Early diagnosis improving the outcome of an infant with epileptic encephalopathy with cytoplasmic FMRP interacting protein 2 mutation

Abstract

Rationale: Early infantile epileptic encephalopathy (EIEE) 65 was recently shown to be caused by the cytoplasmic FMRP interacting protein 2 (CYFIP2) mutation. To date, only 5 cases have been reported in two articles, and all the outcomes in all cases were poor.Patient concerns: In this study, we reported an 8-month-old girl with a 1 month-long history of seizures and developmental delay. Over 1 month later, she developed epileptic spasms in clusters with hypsarrhythmia on electroencephalography. Diagnosis:The patient was diagnosed with EIEE 65 and trio-based whole-exome sequencing revealed a causative de novo CYFIP2 mutation c.260G >T (p.Arg87Leu). Interventions:The proband was successively treated with multiple antiepileptic drugs, including levetiracetam, phenobarbital, VitB6, topiramate, methylprednisolone, prednisone, valproic acid and vigabatrin.Outcomes: After resistance to multiple anti-epileptic drugs over 2 months of treatment, she finally achieved seizure-free several days after vigabatrin administration and her developmental delay steadily improved.Lessons: Our case confirmed that CYFIP2 was the pathogenic gene of EIEE 65. We also first demonstrated vigabatrin might be effective for control of seizures and helpful for the improved outcomes of these patients.Abbreviations: CYFIP2 = cytoplasmic FMRP interacting protein 2, EE = epileptic encephalopathy, EEG = electroencephalography, EIEE = early infantile epileptic encephalopathy, GTCSs = generalized tonic-clonic seizures, MRI = magnetic resonance imaging, SD = standard deviation, WAVE = WASP-family verprolin-homologous protein, WES = whole-exome sequencing.

Haploinsufficiency of Cyfip2 Causes Lithium‐Responsive Prefrontal Dysfunction

“…In conclusion, our study suggests that L5‐specific prefrontal dysfunction, especially hyperexcitability, underlies both the pathophysiology and the lithium‐mediated amelioration of neurobehavioral phenotypes in adult Cyfip2 +/− mice. Beyond CYFIP2 haploinsufficiency, these results, if supported by follow‐up studies, might also be implicated in ID and epilepsy of patients with CYFIP2 missense variants, 7–10 because both types of CYFIP2 variants are expected to induce common molecular changes, such as aberrant actin polymerization 18,60 . Prefrontal L5 neurons might be more vulnerable to these CYFIP2‐dependent changes in the maintenance of their normal function.…”

“…Whether the age‐specific differences in the regulation of potassium channel genes in the PFC and possibly other brain regions are involved in the age‐specific phenotypes of Cyfip2 +/− mice requires further investigation. More importantly, patients with CYFIP2 missense variants show early‐onset clinical symptoms 7–10 . Therefore, our results for adult Cyfip2 +/− mice should be interpreted with caution and might not translate directly to human CYFIP2 ‐associated brain disorders.…”

“…Based on the hyperexcitability of Cyfip2 +/− neurons, we investigated the seizure susceptibility of Cyfip2 +/− mice, which might potentially be implicated in epilepsy commonly seen in patients with CYFIP2 deletions and missense variants 5,7–10 . We induced seizures in mice by injecting PTZ and assessed seizure behaviors.…”

“…Regarding CYFIP2 , interstitial deletions of the chromosomal region 5q33.3–q35.1 harboring CYFIP2 (ie, haploinsufficiency) were identified in individuals with developmental delay, mild to severe ID, and seizures 5,6 . Moreover, recent whole‐exome and whole‐genome sequencing studies identified de novo CYFIP2 missense variants in patients with developmental delay, early‐onset epileptic encephalopathy, and severe ID 7–10 …”

Enhanced Prefrontal Neuronal Activity and Social Dominance Behavior in Postnatal Forebrain Excitatory Neuron-Specific Cyfip2 Knock-Out Mice

“…Large chromosomal deletions harboring CYFIP2 have been identified in patients with developmental delay, ID, and seizures (Spranger et al, 2000;Lee et al, 2016). Moreover, recent whole-exome and whole-genome sequencing studies have identified de novo CYFIP2 variants in patients with developmental delay, ID, and early-onset epileptic encephalopathy (Nakashima et al, 2018;Peng et al, 2018;Lee et al, 2019b;Zhong et al, 2019;Zweier et al, 2019).…”