Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome (ORPHA:500144)
A rare, genetic neurological disorder characterized by early-onset severe global developmental delay with regression, congenital or acquired microcephaly, hearing loss, truncal hypotonia, appendicular spasticity, and dystonia and/or myoclonus.
Epidemiology
Currently only five affected individuals from four unrelated families (three consanguineous and one non-consanguineous) have been reported in the literature.
Clinical description
The clinical phenotypes of the affected individuals are similar: severe global development delay often with regression, epilepsy, congenital or postnatal microcephaly, hearing loss, dysphagia or reflux, scoliosis, truncal hypotonia, dystonia and/or myoclonus and spasticity. Eye and vision problems, such as optic atrophy and cortical visual impairment, neonatal hypertension, vocal cord paralysis, neurogenic bladder and hip subluxation have been described. In patients with no history of seizures at the time of diagnosis, electroencephalography can show paroxysmal discharges. Regarding neuroradiological features, the characteristic brain imaging findings are the following in various combinations: pons hypoplasia, partial or total agenesis of the corpus callosum, ventriculomegaly/hydrocephaly, marked cortical brain atrophy and simplified frontal gyri; cerebellar atrophy is present in two-thirds of patients. The basal ganglia is relatively spared.
Etiology
The syndrome is caused by homozygous variants or compound-heterozygous variants in the TRAPPC12 gene (2p25.3). TRAPPC12 is a component of the TRAPP multi-subunit tethering complex involved in intracellular vesicle trafficking and has also been reported to play a role in mitosis.
Diagnostic methods
Diagnosis is based on clinical examination, neurophysiological analysis, neuroradiological studies and cytogenetic and molecular studies (TRAPPC12 molecular analysis, NGS panel or whole-exome sequencing followed by Sanger sequencing).
Differential diagnosis
The differential diagnosis includes numerous genetic and metabolic diseases.
Antenatal diagnosis
Recurrent abortions and polyhydramnios are common in the mothers of the affected individuals. Prenatal signs are non-specific: agenesis of the corpus callosum, ventriculomegaly/hydrocephaly. Detection of the mutation by chorionic villus biopsy or amniocentesis should be discussed with the parents of an index case during subsequent pregnancies.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Management requires a lifelong multidisciplinary approach. Regular follow‐up by a pediatrician, neurologist, psychologist/psychiatrist will be very helpful. Periodical evaluations are required to find the most suitable medical services for the individual patient. Symptomatic medications can be used (antiepileptic and antispasticity drugs).
Prognosis
The course of the disease is progressive. Longitudinal data are insufficient to determine the life expectancy and the real amplitude of the phenotypic spectrum.

                            Last update: 
                            May 2022


                            - Expert reviewer(s): 
                            Dr Carlo FUSCO  - Dr Susanna RIZZI