders—an update on childhood motor stereotypies. Dev Med Child Neurol. 2011;53(11):979-985. doi:https://doi.org/10.1111/j.1469-8749.2011.04058.x

135.

Hedrich

UBS

Lauxmann

Wolff

, et al. 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy. Sci Transl Med. 2021;13(609):eaaz4957. doi:https://doi.org/10.1126/scitranslmed.aaz4957

136.

Abou Chaar

Eranki

Stevens

, et al. Clinical, radiological and pathological features of a large American cohort of spinocerebellar ataxia (SCA27B). Ann Neurol. 2024;96(6):1092-1103. doi:https://doi.org/10.1002/ana.27060

137.

Koy

Cirak

Gonzalez

, et al. Deep brain stimulation is effective in pediatric patients with GNAO1 associated severe hyperkinesia. J Neurol Sci. 2018;391(1–2):31-39. doi:https://doi.org/10.1016/j.jns.2018.05.018

138.

Zaman

Straka

Pinto

, et al. Deep brain stimulation for medically refractory status dystonicus in UBA5-related disorder. Mov Disord. 2023;38(9):1757-1759. doi:https://doi.org/10.1002/mds.29428

139.

Caviness

. Treatment of myoclonus. Neurotherapeutics. 2014;11(1):188-200. doi:https://doi.org/10.1007/s13311-013-0216-3

140.

Keros

Heim

Hakami

, et al. Lisdexamfetamine therapy in paroxysmal non-kinesigenic dyskinesia associated with the KCNMA1-N999S variant. Mov Disord Clin Pract. 2022;9(2):229-235. doi:https://doi.org/10.1002/mdc3.13394