GRIN2A

Samantha Turner

Angela Mayes

Andrea Verhoeven

Simone Mandelstam

Angela Morgan

Ingrid Scheffer

Objective:

To delineate the specific speech deficits in individuals with epilepsy-aphasia syndromes associated with mutations in the glutamate receptor subunit gene GRIN2A.

Methods:

We analyzed the speech phenotype associated with GRIN2A mutations in 11 individuals, aged 16 to 64 years, from 3 families. Standardized clinical speech assessments and perceptual analyses of conversational samples were conducted.

Results:

Individuals showed a characteristic phenotype of dysarthria and dyspraxia with lifelong impact on speech intelligibility in some. Speech was typified by imprecise articulation (11/11, 100%), impaired pitch (monopitch 10/11, 91%) and prosody (stress errors 7/11, 64%), and hypernasality (7/11, 64%). Oral motor impairments and poor performance on maximum vowel duration (8/11, 73%) and repetition of monosyllables (10/11, 91%) and trisyllables (7/11, 64%) supported conversational speech findings. The speech phenotype was present in one individual who did not have seizures.

Conclusions:

Distinctive features of dysarthria and dyspraxia are found in individuals with GRIN2A mutations, often in the setting of epilepsy-aphasia syndromes; dysarthria has not been previously recognized in these disorders. Of note, the speech phenotype may occur in the absence of a seizure disorder, reinforcing an important role for GRIN2A in motor speech function. Our findings highlight the need for precise clinical speech assessment and intervention in this group. By understanding the mechanisms involved in GRIN2A disorders, targeted therapy may be designed to improve chronic lifelong deficits in intelligibility.

Supplementary Material

Video:

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From the Department of Paediatrics (S.J.T., S.A.M., A.T.M., I.E.S.), The University of Melbourne, The Royal Children's Hospital, Parkville; Language and Literacy Group (A.K.M., A.T.M.), Population Health Theme, Murdoch Childrens Research Institute, Parkville; Speech Pathology Department (A.V.), The Royal Children's Hospital, Parkville; Department of Radiology (S.A.M.), The University of Melbourne, Parkville; Epilepsy Research Centre (I.E.S.), Department of Medicine, The University of Melbourne, Austin Health, Melbourne; and Florey Institute of Neuroscience and Mental Health (S.A.M., I.E.S.), Melbourne, Australia.

^{Corresponding author.}

Correspondence to Prof. Scheffer: ua.ude.bleminu@reffehcs

^{These authors contributed equally to this work.}

Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Correspondence to Prof. Scheffer: ua.ude.bleminu@reffehcsGo to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Received 2014 May 5; Accepted 2014 Oct 10.

Abstract

Objective:

To delineate the specific speech deficits in individuals with epilepsy-aphasia syndromes associated with mutations in the glutamate receptor subunit gene GRIN2A.

Methods:

Results:

Conclusions:

Abstract

Language and speech impairment are integral to the epilepsy-aphasia syndromes (EAS). At the severe end of the epilepsy-aphasia spectrum lie two disorders associated with regression and continuous spike and wave during sleep, defined by bilaterally synchronous discharges occupying >85% of slow-wave sleep. Language regression, typically with verbal auditory agnosia, is characteristic of Landau-Kleffner syndrome, often associated with treatable focal seizures. Global regression is usual in epileptic encephalopathy with continuous spike and wave during sleep (ECSWS) associated with multiple seizure types. Next in the continuum is intermediate epilepsy-aphasia disorder (IEAD) with abnormal cognitive development or regression, with or without seizures, with epileptiform activity occupying <85% sleep.¹ At the mild end, impaired language and literacy skills are described in benign childhood epilepsy with centrotemporal spikes.² Ictal oromotor and speech impairment as well as interictal speech sound disorder have also been reported.³,⁴ Speech dyspraxia occurs in rare families with rolandic epilepsy and cognitive impairment.⁵^–⁷ Impairment in language (understanding and use of words) is central to the EAS, yet speech (how speech sounds are produced or articulated) has not been carefully investigated.

Inherited and de novo mutations in GRIN2A, encoding the NR2A subunit of the glutamate NMDA receptor, are found in 9% to 20% of probands with EAS.⁸^–¹⁰ We identified mutations in GRIN2A in 4 of 519 patients with epileptic encephalopathies of unknown cause and found all 4 patients had EAS disorders.⁸ This finding was replicated in French and German studies.⁹,¹⁰ Here, we studied the speech phenotype of 3 families with EAS associated with GRIN2A mutations.

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ACKNOWLEDGMENT

The authors sincerely thank the families for their participation in this study. The authors thank Associate Professor Lynette Sadleir for referring a family and Professor Susan Gathercole for use of the Nonword Memory Test. The authors are grateful to Professor Eliane Roulet-Perez for helpful advice regarding the manuscript.

ACKNOWLEDGMENT

GLOSSARY

ADRESD	autosomal dominant rolandic epilepsy with speech dyspraxia
EAS	epilepsy-aphasia syndromes
ECSWS	epileptic encephalopathy with continuous spike and wave during sleep
GRIN2A	glutamate receptor, ionotropic, N-methyl d-aspartate 2A
IEAD	intermediate epilepsy-aphasia disorder

GLOSSARY

Footnotes

Supplemental data at Neurology.org

Footnotes

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