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Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (NEDESBA) is an autosomal recessive disorder characterized by severely impaired global d...

Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (NEDESBA) is an autosomal recessive disorder characterized by severely impaired global development apparent soon after birth. Affected individuals develop seizures in the first year of life and achieve almost no psychomotor progress, resulting in feeding difficulties and an inability to walk or speak. Other features include hypotonia, peripheral spasticity with contractures, cortical visual impairment, and dysmorphic features, including microcephaly. Death in childhood may occur (summary by Van Bergen et al., 2020).

Van Bergen et al. (2020) noted that the molecular mechanism of this disorder can be classified into a group of similar phenotypes resulting from mutations in genes associated with transport protein particles, sometimes referred to as 'TRAPPopathies' (review by Sacher et al., 2019).

▼ Clinical Features
Van Bergen et al. (2020) reported 8 children from 3 unrelated families of Caucasian, Turkish, and French-Canadian descent with a similar syndromic neurodevelopmental disorder. Four of the patients died in the first years of life. The remaining patients, who ranged in age from 17 months to 17 years, had a severe phenotype with hypotonia, peripheral spasticity, almost no psychomotor development, and inability to walk or speak. They had severe feeding difficulties, necessitating tube-feeding in most. Symptom onset was soon after birth, when delayed milestones were first observed. All developed early-onset seizures of various types within the first year of life, which were often associated with EEG abnormalities, such as slow background and multifocal epileptic discharges. Most had cortical visual impairment and/or poor visual tracking, and 2 also had impaired hearing. All had dysmorphic features, including microcephaly (down to -7 SD), bitemporal narrowing, full cheeks, prominent nasal tip, long philtrum, wide open mouth with thin tented upper lip, and pointed chin. More variable features included progressive scoliosis, contractures, congenital hip dislocation, osteopenia, abnormal dentition, dystonia, and tremor. Brain imaging, performed in 4 patients, showed progressive cortical and cerebellar atrophy. There was no evidence of iron deposition.

Ghosh et al. (2021) reported 23 patients from 17 unrelated families. who developed a severe and progressive encephalopathy with developmental stagnation in the first few months of life. Some of the patients also had psychomotor regression. The patients all developed microcephaly and all developed seizures in the first 6 months of life. Neurologic examination in the patients showed spastic tetraplegia and hyperreflexia in all patients, and abnormal movements including ataxia and dystonia in some patients. Three patients had bilateral cataracts, and visual pursuits were absent in all patients. Two patients had hearing loss. Brain MRI demonstrated cerebral atrophy in all patients. In many patients, MRI also demonstrated white matter loss, ventriculomegaly, and cerebellar atrophy. Facial dysmorphisms in the patient cohort included bitemporal narrowing, thick eyebrows, full cheeks, a long philtrum, wide mouth, thick and tented upper lip, and pointed chin.

▼ Inheritance
The transmission pattern of NEDESBA in the families reported by Van Bergen et al. (2020) was consistent with autosomal recessive inheritance.

▼ Molecular Genetics
In 7 children from 3 unrelated families with NEDESBA, Van Bergen et al. (2020) identified a homozygous splice site mutation in the TRAPPC4 gene (610971.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. It was found at a low frequency (0.0002419) in only heterozygous state in the gnomAD database. Analysis of fibroblasts derived from 1 patient confirmed the splicing defect, and Western blot analysis showed some production of the wildtype protein, but at significantly decreased levels compared to controls; a truncated protein was not detected, consistent with nonsense-mediated mRNA decay of the mutant transcript. Fibroblasts derived from 1 patient showed overall decreased levels of fully-assembled TRAPP complexes compared to controls. Haplotype analysis was not consistent with a founder effect, but rather suggested a mutational hotspot. Detailed functional studies of patient fibroblasts showed ER/Golgi secretory defects that could be rescued by transfection of wildtype TRAPPC4, as well as defects in autophagy and autophagosome formation. Similar defects, including decreased levels of the assembled TRAPP complex and secretion and autophagy defects, were observed in a yeast trs23 temperature-sensitive mutant with decreased levels of the Trappc4 ortholog. The findings suggested that the pleiotropic effects of the phenotype resulted from defects in both cellular trafficking and autophagy. (Van Bergen (2020) noted that several errors appeared in the pedigrees in Figure 2A of their article; correct information appears in their Supplementary Table 1. One of the deceased patients in Family 2 (2-II-1) is not listed in Supplementary Table 1 because DNA from this patient was not available for testing.)

In 23 patients from 17 unrelated families with NEDESBA, Ghosh et al. (2021) identified homozygosity for the recurrent splice site mutation in the TRAPPC4 gene (c.454+3A-G; 610971.0001) that had previously been identified by Van Bergen et al. (2020). The mutation was identified by whole-exome or whole-genome sequencing. RNA sequencing in skin fibroblasts from 1 patient (patient 15) revealed partial exon 3 skipping of TRAPPC4 due to use of a cryptic splice donor site, which was predicted to result in a premature stop and nonsense-mediated decay. Ghosh et al. (2021) reported that the c.454+3A-G mutation was relatively common across populations worldwide, and that it was unlikely that the variant was derived from a shared common ancestor because a shared haplotype was not identified.

Tags: 11q23.3