Movement Disorders in <scp><i>GRIA2</i></scp>‐Related Disorder – Expanding the Genetic Spectrum of Developmental Dyskinetic Encephalopathy

Vijayaraghavan, Asish; Urulangodi, Madhusoodanan; Ajit Valaparambil, Karthika; Sundaram, Soumya; Krishnan, Syam

doi:10.1002/mdc3.13797

Cited by 4 publications

(1 citation statement)

References 8 publications

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“…The pathogenic variants in glutamate ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, such as GRIA2 and GRIA3 genes, have also been associated with movement disorders. Particularly, chorea or choreoathetoid movements with an onset within the first year of age have been described in patients with GRIA2 pathogenic variants [ 73 , 78 ]. GRIA2 -related encephalopathy is characterized by early-onset developmental and epileptic encephalopathy, complex movement disorders (including chorea, dystonia, and dyskinesia) with or without epilepsy, varying combinations of tone abnormalities at birth, and neurobehavioral and/or psychiatric disorders [ 73 ].…”

Section: Chorea and Epileptic–dyskinetic Encephalopathymentioning

confidence: 99%

Exploring the Genetic Landscape of Chorea in Infancy and Early Childhood: Implications for Diagnosis and Treatment

Spoto,

Ceraolo,

Butera

et al. 2024

CIMB

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Chorea is a hyperkinetic movement disorder frequently observed in the pediatric population, and, due to advancements in genetic techniques, an increasing number of genes have been associated with this disorder. In genetic conditions, chorea may be the primary feature of the disorder, or be part of a more complex phenotype characterized by epileptic encephalopathy or a multisystemic syndrome. Moreover, it can appear as a persistent disorder (chronic chorea) or have an episodic course (paroxysmal chorea). Managing chorea in childhood presents challenges due to its varied clinical presentation, often involving a spectrum of hyperkinetic movement disorders alongside neuropsychiatric and multisystemic manifestations. Furthermore, during infancy and early childhood, transient motor phenomena resembling chorea occurring due to the rapid nervous system development during this period can complicate the diagnosis. This review aims to provide an overview of the main genetic causes of pediatric chorea that may manifest during infancy and early childhood, focusing on peculiarities that can aid in differential diagnosis among different phenotypes and discussing possible treatment options.

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Section: Chorea and Epileptic–dyskinetic Encephalopathymentioning

confidence: 99%

Exploring the Genetic Landscape of Chorea in Infancy and Early Childhood: Implications for Diagnosis and Treatment

Spoto,

Ceraolo,

Butera

et al. 2024

CIMB

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Recent advances in non-Huntington's disease choreas

Cincotta,

Walker

2024

Parkinsonism & Related Disorders

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Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes

Rinaldi,

Bayat,

Zachariassen

et al. 2023

Brain

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AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1-GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally. Here, we evaluated the impact on AMPAR function of one frameshift and 43 rare missense GRIA3 variants identified in patients with NDD by electrophysiological assays. Thirty-one variants alter receptor function and show loss-of-function (LoF) or gain-of-function (GoF) properties, whereas 13 appeared neutral. We collected detailed clinical data from 25 patients (from 23 families) harbouring 17 of these variants. All patients had global developmental impairment, mostly moderate (9/25) or severe (12/25). Twelve patients had seizures, including focal motor (6/12), unknown onset motor (4/12), focal impaired awareness (1/12), (atypical) absence (2/12), myoclonic (5/12), and generalized tonic-clonic (1/12) or atonic (1/12) seizures. The epilepsy syndrome was classified as developmental and epileptic encephalopathy in eight patients, developmental encephalopathy without seizures in 13 patients, and intellectual disability with epilepsy in four patients. Limb muscular hypotonia was reported in 13/25, and hypertonia in 10/25. Movement disorders were reported in 14/25, with hyperekplexia or non-epileptic erratic myoclonus being the most prevalent feature (8/25). Correlating receptor functional phenotype with clinical features revealed clinical features for GRIA3-associated NDDs and distinct NDD phenotypes for LoF and GoF variants. GoF variants were associated with more severe outcomes: patients were younger at the time of seizure onset (median age one month), hypertonic, and more often had movement disorders, including hyperekplexia. Patients with LoF variants were older at the time of seizure onset (median age 16 months), hypotonic, and had sleeping disturbances. LoF and GoF variants were disease-causing in both sexes but affected males often carried de novo or hemizygous LoF variants inherited from healthy mothers, whereas all but one affected females had de novo heterozygous GoF variants.

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Movement Disorders in GRIA2‐Related Disorder – Expanding the Genetic Spectrum of Developmental Dyskinetic Encephalopathy

Cited by 4 publications

References 8 publications

Exploring the Genetic Landscape of Chorea in Infancy and Early Childhood: Implications for Diagnosis and Treatment

Exploring the Genetic Landscape of Chorea in Infancy and Early Childhood: Implications for Diagnosis and Treatment

Recent advances in non-Huntington's disease choreas

Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes

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