CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum

Abstract

We describe the clinical features of nine unrelated individuals with rare de novo missense or in‐frame deletions/duplications within the “HX motif” of exon 7 of ATN1. We previously proposed that individuals with such variants should be considered as being affected by the syndromic condition of congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA), distinct from dentatorubral‐pallidoluysian atrophy (DRPLA) secondary to expansion variants in exon 5 of ATN1. We confirm that the universal phenotypic features of CHEDDA are distinctive facial features and global developmental delay. Infantile hypotonia and minor hand and feet differences are common and can present as arthrogryposis. Common comorbidities include severe feeding difficulties, often requiring gastrostomy support, as well as visual and hearing impairments. Epilepsy and congenital malformations of the brain, heart, and genitourinary systems are frequent but not universal. Our study confirms the clinical entity of CHEDDA secondary to a mutational signature restricted to exon 7 of ATN1. We propose a clinical schedule for assessment upon diagnosis, surveillance, and early intervention including the potential of neuroimaging for prognostication.

A novel variant in the HX repeat motif of ATN1 in a Chinese patient with CHEDDA syndrome and literature review

“…In addition, epilepsy, structural brain malformation, heart defect, hearing impairment, genitourinary and skeletal abnormality were also frequent among patients (Table 1 ). It was noteworthy that the insertion variant in our study, as well as three indel variants, c.3615_3176del(p.Ile1057_His1060del), c.3188_3193del(p.Leu1063_His1064del), and p.Leu1063_His1064dup, reported in CHEDDA patients in 2021 (Palmer et al, 2021 ), did not interrupt the HX arrangement but change the length of HX repeats. Therefore, both the strict arrangement and length of HX motif might be critical for ATN1 function.…”

“…The database included PubMed, Medline, ClinVar, and HGMD. By carefully verifying and avoiding the duplication of cases, we finally found 4 articles including 17 cases with CHEDDA and 15 variants, including 10 missense mutations and 5 indels (Figure 1b ) (Hui et al, 2020 ; Mosca et al, 2007 ; Palmer et al, 2019 , 2021 ). By comparing the clinical manifestations of all CHEDDA patients, we found that all patients presented infantile hypotonia, global developmental delay, and dysmorphic facial features.…”

“…Therefore, both the strict arrangement and length of HX motif might be critical for ATN1 function. In addition, it was supposed an insertion of a histidine and another amino acid, compared with missense and other types of indel variants, may correlate with milder phenotype and better response to therapy (Palmer et al, 2021 ). It is true that our patient who carried an insertion of a histidine and leucine has milder motor developmental delay (walk unsteadily), however, she has profound cognitive and speech impairment, and early intervention had no obvious improvement.…”

“…CHEDDA syndrome is a recently identified neurodevelopmental disorder characterized as severe global developmental delay including significant motor disability and impaired intellectual development, dysmorphic facial features, and variable congenital anomalies. Palmer et al suggested global developmental delay, feeding difficulties, and distinctive facial features as the core phenotypic features of CHEDDA (Palmer et al, 2021 ). The structural brain abnormalities have been documented to be associated with more severely impaired in neurodevelopment.…”

“…Unlike DRPLA caused by the glutamine expansion in the glutamine‐rich region in exon 5 of ATN1, CHEDDA results from the indels and missense variants in the HX repeat motif in exon 7 encoding the residues 1049–1065. By reviewing literatures, we noted that the patients with an insertion of a histidine and another amino acid have milder phenotypes compared with those with a missense mutation, or a deletion of one amino acid, or insertion of two X (X is any amino acid except histidine) (Palmer et al, 2021 ). However, clinical heterogeneity was observed, even in individuals harboring the same or similar variants.…”