Clinical Description
The clinical spectrum of GRIN2A-related speech disorders and epilepsy is broad and may vary within a family (e.g., from mild isolated speech impairment to rolandic epilepsy with speech dyspraxia) [Turner et al 2015b].
Disease progression is variable: some individuals have normal development and spontaneous remission of seizures, while others develop medically refractory epilepsy and severe developmental impairment. Language and/or global developmental regression often occurs in those with the more severe epilepsy-aphasia disorders.
Speech and language were impaired in 100% of individuals in a study of the speech manifestations of GRIN2A-related disorders [Turner et al 2015a]. Abnormalities included dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression.
Mildly affected individuals may display subtly impaired intelligibility of conversational speech, most commonly characterized by hypernasality, imprecise consonant production, and impaired pitch and prosody [Turner et al 2015a].
Intellectual disability, observed in 38%-67% of affected individuals, ranges from mild to severe [Carvill et al 2013, Lemke et al 2013].
Epilepsy occurs in approximately 90% of individuals [Lemke et al 2013, Lesca et al 2013].
Seizure onset is typically between ages three and six years (mean 4.6 years), although individuals may present from infancy to adolescence [Endele et al 2010, Lesca et al 2012, Carvill et al 2013, Lemke et al 2013, Venkateswaran et al 2014].
The most common seizure type overall is focal seizures. These are often associated with an aura of perioral paresthesia, and frequently evolve to generalized tonic-clonic convulsions. The predominant seizure type(s) in a given individual vary depending on which clinical syndrome is present.
The most common GRIN2A-related speech disorder and epilepsy is epilepsy-aphasia syndromes (EAS), a spectrum of disorders that includes: Landau-Kleffner syndrome (LKS); epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS); childhood epilepsy with centrotemporal spikes (CECTS); atypical childhood epilepsy with centrotemporal spikes (ACECTS); and autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD) [Tsai et al 2013]. Other epilepsy phenotypes can be broadly divided into infantile-onset epileptic encephalopathy and unclassified childhood epilepsy.
Landau-Kleffner syndrome (LKS) [Landau & Kleffner 1957, Wang et al 2006, Hughes 2011]
Onset in childhood (peak age range 5-8 years)
Acquired aphasia, with auditory agnosia (impaired recognition of sounds) frequently described as the earliest feature
Seizures in approximately 70% of cases, most commonly atypical absence, with focal motor, atonic, and focal seizures evolving to bilateral tonic-clonic seizures also described
Developmental regression limited to language domains
Normal development prior to onset of aphasia or
isolated language impairment
EEG showing frequent, sleep-activated, bilateral sharp and slow wave discharges (centrotemporal or perisylvian field), eventually evolving to continuous spike-and-wave in sleep (CSWS)
Epileptic encephalopathy with continuous spike-and-wave during sleep
(ECSWS) [Van Bogaert 2013]
Onset in childhood (peak age range 4-5 years)
Seizures in approximately 80% of cases, most commonly hemiclonic or generalized tonic-clonic in sleep and atypical absence while awake
Global developmental regression (as distinct from the pure language regression of LKS)
EEG showing near-continuous (>85% of recording), bilateral sharp and slow wave discharges in slow wave sleep (i.e., CSWS)
Childhood epilepsy with centrotemporal spikes (CECTS) [Guerrini & Pellacani 2012]
Onset is in childhood (peak age range 5-8 years; range 3-13 years).
Seizures have a characteristic aura of perioral paresthesia which may involve the tongue, cheeks, and mouth. There is often speech arrest and a motor component involving the oropharyngeal muscles, unilateral facial tonic or clonic activity, and (less commonly) an upper limb. The majority of events occur during sleep, and classically involve drooling. Bilateral tonic-clonic seizures are also commonly observed.
Seizure frequency is low: half of patients have fewer than six seizures in their lifetime.
Epilepsy follows a self-limited course with duration less than five years in the majority of individuals.
EEG background is normal and shows focal epileptiform discharges from the centrotemporal regions, potentiated in sleep. In 40% of affected individuals, the centrotemporal discharges are bilateral and independent.
Atypical childhood epilepsy with centrotemporal spikes (ACECTS) [Aicardi & Chevrie 1982]
Epilepsy course is similar to CECTS with onset and spontaneous remission occurring in childhood.
Seizures are different from those seen in CECTS, and include negative myoclonus and atypical absence seizures.
Developmental regression or slowing is coincident with seizure onset; however, long-term developmental outcome may be normal.
EEG is similar to CECTS in that focal centrotemporal discharges potentiated in sleep are seen; however, focal or diffuse background slowing is also often present.
Autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD) [Scheffer 2000, Turner et al 2015b]
Seizure characteristics and epilepsy course are identical to CECTS in most family members. One individual had an encephalopathic presentation associated with cognitive regression.
Affected individuals have oral and speech dyspraxia with dysarthria.
Individuals may have
isolated speech dysfunction without seizures.
Cognitive function is usually within the normal range.
Infantile-onset epileptic encephalopathy [Endele et al 2010, Venkateswaran et al 2014, Yuan et al 2014, Allen et al 2016]
Multiple different seizure types may be present, including tonic seizures, focal impaired awareness with evolution to bilateral seizures, infantile spasms, and myoclonic seizures.
Severe intellectual disability was seen in the three individuals reported.
EEG findings vary in the few reported cases and include background slowing, hypsarrhythmia, and focal spikes.
Brain MRI may show bilateral parenchymal volume loss and thin corpus callosum.
Unclassified childhood-onset epilepsy [Reutlinger et al 2010, DeVries & Patel 2013]
Focal seizures are the most commonly seen; myoclonic, eyelid myoclonia, and atypical absence have also been reported.
Development ranges from normal to severely impaired.
EEG usually shows multifocal epileptiform discharges.
Contiguous gene deletions.
Reutlinger et al [2010] described three individuals with 16p13 deletions involving multiple genes and complete or partial heterozygous deletion of GRIN2A. All had mild dysmorphic features, intellectual disability, and epilepsy involving the rolandic region.
EEG most commonly shows bilateral epileptiform discharges (usually spike or spike-wave) in the central-temporal or temporal-parietal regions which may be independent or bilaterally synchronous. These abnormalities become more frequent in sleep, often evolving to continuous spike-and-wave in sleep (CSWS). CSWS is defined as near-continuous (>85% of non-REM sleep recording) bilateral sharp and slow wave discharges in slow wave sleep. CECTS is classically associated with a horizontal dipole; tangential dipole across the Sylvian fissure has been reported in LKS [Morrell et al 1995, Dalla Bernardina et al 2005].
Brain imaging. Brain MRI is normal in the vast majority. Severely affected individuals may have enlargement of extra-axial spaces and a thin corpus callosum [Reutlinger et al 2010, Pierson et al 2014, Venkateswaran et al 2014, Yuan et al 2014]. One individual with focal cortical dysplasia was reported [Lesca et al 2013].
Positron emission tomography (PET) showing diffuse cortical hypometabolism was reported in one individual [DeVries & Patel 2013].
Nomenclature
Landau-Kleffner syndrome (LKS) has also been referred to as epileptic acquired aphasia.
Epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS) has also been referred to as continuous spike-and-wave during slow-wave sleep (CSWS) and electrical status epilepticus during sleep (ESES).
Childhood epilepsy with centrotemporal spikes (CECTS) has been commonly referred to as benign epilepsy with centrotemporal spikes (BECTS) and benign rolandic epilepsy of childhood (BREC).
Atypical childhood epilepsy with centrotemporal spikes (ACECTS) has been known as atypical benign partial epilepsy (ABPE), pseudo-Lennox syndrome, and atonic-benign childhood epilepsy with centrotemporal spikes.