The cognitive phenotype of juvenile absence epilepsy and its heritability: an investigation of patients and unaffected siblings

ObjectiveThe cognitive profile of juvenile absence epilepsy (JAE) remains uncharacterized. This study aimed to: (i) elucidate the neuropsychological profile of JAE; (ii) identify familial cognitive traits, by investigating unaffected JAE siblings; (iii) determine whether cognitive traits across the idiopathic generalized epilepsy (IGE) spectrum are shared or syndrome-specific, by comparing JAE to JME; and (iv) identify associations between cognitive abilities and clinical characteristics. MethodsWe investigated 123 participants: 23 patients with JAE, 16 unaffected siblings of JAE patients, 45 healthy controls, and 39 patients with JME, who underwent a comprehensive neuropsychological test battery including measures within four cognitive domains: attention/psychomotor speed, language, learning, and executive function. We also correlated clinical measures with cognitive performance data to decode effects of age at onset and duration of epilepsy. ResultsPatients with JAE performed worse than controls across tests of psychomotor speed, language, learning and executive function. Patients and siblings were similarly impaired on language measures of verbal comprehension, phonemic fluency, and semantic fluency compared to controls. Receiver operating characteristic curves indicated successful discrimination of patients with JAE and siblings from controls via linguistic measures. Individuals with JME also presented with multidomain cognitive impairment and had worse response inhibition than those with JAE. Across all patients, those with older age at onset had better performance on psychomotor speed and executive function tests. SignificanceJAE is associated with wide-ranging cognitive difficulties that encompass domains reliant on frontal lobe processing, including language, attention, and executive function. JAE siblings demonstrate shared impairment with patients on linguistic measures, indicative of a familial trait. Executive function subdomains may be differentially affected across the IGE spectrum. Cognitive abilities are detrimentally modulated by an early age at seizure onset. KEY POINTSO_LIJAE presents with multidomain cognitive impairment involving language, attention/ psychomotor speed, executive function, and learning. C_LIO_LIImpaired language is common to people with JAE and their unaffected siblings, suggestive of a familial trait (endophenotype). C_LIO_LIResponse inhibition is worse in JME than JAE, indicating distinct cognitive profiles across the IGE spectrum. C_LIO_LIEarly age at epilepsy onset is associated with worse cognitive performance in JAE and JME. C_LI