NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Abstract

R628* (x 5) R322* (x 4) K1396Rfs*3 C146* G681Vfs*11 K734Sfs*24 R481*(x 3) G1018Dfs*2 R528Efs*4 R218* (x 3) Q141Rfs*7 L209Pfs*3 R313* N573Sfs*11 S1157* S1200Ifs*5 (x3) R62Efs*22

Candidate Genes for Eyelid Myoclonia with Absences, Review of the Literature

“…One year later, Myers et al reported two other sisters diagnosed with MAE with a point mutation at NEXMIF (p.Arg322*) in their search of parental gonadal mosaicism in apparently de novo epileptic encephalopathies [ 41 ]. These two cases and their clinical features have recently been reviewed by Stamberger et al (2021) [ 42 ]. Analyzing the phenotype of 87 patients with NEXMIF -related encephalopathy, 10 females were diagnosed with EMA, 2 of them with an earlier onset (one year or younger), and 5 more cases (2 males and 3 females) presented a combination of EMA and MAE syndromes, including the case reported by Myers et al (2018)) ( Table 2 ) [ 42 ].…”

“…These two cases and their clinical features have recently been reviewed by Stamberger et al (2021) [ 42 ]. Analyzing the phenotype of 87 patients with NEXMIF -related encephalopathy, 10 females were diagnosed with EMA, 2 of them with an earlier onset (one year or younger), and 5 more cases (2 males and 3 females) presented a combination of EMA and MAE syndromes, including the case reported by Myers et al (2018)) ( Table 2 ) [ 42 ]. According to Stamberger et al, there was no correlation between phenotype and XCI status in their series, based on 1) the comparison of females with skewed and random XCI and 2) the families with sisters each presenting skewed and random XCI (families F4 and F7).…”

“…Although specific information for each patient was not available, only 16% of the patients from the total cohort were seizure-free. It is outstanding that only 7% of the females, compared to 47% of males, were seizure-free ( p = 0.001 Fisher’s exact) [ 42 ].…”

Cortical and Subcortical Network Dysfunction in a Female Patient With NEXMIF Encephalopathy

“…Subsequently, affected females have been described ( 10 – 14 ) and recently a large multicentric study outlined the epilepsy phenotype of affected females ( 15 ) which is consistent with a generalized DEE characterized by myoclonic–atonic epilepsy overlapping with eyelid myoclonia with absence. Notably a considerable proportion of affected females present prolonged seizures characterized by absence status with eyelid myoclonia ( 15 , 16 ). We report a female patient with a de novo NEXMIF pathogenic variant and recurrent prolonged episodes of absence status with eyelid myoclonia.…”

“…Pathogenic NEXMIF variants were first identified in males with non-syndromic X-linked ID with poor or absent speech, subtle dysmorphic features, and sometimes epilepsy (8,9). Subsequently, affected females have been described (10)(11)(12)(13)(14) and recently a large multicentric study outlined the epilepsy phenotype of affected females (15) which is consistent with a generalized DEE characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Notably a considerable proportion of affected females present prolonged seizures characterized by absence status with eyelid myoclonia (15,16).…”