Encephalopathy, Progressive, Early-Onset, With Brain Atrophy And Spasticity

A number sign (#) is used with this entry because of evidence that early-onset progressive encephalopathy with brain atrophy and spasticity (PEBAS) is caused by homozygous or compound heterozygous mutation in the TRAPPC12 gene (614139) on chromosome 2p25.

Clinical Features

Milev et al. (2017) reported 3 children from 2 unrelated families with severe early-onset progressive encephalopathy characterized by microcephaly, global developmental delay, and hearing loss. One patient, born of consanguineous Palestinian parents, presented with brief flexion seizures at age 5 months and subsequently showed developmental regression and stagnation with loss of smiling, visual tracking, and social overtures. EEG showed hypsarrhythmia. Family history in this patient was notable for the mother having 5 previous pregnancies ending in spontaneous abortions, a sixth terminated for multiple anomalies, and another child born at 24 weeks' gestation who died soon after birth. In the second family, 2 sisters were similarly affected. Both had small developmental gains in infancy, but then plateaued or showed regression and had severe global developmental deficits. Additional features in all patients included truncal hypotonia, appendicular spasticity, dystonia and/or myoclonus, optic atrophy or cortical visual impairment, scoliosis, and dysphagia, necessitating G-tube placement in the sisters. Brain MRI in all patients showed a similar pattern of pontine hypoplasia, partial agenesis of the corpus callosum, simplified frontal gyri, and diffuse cortical atrophy with enlarged ventricles and relative sparing of the cerebellum. Two of the 3 patients had seizures. One of the sisters died of respiratory insufficiency at age 4 years, 9 months.

Inheritance

The transmission pattern of PEBAS in the families reported by Milev et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from 2 unrelated families with PEBAS, Milev et al. (2017) identified homozygous or compound heterozygous mutations in the TRAPPC12 gene (614139.0001-614139.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Fibroblasts derived from all 3 individuals showed a fragmented Golgi that could be rescued by expression of wildtype TRAPPC12. Patient cells also showed delayed mitosis and delayed transport of proteins from the endoplasmic reticulum to and through the Golgi, suggesting that defects in membrane protein transport are causative of the disorder.