Neurodevelopmental Disorder With Spastic Quadriplegia And Brain Abnormalities With Or Without Seizures

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures (NEDSBAS) is caused by homozygous mutation in the WDR45B gene (609226) on chromosome 17q25.

Clinical Features

Suleiman et al. (2018) reported 6 patients from 3 unrelated consanguineous families with profound developmental delay and intellectual disability. The patients ranged in age from 9 months to 20 years. All patients except 1 (patient 6) had onset of refractory seizures in the first weeks or months of life, and in most patients, the seizures became controlled later in childhood. All patients had little developmental progress and were unable to walk or communicate. Features included spastic quadriplegia, axial hypotonia, contractures, kyphoscoliosis, and no response to visual stimuli. EEG in those with seizures showed slowed background activity and intermittent multifocal epileptiform activity. Three affected individuals from 2 families (families 2 and 3) had microcephaly (up to -4 to -9 SD). Brain imaging showed enlarged ventricles, thinning of the cortex, hypoplastic cerebrum, thin corpus callosum, and reduced white matter volume. These brain abnormalities were progressive in 1 patient who had serial imaging.

Inheritance

The transmission pattern of NEDSBAS in the families reported by Suleiman et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 patients from 3 unrelated consanguineous families with NEDSBAS, Suleiman et al. (2018) identified homozygous nonsense mutations in the WDR45B gene (R225X, 609226.0001 and Q267X, 609226.0002). The mutations, which were found by screening of a neurology gene panel or whole-exome sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a complete loss of function.

Suleiman et al. (2018) stated that Anazi et al. (2017) had identified a homozygous R225X mutation in the WDR45B gene in an unrelated child (patient 15DG1306) with global developmental delay and microcephaly, and that Najmabadi et al. (2011) had identified a homozygous missense variant in the WDR45B gene (R109Q) in 3 members of a consanguineous family (family 8500320) with intellectual disability and microcephaly. Additional details were not provided and no functional studies of those variants were performed. The study by Anazi et al. (2017) included a cohort of 337 patients with intellectual disability (documented IQ of 70 or less) who underwent genetic studies, including molecular karyotyping, analysis of a multigene panel, and whole-exome sequencing. The study by Najmabadi et al. (2011) included homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability.