Spastic Paraplegia, Intellectual Disability, Nystagmus, And Obesity

A number sign (#) is used with this entry because of evidence that spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) is caused by heterozygous mutation in the KIDINS220 gene (615759) on chromosome 2p25.

Description

Spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) is an autosomal dominant neurologic disorder characterized by rapid growth in infancy, global developmental delay, spastic paraplegia, variable ophthalmologic defects, and dysmorphic facial features (summary by Josifova et al., 2016).

Clinical Features

Josifova et al. (2016) reported 3 unrelated children with a similar intellectual disability syndrome. Prenatal ultrasound of all 3 showed dilated lateral ventricles. All had significant growth during the first year of life, resulting in height, weight, and head circumference in the high 90th percentiles. At ages 7, 14, and 15 years, respectively, the 2 older patients remained obese despite normal eating and exercise. Neurologic features included global developmental delay with delayed speech, axial hypotonia, and spastic paraplegia with increased tone and hyperreflexia. One patient was unable to walk independently at age 7 years. The patients had poor visual acuity with nystagmus, hypermetropia, astigmatism in 2, and pale optic discs in 1. Dysmorphic features included brachyplagiocephaly, prominent forehead, full cheeks, and deep-set eyes. Brain imaging showed reduced white matter bulk, delayed myelination, and cerebral atrophy; 1 patient had partial agenesis of the corpus callosum.

Molecular Genetics

In 3 unrelated patients with SINO, Josifova et al. (2016) identified 3 different de novo heterozygous truncating mutations in the KIDINS220 gene. The first 2 mutations (W1350X, 615759.0002; Q1366X, 615759.0002) were found by next-generation sequencing analysis of a targeted gene panel, and the third mutation (c.4530dup; 615759.0003) by whole-exome sequencing. Analysis of cells from the first 2 patients showed that their mutations resulted in the production of truncated proteins that were similar to functional KIDINS220 splice variants with alternative terminal exon splicing as described by Schmieg et al. (2015). These 2 mutations resulted in truncation before the KIM motif, whereas the c.4530dup mutation was predicted to form a truncated protein with the KIM motif. Josifova et al. (2016) suggested that the constitutive expression of these truncated isoforms may interfere with the complex spatiotemporal regulation of splicing of KIDINS220 that is necessary for proper neuronal and neurite development. Three different truncating variants in the KIDINS220 gene were present in 5 unaffected individuals in the ExAC database (September 2015): E1530X, R1736X, and S1740X. These changes also occurred in the last exon of the gene, suggesting that not every loss-of function variant causes the phenotype.