Monoallelic pathogenic variants in GRIA2 (OMIM *138247) that encodes inotropic glutamate receptor subunit 2 (GluR2) causes neurodevelopmental disorder (NDD) with language impairment and behavioral abnormalities (NEDLIB) (OMIM#618917). 1 , 2 The clinical manifestations encompass intellectual disability (ID), global developmental delay (GDD), autism spectrum disorders (ASD), lack of meaningful speech, Rett‐like phenotype and epilepsy/epileptic encephalopathy. Movement disorders previously described in this entity are motor stereotypies, ataxia and dyspraxia. 2 However, non‐epileptic myoclonus, hyperekplexia, oculogyric crisis, chorea, dyskinesia, and dystonia have been variably reported in disorders of other glutamate receptors. 3 , 4 We report a patient with pathogenic variant in GRIA2 presenting as GDD, chorea, dystonia and stereotypies thereby extending the repertoire of genes causing infantile onset movement disorders with NDD.
Three‐year‐old boy, only child of non‐consanguineous parentage, delivered at term by emergency caesarean section (indication—antepartum hemorrhage) without any post‐natal complications, presented with GDD, ASD and hyperkinetic movements. He could sit independently and has no meaningful speech or social interactions. Parents noticed involuntary movements of the extremities from age 10 months which disappears in sleep. He had a single episode of brief unprovoked generalized tonic seizure at age 3 years and was not on regular antiepileptic drugs. Family history was unremarkable. On examination, the child had macrocephaly (51 cm), facial dysmorphism (frontal bossing, dolichocephaly, low set ears, thin upper lip, broad nasal bridge and anti‐mongoloid slant), short neck, club foot, overriding toes (Video 1 segment 1a) and profound hypotonia. He was hyperactive and irritable without any eye contact or emotional reciprocity.
VIDEO 1.
Segment 1a: Dysmorphic facies—macrocephaly, frontal bossing, dolichocephaly, low set ears, thin upper lip, short neck, broad nasal bridge, anti‐mongoloid slant, club foot and overriding toes. Repetitive purposeless, organized hand movements (hand flapping) and side to side head movements which were distractible suggestive of stereotypy. Video segment 1 b: Non‐patterned, random involuntary movements flowing from one body part to another suggestive of generalized chorea. Violent movements with increased amplitude were seen at times indicating ballismus. Video segment 1 c: Reduction in involuntary movements after treatment with clonazepam and haloperidol and only repetitive hand movements were seen 4 months later.
The child had non‐patterned, random involuntary movements flowing from one body part to another indicating generalized chorea. These movements would frequently become violent with large amplitude attaining a ballistic character (Video 1 segment 1b). He also had dystonic posturing of the fingers and bilateral striatal toe. Clinical exome sequencing covering 6675 genes (included genes associated with NDDs, epilepsy and movement disorders) revealed a pathogenic heterozygous missense variant, C1932G (p.Phe644Leu) in GRIA2 (NM_000826.6:c.1932C>G) (Fig. 1). His mother did not have this variant and the paternal sample was not available. No other abnormal variants in genes causing movement disorders were detected.
Figure 1.
Pedigree chart (A) and Sanger sequencing of mother (B) and child (C) showing exome sequencing in GRIA2 based on forward primer. The nucleotide base cytosine (C) is replaced by guanine (G) at position 1932 (arrow in C).
Magnetic resonance imaging (MRI) of brain and electroencephalogram was normal. He had significant improvement in the choreo‐ballistic movements with clonazepam (1.5 mg/day) and haloperidol (0.75 mg/day) (Video 1 segment 1c). Repetitive purposeless, stereotyped hand movements and side‐to‐side head movements (distractible) were noticed on follow‐up (Video 1 segment 1c) suggesting motor stereotypy.
Epileptic‐dyskinetic encephalopathy (EDE) is a recently described entity characterized by early onset epileptic encephalopathy with an associated movement disorder. Many genetic (SCN1A, SCN2A, SCN8A, KCNT1, GABRA1, GNAO1, FOXG1, GRIN1, SLC13A5, ARX, FRRS1L, and TBC1D24) and acquired conditions can cause EDE. 3 However, genetic disorders involving ADCY5, KMT2B, ATP1A3, GPR88 and PDE10A can have NDD with movement disorders but without refractory epilepsy. 5 Hence we propose the term “developmental dyskinetic encephalopathy (DDE)” for early onset movement disorders associated with developmental encephalopathy/NDD and we would like to add GRIA2 to the list.
Here we describe a case of NEDLIB with hyperkinetic movement disorders (chorea and dystonia) caused by pathogenic variant in GRIA2. GRIA2‐related disorders are rare and the phenotypic spectrum is highly variable. The clinical description includes ID, GDD, ASD, Rett‐like phenotype, ataxia, dyspraxia, hyperventilation episodes, abnormal sleep rhythm, progressive microcephaly and progressive cerebral and cerebellar atrophy with or without white matter changes. 2 The GluR2 accounts for the majority of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPAR) in brain, thereby playing a vital role in the fast‐excitatory glutamatergic transmission, synaptic communication and plasticity. 6 , 7 This subunit also regulates the Ca2+ penetration and voltage rectification of AMPAR, causing abnormal excitation of the basal ganglia circuits. 8 These pathophysiological mechanisms may contribute to the various clinical manifestations described above. The movement disorders previously reported in GRIA2‐related disorders were mainly stereotypies, ataxia and dyspraxia as part of Rett phenotype but our patient had a combination of movement disorders, including chorea, and dystonia which were not yet described. The stereotypies were prominent when the choreo‐ballistic movements were suppressed by medications. Chorea and dystonia are reported in association with other ionotropic glutamate receptors such as GRIA4, GRIN1, GRIN2B and GRIN2D and also with other EDE, particularly GNAO1, FOXG1 and SCN8A. 3 , 8 , 9
A recent study of 28 unrelated patients with GRIA2‐related disorders, heterozygous missense variants were causative in the majority. C1932G variant is located in the ligand‐gated ion channel region of GluR2 and was reported in an 8‐year‐old girl from Korea who presented with severe hypotonia, GDD, severe ID and ASD but without any movement disorder. 2
Our case expands the list of genetic DDE spectrum and is expected to further expand significantly with the wide availability of genetic assays and deep endophenotyping. No definitive treatment is available at present, but the knowledge about these rare disorders could foster further research in the molecular mechanisms and precision medicine.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Data Analysis: A. Design B. Execution C. Review and critique; (3) Manuscript preparation: A. Writing of the first draft B. Review and critique.
A.V.: 1A, 1B, 1C, 3A
M.U.: 1B, 3B
K.A.V.: 3B
S.S.: 1A, 1B, 1C, 3B
S.K.: 1C, 3A, 3B
Disclosures
Ethical Compliance Statement: Written informed consent was taken from the patient. The authors confirm that the approval of the institutional review board was not required for this work. 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 conflicts of interest relevant to this work.
Financial Disclosures for Previous 12 Months: The authors declare that there are no additional disclosures to report.
Acknowledgments
Authors are thankful for Ms Glenda Mary's contribution in acquisition of patient's video. Authors are also grateful to the parents who have consented to the publication of their child's clinical details.
Relevant disclosures and conflict of interest are listed at the end of this article.
References
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