Action Induced Myoclonus in a 11-Year-Old Boy with Silver-Russell Syndrome

Silver-Russel syndrome (SRS) is a rare genetic disorder that is characterized by intrauterine and/or postnatal growth restriction and a unique craniofacial gestalt.¹ Hyperkinetic movement disorders have been reported in patients with SRS. In 2008, the first patient with SRS and myoclonus-dystonia was reported.² Up to eight SRS patients with movement disorder have been described to date.^2-8

An 11-year-old boy presented to the Movement Disorder Unit with learning difficulties, dysmorphic features, failure to thrive, and upper extremity action-induced myoclonus that impeded his writing ability. At the age of 5, he started with sudden, brief, involuntary jerking movements in the upper limbs. He had myoclonus during manual activities and did not worsen with fatigue or a febrile illness. Since the age of 10, he has exhibited motor (blinking) and phonic (throat clearing, rales, snorting, and bruxism) tics. Action-induced myoclonus manifested most prominently when he was writing, pouring water from one glass to another, and drinking with a spoon (Video 1 and Video 2). He did not show dystonia.

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Video 1

Patient at the age of 7 without treatment. (A) Brief, sudden movements of the left hand are observed at the start of writing, consistent with myoclonus. (B) Multiple myoclonus is observed in the upper extremities when water is transferred from one glass to another. To reduce this myoclonus, the patient performs a compensatory hyperextension of the upper extremities. (C) When attempting to drink water with a teaspoon, the patient displays myoclonus, which is most pronounced in the shoulders.

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Video 2

Patient at the age of 10 without treatment. (A) Action-induced upper limb myoclonus persists when writing. (B) Pouring water from one glass to another. (C) Attempting to drink water with a teaspoon. In addition, myoclonus of the upper extremities is observed when his hands are extended. He attempts to reduce the myoclonus by crossing his legs.

Due to the dysmorphic characteristics, the Face2Gene app suggested the diagnosis of SRS. Face2Gene is a framework for facial image analysis, DeepGestalt, that uses computer vision and deep-learning algorithms to quantify similarities to hundreds of syndromes.⁹ Consequently, a genetic dosage and methylation study of 11p15.5 (SALSA MLPA Probemix ME032 UPD7-UPD14) reveals maternal uniparental disomy of chromosome 7 (mUPD7), confirming the diagnosis of SRS.¹⁰ Since the diagnosis, Clonazepam (CZP) treatment has been indicated. The current dose of CZP (0.09 mg/kg/day) has been shown to reduce the intensity of myoclonus during some activities (such as writing), but not others (eg, eating, dressing, etc.).

SRS is clinically and genetically heterogeneous, making diagnosis difficult. Recognizing the phenotype of SRS is crucial because genetic testing must be directed towards the suspected diagnosis. Hypomethylation of the imprinted control region 1 (ICR1) at 11p15.5 causes SRS in 35–50% of patients, and maternal uniparental disomy (mUPD7) causes SRS in 7–10% of patients.¹¹ After excluding the changes in 11p15 and chromosome 7, further genetic tests may include CNV analysis, DNA methylation analysis at chromosome 14q32 and for other rare molecular anomalies.¹

Nine patients with SRS and movement disorders have been reported (Table 1).^2-8 The severity of myoclonus is variable and, in most cases, is triggered by intentional movement and less frequently by fatigue, illness, or stress. Dystonia, on the other hand, frequently has a focal distribution. Our patient is the only one described with motor and phonic tics. Although tics may be present in other genetic disorders, we believe that, given the high prevalence of tics in this age group, it is most likely a causal association in this case. On the other hand, behavioral problems like ADHD can be associated with SRS and that has been described previously.¹

TABLE 1. Summary of the reported cases of SRS and movement disorders

Reference	Sex, age (years) genetics	Myoclonus	Other movement disorders	Other clinical features	Treatment
Guettard, 2008	M, 36, mUPD7	Started at the age of 17. Generalized myoclonus characterized by “shock-like” jerks of all extremities and the face	Mild retrocolis, blepharospasm and writer's cramp	IUGR, feeding difficulties, PGR and premature puberty	No treatment described. Myoclonic jerks have a very good response to alcohol
Stark, 2010	F, 6, mUPD7	Generalized myoclonus, since an early age, becoming progressively worsening, with “shock-like” jerks of all extremities, triggered by intentional movements, and fatigue	No dystonia or ataxia	Feeding difficulties, PGR, hypercalcemia, Duane anomaly and clinodactyly	Excellent response to CZP. There was no response to VPA or LEV
Wakeling, 2010	NA, 14.9, NA	NA	Intermittent episodes of head shaking	NA	NA
	NA, 14.2, NA	NA	Slight tremor affecting extremities	NA	NA
	NA	Myoclonic jerk from 3 weeks to 1 year	NA	NA	NA
Augustine, 2013	F, 7, mUPD7	Since 5 years of age, multifocal myoclonus at rest, most prominent in the head, shoulders, torso, and upper extremities, triggered by intentional movement. Myoclonic jerks of all extremities and face, exacerbated by illness and fatigue, occasionally “shock-like” or accidental object throwing	Writer's cramp	IUGR, PGR, lower limb size asymmetry	No treatment
Sheridan, 2013	M, 24, mUPD7	Myoclonic jerking of upper extremities triggered by intentional movements	Transient dystonic posturing of upper extremities	IUGR, short stature, clinodactyly, arm length asymmetry, café au lait spots, panic attacks	CZP significantly reduced the symptoms. Alcohol reduces the frequency of movement disorders
Shpiner, 2019	F, 19, mUPD7	Action myoclonus of all extremities and head since 13 years of age	Dystonic posturing of all extremities, neck and trunk	IUGR, short arms, clinodactyly, café au lait spots	TPM, escitalopram, risperidone, GBP, propranolol, and tetrabenazine did not help
Martins, 2020	F, 14, mUPD7	Action and stimulus-induced (sound) myoclonus at 6 years of age, progressive and interfered with daily tasks, particularly eating and writing. Multifocal myoclonus at rest. More prominent myoclonus in the head, shoulders, and upper extremities	Writer's cramp, dystonic posture of the forearm, and elevation of the right shoulder, slight dystonic postures evident in the neck with right torticollis and right upper arm during gait	IUGR, PGR, gray-bluish sclera, ADHD, obsessive and depressive symptoms	CZP provides partial relief of myoclonus and focal dystonia. GH, risperidone, methylphenidate, and sertraline

• Abbreviations: M, male; F, female; NA, not available; mUPD7, maternal uniparental disomy of chromosome 7; IUGR, intrauterine growth restriction; PGR, postnatal growth restriction; ADHD, attention deficit hyperactivity disorder; VPA, valproic acid; LEV, levetiracetam; CZP, clonazepam; TPM, topiramate; GBP, gabapentin.

Pathophysiologically, in mUPD7, maternal imprinting leads to functional absence of SGCE gene expression, likely to account for the movement disorder in SRS.¹ CZP improves completely or partially myoclonus and dystonia in three patients, while alcohol consumption improves myoclonus in two patients. Taking into account the pathophysiology of the disorder, zonisamide may provide relief for motor symptoms, as was demonstrated for SGCE-related disorders.¹² Other treatments (VPA, LEV, TPM, gabapentin, escitalopram, methylphenidate, propranolol, risperidone, sertraline) have not been helpful in controlling myoclonus in these patients (Table 1).

In conclusion, symptoms of SRS may include movement disorders such as myoclonus and dystonia. Patients with myoclonus, growth retardation, and/or the distinctive gestalt should raise suspicions of SRS. Further research regarding clinical presentation and treatment is required.

Acknowledgments

The authors would like to thank the patient and his family.

Author Roles

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

L. N-F.: 1C, 3A

D. G-N.: 1C, 3B

H. G.-M.: 1C, 3B

L. M.: 1C, 3B

J. D. O-E.: 1A, 1B, 1C, 3B

Disclosures

Ethical Compliance Statement: The legal guardians gave their written consent to the recording of the patient for publication, and the study received ethical approval by the Ethics Committee. 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.

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

Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.