Neurodevelopmental Disorder With Spastic Diplegia And Visual Defects

A number sign (#) is used with this entry because neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) is caused by heterozygous mutation in the CTNNB1 gene (116806) on chromosome 3p22.

Description

Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) is characterized by global developmental delay, impaired intellectual development, axial hypotonia, and dysmorphic craniofacial features with microcephaly. Many patients have visual abnormalities, ranging from strabismus to optic nerve atrophy and retinal abnormalities. Affected individuals also develop spasticity, particularly of the lower limbs, and may have behavioral abnormalities (summary by Kuechler et al., 2015 and Kharbanda et al., 2017).

Clinical Features

From a cohort of 100 individuals with severe intellectual disability, de Ligt et al. (2012) identified 2 with a mutation in the CTNNB1 gene. One patient (patient 70) was a 29-year-old woman who had been evaluated at the age of 6 months for regression, which was followed by a slow progression in development. She learned to sit at age 2, and at the age of 12 she could walk with little support. She spoke her first words between the ages of 9 and 10. Behavioral problems included aggression, automutilation, and fecal smearing. At age 29 years, she was microcephalic and short. Facial dysmorphism included a low columella, long philtrum, high and narrow palate, and small posteriorly rotated ears. In a replication sample of 765 individuals, de Ligt et al. (2012) identified a third similarly affected patient with a CTNNB1 mutation. All of the patients had similar features comprising severe intellectual disability with absent or very limited speech, microcephaly, and spasticity which severely impaired the ability to walk.

Tucci et al. (2014) reviewed the clinical features of the patients reported by de Ligt et al. (2012) and reported another affected individual. The individuals had common recognizable features, including microcephaly, full nasal tip, and thin upper lip. Other common features included childhood hypotonia, autistic features, progressive spastic diplegia, and hypoplasia of the corpus callosum.

Kuechler et al. (2015) identified 16 patients from 15 families with NEDSDV confirmed by genetic analysis; there were 8 girls and 8 boys. Detailed descriptions of each patient, as well as an overall analysis of common clinical features, were provided. All patients had hypotonia and delayed psychomotor development from infancy. Almost all developed peripheral spasticity, resulting in an unsteady gait or inability to walk. All had intellectual disability, 9 had behavioral abnormalities including autistic features or aggression, and all had variable speech impairment, ranging from mild to severe. Eleven patients had visual defects. About half of patients had primary microcephaly. Most had mild dysmorphic facial features; common features included broad nasal tip with small alae nasi, long or flat philtrum, and thin upper lip, and more variable features included upslanting palpebral fissures and ear abnormalities. None had seizures or hearing loss.

Cytogenetics

Dubruc et al. (2014) reported a 5.5-year-old Caucasian girl, born of unrelated patients, with intellectual disability associated with a de novo heterozygous 333-kb deletion of chromosome 3p22 including the entire CTNNB1 gene and the last 3 exons of the ULK4 gene. She had intrauterine growth retardation, and birth was complicated by the umbilical cord wrapped around the neck and neonatal respiratory distress syndrome. In the first years of life, she developed progressive microcephaly, truncal hypotonia, delayed psychomotor development, and poor speech. She was friendly and hyperactive. She had thin, sparse hair, fair skin, thin lips, low-set ears, hyperopia, and a sacral dimple. Ataxic gait and spasticity with hyperreflexia and extensor plantar responses became apparent around age 4 years. The deletion was found by array CGH and was absent in both her parents. Dubruc et al. (2014) concluded that the phenotype resulted from haploinsufficiency of the CTNNB1 gene.

Molecular Genetics

In 3 patients with severe intellectual disability, microcephaly, and spasticity, de Ligt et al. (2012) identified heterozygous loss-of-function mutations in the CTNNB1 gene (116806.0017-116806.0019). Two of the mutations were known to be de novo; in the third patient, the mutation was not inherited from the mother and the father's DNA was not available for testing.

Tucci et al. (2014) identified a de novo heterozygous truncation mutation in the CTNNB1 gene (116806.0020) in a patient with NEDSDV. The findings indicated that CTNNB1 haploinsufficiency is responsible for the phenotype.

In 16 patients from 15 families with NEDSDV, Kuechler et al. (2015) identified 15 different de novo heterozygous truncating mutations in the CTNNB1 gene. Functional studies and studies on patient cells were not performed.

By interrogating the DECIPHER database, Kharbanda et al. (2017) identified 11 patients with an inactivating mutation in the CTNNB1 gene (see, e.g., 116806.0021). In the 10 patients for whom clinical details were available, the authors confirmed features previously described in patients with inactivating CTNNB1 mutations, including intellectual disability, postnatal microcephaly, truncal hypotonia and peripheral spasticity, mild dysmorphic features, and behavioral problems. In addition, these patients exhibited fair skin and fine, fair hair with unusual hair patterning that appeared to be out of keeping with the familial background.

In a 15-month-old Chinese boy who presented with retinal detachment as well as lens and vitreous opacities and showed no reaction to light, who was negative for mutation in exudative vitreoretinopathy (see 133780)-associated genes, Li et al. (2017) performed whole-exome sequencing and identified heterozygosity for a de novo nonsense mutation in the CTNNB1 gene (Q558X; 116806.0022). The child also exhibited microcephaly, developmental delay, and mild thumb adduction.

In a 3-year-old Chinese boy with exudative vitreoretinopathy, developmental delay, and dysmorphic facial features, Panagiotou et al. (2017) identified heterozygosity for a de novo 1-bp insertion in the CTNNB1 gene (116806.0023).

Animal Model

Tucci et al. (2014) identified a mouse mutant, designated 'batface' (Bfc), resulting from a heterozygous T653K mutation in the C-terminal armadillo repeat of the Ctnnb1 gene. Mutant mice had craniofacial abnormalities, including shortened anteroposterior axis, broad face, and shortened nasal length, as well as morphologic brain changes, such as larger deep brain structures, reduced cerebellar and olfactory bulb volume, and underdeveloped corpus callosum. Mutant mice demonstrated behavioral and cognitive abnormalities, including defects in prepulse inhibition, motor deficits, decreased vocalization complexity, and decreased hippocampal-dependent memory performance. In vitro cellular studies showed that the T653K mutation disrupted the association between Ctnnb1 and cadherin, consistent with a dominant-negative effect. Brains of heterozygous mutant mice initially showed increased length and number of neurons, but later showed decreased dendritic branching compared to controls. Knockdown of Ctnnb1 using siRNA caused a similar decrease in neuritic length and number of processes in wildtype neurons, suggesting that the T653K mutation also causes a loss of function. Electrophysiologic studies of mutant neurons indicated higher excitability of neural networks and less efficient functional connectivity compared to wildtype. The findings indicated that CTNNB1 plays a key role in many aspects of neurodevelopment and synaptic function.