Neurophysiological Analysis of Cortical Myoclonic Tremor and Excessive Startle in ARHGEF9 Deficiency

Jerky movements are a heterogeneous group of rapid and involuntary hyperkinetic movement disorders that include myoclonus, startle, and tics. ¹ Because of their nature, clinical evaluation is challenging even for expert clinicians, and proper recognition/classification often requires a neurophysiological assessment to guide diagnosis and treatment. ¹

ARHGEF9 encodes collybistin, a Rho‐like GTPase, involved in the organization and stabilization of gephyrin‐dependent glycine and GABA type A receptors at the post‐synaptic cleft. ² ARHGEF9 deficiency has been associated with neurodevelopmental disorders, epilepsy, behavioral problems, and sleep disorders. ²

Here, we describe the clinical and neurophysiological phenotype of a patient with intellectual disability, cortical myoclonic tremor, and excessive startle due to a de novo variant in ARHGEF9.

A 30‐year‐old man was born from non‐consanguineous healthy parents. He could walk at 20 months and speak his first words at 36 months. At 15 months, a febrile seizure and at 8 years a single generalized motor seizure occurred, with electroencephalography (EEG) revealing anterior poly‐spike‐waves complexes. Since then, he has also manifested frequent generalized jerks, eventually leading to falls, which were at first interpreted as epileptic and were reduced by clobazam and valproate treatment (up to 40 mg and 1500 mg per day, respectively).

From adolescence, the patient also developed an action‐induced jerky‐tremor of his hands.

Neurological examination at 30 showed moderate intellectual disability (Wechsler Intelligence Scale for Children‐Revised total intelligence quotient = 40), mild bradykinesia, a cautious, slightly wide‐based gait, clumsiness, and a high frequency, low amplitude, distal jerky action tremor (Video 1). In addition, generalized jerks were observed on examination evoked by unexpected auditory and somatosensory stimuli.

Video 1.

Segment 1, Postural tremor: A slightly irregular, low‐amplitude, high frequency, oscillating movement is observed when the patients is asked to maintain his arms outstretched. Tremor is more evident when the patient is asked to keep hands outstretched (left hand seems more affected than the contralateral). Segment 2, Kinetic tremor: During action, a tremor with the same characteristics is observed during a movement. Tremor characteristics do not change throughout the whole movement.

A next‐generation sequencing epilepsy panel disclosed a de novo c.1300G>C [p.(Gly434Arg)] likely pathogenic variant in ARHGEF9.

A neurophysiological examination was performed, including EEG–electromyography (EMG)‐video registration, jerk‐locked back averaging (JLBA), cortico‐muscular coherence (CMC) analysis, phase analysis and estimated time conduction, and somatosensory‐evoked potentials (SSEP). EEG–EMG data analysis was performed with Brainstorm, ³ which is documented and freely available for download online under the GNU general public license (http://neuroimage.usc.edu/brainstorm). For details on the recording techniques and analysis, see Appendix S1.

EMG polygraphy of jerky‐tremor revealed a synchronous agonist–antagonist activity with short EMG bursts (20–60 ms) (Fig. S1 in Appendix S1). EMG frequency analysis revealed a slightly broad main peak at 8 Hz. JLBA showed a transient EEG waveform over the contralateral central area, and CMC analysis resulted in a highly significant coherence peak in the β and γ bands (13–38 Hz) (Fig. 1). The phase analysis revealed that EEG preceded EMG signal, with an estimated time conduction of 11 ms. SSEP disclosed an enlarged N25‐P35 interpeak amplitude of 8.12 μV.

Fig. 1.

(A) Show a jerk‐locked back averaging of 140 electromyography (EMG) discharges: on the left part of (A), electroencephalography (EEG) signals of central areas (C3, Cz, C4) and EMG signals (EMG1+ = left extensor carpi) is shown. An EEG wave of around 5 μV can be observed on C4, with a maximal positive peak around 24 ms before the onset of the EMG discharge of the extensor carpi radialis (EMG1+, rectified signal). No recognizable waveform is seen on Cz and C3 signals. The right part of (A) show the scalp EEG voltage map of the 50 ms preceding myoclonus. Red color indicates a positive voltage, white color indicates an isoelectric voltage, and blue color a negative voltage. At −26 ms, a positive deflection can be observed on C4 area and on 0 ms negative polarity is maximal over C4 and P4 area. (B) Show the power spectrum of cortical myoclonic tremor, which result in a slight broad main 8 Hz peak. (C) Show the CMC analysis result: a broad and significant CMC is seen in the β and the γ‐band from 13 to 38 Hz. Statistical limit is set at 95% and is represented by the blue line set at 0.098.

The generalized jerks showed a cranio‐caudal EMG activation triggered by unexpected auditory and somatosensory stimulation. EMG bursts were longer than 150 ms, not preceded by epileptiform activity, with a slow cranio‐caudal EMG activation pattern (Fig. S2 in Appendix S1). Pharmacological treatment was modified and clobazam was replaced by clonazepam (2 mg/day) with better control of startle episodes with falls.

Through neurophysiological evaluation, we have described a patient with ARHGEF9 deficiency with cortical myoclonic tremor and exaggerated startle syndrome, expanding the ARHGEF9 clinical phenotype.

Cortical myoclonic tremor or rhythmic cortical myoclonus, is a rhythmic form of cortical myoclonus, characterized by high‐frequency and low‐amplitude distal jerks activated by action. ⁴

Cortical myoclonic tremor fulfills the neurophysiological criteria of cortical myoclonus, but has a certain degree of rhythmicity (although the degree of regularity is a matter of debate), as observed in this patient (Table S1 in Appendix S1). ⁴ , ⁵ , ⁶

Historically, genetic causes of cortical myoclonic tremor are represented by familial cortical myoclonic tremor and epilepsy (FCMTE). ⁴ However, the association of cortical myoclonic tremor and intellectual disability is rare in FCMTE (possibly except for FCMTE 2) and may lead to consider specific neurodevelopmental disorders such as Angelman Syndrome, or DHDDS and NUS1 deficiency, in which this association has been recently described. ⁴ , ⁷ , ⁸ , ⁹

Cortical myoclonic tremor has not been associated with ARHGEF9 deficiency yet, and myoclonus has only been reported within seizures. ¹⁰

Abnormal interactions between hyperexcitable cortical areas and subcortical structures such as the cerebellum have been hypothesized to underlie the pathophysiology of cortical myoclonic tremor. ⁴ In ARHGEF9, neuronal hyperexcitability is likely related to impaired GABAergic and glycinergic neurotransmission. ²

Evoked and non‐habituating generalized jerks with slow cranio‐caudal muscular recruiting pattern are compatible with an exaggerated startle reflex. Exaggerated startle, when accompanied by muscular stiffness after startle or in the neonatal period is one of the main features of hyperekplexia, a neurological syndrome typically associated with inherited glycinergic neurotransmission dysfunction. ¹¹ In ARHGEF9 deficiency, where glycinergic neurotransmission is predicted to be impaired at a post‐synaptic level, ² hyperekplexia was described in the first patient reported. ¹² However, diagnostic criteria for hyperekplexia were not fulfilled in our patient, who did not exhibit muscular stiffness. ¹¹

This case demonstrates how neurophysiological evaluation can expand the limited clinical knowledge of rare genetic movement disorders by providing a more precise and objective phenotypical characterization, which may have relevant diagnostic and therapeutic implications.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Data Acquisition and Analysis: A. Acquisition, B. Analysis; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

L.P.: 1A, 1B, 1C, 2A, 2B, 3A, 3B

C.G.: 1B, 1C, 2A, 3B

M.N.: 1B, 1C, 2A, 3B

D.M.: 2B, 3B

F.P.: 2B, 3B

M.D.K.T.: 3B

R.G.: 2B, 3B

V.L.: 2B, 3B

S.G.: 1A, 1B, 1C, 3A, 3B

Disclosures

Ethical Compliance Statement: Written informed consent for offline and online video distribution of the video material was obtained from parents and is available upon request. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work.

Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: M.A.J.T. reports grants from the Netherlands Organization for Health Research and Development ZonMW Topsubsidie (91218013) and ZonMW Program Translational Research (40‐44600‐98‐323). She also received a European Fund for Regional Development from the European Union (01492947) and an European Joint Programme on Rare Diseases Networking Support Scheme. She has received funding from the province of Friesland, the Stichting Wetenschapsfonds Dystonie, and unrestricted grants from Actelion, Ipsen, and Merz. Other authors have nothing to declare.

Supporting information

Appendix S1. Supplementary material.