Spastic Diplegia and Visual Defects in CTNNB1 Gene Mutation: Genetic Mimic of Cerebral Palsy

To the Editor: A 4-y-old-girl, firstborn to non-consanguineous parents with a normal perinatal period, presented with global developmental delay (GDD) within the first year of life with paucity of overall motor movements. On examination, she had hyperactivity, excessive sweating, fair skin, normal head circumference (48 cm), axial hypotonia, intermittent dystonia, intermittent oculogyric movements, and dysarthria. A clinical diagnosis of intellectual impairment with intermittent dystonia was considered. Blood carnitine and amino-acid profiles, and urine organic acids were unremarkable. Magnetic resonance imaging (MRI) brain at three years of age showed a left choroidal fissure cyst. A diagnosis of neurotransmitter disorder was suspected at this time. Exome sequencing showed a pathogenic, autosomal dominant, heterozygous single base pair duplication c.1781dup in exon 11 of the CTNNB1 gene (chr3:g.41277310dupA), resulting in a frameshift and premature truncation of protein, 15 amino acids downstream to codon 594 (p.Asn594LysfsTer15;ENST00000349496.5), suggestive of Neurodevelopmental Disorder with Spastic Diplegia and Visual Defects (NEDSDV). Parental testing did not harbor the variant.

NEDSDV (MIM#615075) is caused by heterozygous variations in CTNNB1 gene on chromosome 3p22 [1, 2]. CTNNB1 encodes b-catenin protein that has a role in cell adhesion, stabilization of actin cytoskeleton, and postnatal neuronal dendritic development [3]. The essential clinical features include postnatal microcephaly, GDD, intellectual disability, behavioral problems, truncal hypotonia, peripheral spasticity, strabismus, optic atrophy, retinal abnormalities, fair skin, mild dysmorphism, growth retardation, and hyperekplexia [1, 4]. The radiological features include corpus callosum hypoplasia, left temporal lobe atrophy, arachnoid cyst, enlarged sylvius sulcus, and choroid fissure cyst [4]. The index child had GDD, extrapyramidal features such as intermittent dystonic posturing, and oculogyric movements, and only choroid fissure cyst on neuroimaging. Management includes personalized treatment plans with a multidisciplinary care team. In children with intellectual disability with normal perinatal period, with non-specific clues on neuroimaging and metabolic workup, CTNNB1-associated intellectual disability can be considered.