ATN1 – congenital hypotonia, epilepsy, developmental delay, and digital anomalies

ATN1 is implicated in a neurodevelopmental syndrome characterized by congenital hypotonia, epilepsy, developmental delay, and digital anomalies (congenital hypotonia, epilepsy, developmental delay, and digital anomalies, CHEDDA). This autosomal dominant disorder arises from de novo missense variants affecting an evolutionarily conserved histidine-rich motif within ATN1. Clinical features include global developmental delay, early-onset drug-resistant epileptic spasms, digital malformations, and hypotonia, often progressing to developmental and epileptic encephalopathy. To date, 12 unrelated patients (11 from literature and one newly reported) harboring missense variants in ATN1 have been documented with CHEDDA and progression to DEE ([PMID:38262122]). The consistency of phenotype, absence of inherited transmission, and recurrence of mutations at a hotspot support a causal relationship. Additional segregation data are unavailable due to the de novo nature of these mutations.

Most reported variants are heterozygous missense changes clustering within the histidine-rich domain that is critical for nuclear receptor binding and transcriptional regulation. One recurrent variant, c.3155A>C (p.His1052Pro), has been identified in two unrelated individuals, demonstrating variable seizure severity despite identical amino acid alterations ([PMID:38262122]). No loss-of-function or truncating variants have been documented in CHEDDA, suggesting a dominant-negative or gain-of-function mechanism. There are currently no founder effects or population-specific alleles described. All pathogenic variants were discovered by trio exome sequencing, highlighting the power of next-generation sequencing in resolving these diagnoses. The observed de novo mutational events confer strong genetic evidence under ClinGen criteria.

Functional characterization remains limited but implicates disrupted nuclear receptor signaling via the mutated histidine-rich motif. Cellular models suggest altered regulation of cation-chloride cotransporters, which may underlie neuronal hyperexcitability and hypotonia. Therapeutic response to ketogenic diet in one patient indicates metabolic modulation can ameliorate seizure activity, indirectly supporting a functional impact of ATN1 variants on neuronal ion homeostasis ([PMID:38262122]). No animal models or rescue experiments have been reported to date. Further functional studies are needed to clarify the precise molecular mechanism and explore targeted interventions.

No conflicting reports disputing the association between ATN1 missense variants and CHEDDA have been identified. Variants outside the histidine-rich region have not been documented in CHEDDA cohorts, and there is no evidence of benign polymorphisms in population databases correlating with CHEDDA phenotypes. The uniform clinical presentation across unrelated cases argues against locus heterogeneity. Data to date do not suggest alternative diagnoses for ATN1-related CHEDDA.

In conclusion, de novo heterozygous missense variants in ATN1 are convincingly associated with congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA). The genetic evidence is classified as Moderate, supported by 12 probands with recurrent de novo variants and consistent phenotype. Functional evidence is Limited, pending mechanistic and in vivo validation. Routine inclusion of ATN1 in gene panels for early-onset encephalopathies is recommended, and ketogenic diet may offer symptomatic benefit for refractory seizures. Prospective natural history studies and functional assays will further refine genotype–phenotype correlations and therapeutic strategies.

References

• Seizure • 2024 • ATN1-related infantile developmental and epileptic encephalopathy responding to Ketogenic diet. PMID:38262122

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