BACKGROUND: Research has shown gene ATN1 to be associated with the nuclear receptor signaling. Its mutations in an evolutionarily conserved histidine-rich motif may cause CHEDDA, short for congenital hypotonia, epilepsy, developmental delay and digital anomalies, a recently identified neurodevelopmental syndrome that could evolve into developmental and epileptic encephalopathy (DEE). Up to date, there have been reported less than 20 cases, whose clinical features and treatment are worth in-depth exploring.
METHODS: The clinical characteristics and genetic data of an infant with CHEDDA and further DEE were analyzed, who carried a de novo ATN1 variant identified by trio whole-exome sequencing. The alike patients with such a neurodevelopmental syndrome and epileptic seizures were reviewed on the literature.
RESULTS: The infant harboring a de novo missense mutation in ATN1 (c.3155A>C; p.His1052Pro) held almost all features of CHEDDA and presented with drug-resistant epileptic spasms, differing from one case previously reported with the same gene variant exhibiting milder seizures controlled easily. We further reviewed 11 CHEDDA patients with epileptic seizures in the literature and compared the correlation between abnormal cerebral structure and the incidence of intractable epilepsy among CHEDDA patients. Fortunately, this patient\'s seizures decreased remarkably after administering ketogenic diet (KD).
CONCLUSIONS: CHEDDA patients have significant phenotypic differences, especially in the epilepsy severity and their drug resistance, even if they carry the same mutation hotspot. Ketogenic diet and other treatments like Topiramate should be recommended for ATN1-related refractory epilepsy based on their regulation on expression of cation-chloride cotransporters and cellular hyperpolarization.

CHEDDA syndrome is a rare neurodevelopmental syndrome caused by heterozygous missense or indel variants in the HX repeat motif of ATN1 gene. To date, CHEDDA has been identified in a few ethnic groups, and only 17 patients have been reported in literature, and no case has been reported in any country or region in Asia.
Trio-exome sequencing (Trio-ES) examination was conducted in a Chinese girl with global developmental delay and in her parents. Sanger sequencing was performed to confirm the candidate variant.
This patient presented with mental and motor developmental delay, speech delay, and mild dysmorphic facial features, and had no epilepsy and visual impairment. Brain MRI did not show obvious structural abnormality. Through ES we identified a novel and de novo variant, c.3176_c.3177insGCACCT (p.Ser1059_His1060insHisLeu), within the HX motif of ATN1. No other pathogenic variant in another gene was found to support an alternative clinical and molecular diagnosis.
This is the first described case of CHEDDA from China. Together with the available literature data, we found that either disruption of HX motif or alteration of the HX repeat number would lead to ATN1-associated CHEDDA. We also noted that CHEDDA is a clinical heterogenous syndrome, and patients carrying the same or similar variant might have different clinical manifestations and prognosis.