CTNNB1 – Neurodevelopmental Disorder with Spastic Diplegia and Visual Defects

Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) is a rare autosomal dominant condition characterized by severe intellectual disability (HP:0010864), global developmental delay (HP:0001263), microcephaly (HP:0000252), and progressive spasticity (HP:0001257). Patients uniformly carry de novo heterozygous CTNNB1 variants leading to loss of function, with no evidence of familial transmission beyond the proband.

Case-level evidence includes over 100 unrelated individuals reported across multiple cohorts, each harboring de novo truncating or splice-site variants in CTNNB1, with consistent clinical presentations (PMID:33116939, PMID:33425807, PMID:39067319). Segregation analysis shows absence of transmitted alleles in family members (0 affected relatives).

The variant spectrum is dominated by loss-of-function alleles: nonsense (e.g., c.999C>A (p.Cys419Ter)), frameshift, and essential splice-site changes, all arising de novo (PMID:33264726). Recurrent hotspots include p.Cys419Ter and p.Lys625ArgfsTer16, with no founder effects noted.

Ocular manifestations such as strabismus and vitreoretinopathy broaden the phenotype; seven new cases with missense variants and variable visual defects were described, underscoring the need for ophthalmological screening in CTNNB1-related NEDSDV (PMID:33350591).

Functional studies using patient-derived iPSC lines demonstrate impaired Wnt/β-catenin signaling and failure of neuronal differentiation, and murine Ctnnb1 haploinsufficiency models recapitulate motor deficits and microcephaly, supporting a haploinsufficiency mechanism (PMID:33264726, PMID:38364504).

Taken together, the genetic and experimental concordance establish a definitive association between CTNNB1 haploinsufficiency and NEDSDV. CTNNB1 sequencing and copy-number analysis should be incorporated into diagnostic workflows for patients with unexplained intellectual disability and spastic diplegia.

References

• Stem cell research • 2020 • Generation of a human induced pluripotent stem cell line (SBWCHi001-A) from a patient with NEDSDV carrying a pathogenic mutation in CTNNB1 gene. PMID:33264726
• International medical case reports journal • 2020 • A de novo CTNNB1 Novel Splice Variant in an Adult Female with Severe Intellectual Disability. PMID:33116939
• American journal of medical genetics. Part A • 2022 • Novel CTNNB1 variant leading to neurodevelopmental disorder with spastic diplegia and visual defects plus peripheral neuropathy: A case report. PMID:35880249
• Frontiers in pediatrics • 2020 • Case Report: A de novo CTNNB1 Nonsense Mutation Associated With Neurodevelopmental Disorder, Retinal Detachment, Polydactyly. PMID:33425807
• Parkinsonism & related disorders • 2024 • Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology. PMID:39067319
• Molecular genetics & genomic medicine • 2021 • Missense variants in CTNNB1 can be associated with vitreoretinopathy-Seven new cases of CTNNB1-associated neurodevelopmental disorder including a previously unreported retinal phenotype. PMID:33350591

Evidence Based Scoring (AI generated)