Classic “PCH” Genes are a Rare Cause of Radiologic Pontocerebellar Hypoplasia

Abstract

Background: The term Pontocerebellar Hypoplasia (PCH) was initially used to designate a heterogeneous group of fetal-onset genetic neurodegenerative disorders. As a descriptive term, PCH refers to pons and cerebellum of reduced volume. In addition to the classic PCH types, many other disorders can result in a similar imaging appearance.Objective: To review imaging, clinical and genetic features and underlying etiologies of a cohort of children with PCH on imaging.Methods: We systematically reviewed brain images and clinical charts of 38 patients with radiologic evidence of PCH.Results: Our cohort included 21 males and 17 females, with ages ranging between 8 days to 15 years. All individuals had pons and cerebellar vermis hypoplasia, and 63% had cerebellar hemisphere hypoplasia. Supratentorial anomalies were found in 71%. An underlying etiology was identi ed in 65% and included chromosomal (21%), monogenic (34%) and acquired (10%) causes. Only one patient had pathogenic variants in a "classic" PCH gene. Outcomes were poor regardless of etiology, though no one had regression. Approximately one third of patients deceased at a median age of 8 months. All individuals had global developmental delay, 50% were non-verbal, 64% were non-ambulatory and 45% required gastrostomy feeding. Conclusion:Radiologic PCH has heterogenous etiologies and the "classic" PCH genes underlie only a minority of cases. Broad genetic testing, including chromosomal microarray and exome or multigene panels, is recommended in individuals with PCH-like imaging appearance. Our results strongly suggest that the term PCH should be used to designate radiologic ndings, and not to imply neurogenerative disorders.

Case report: A severe clinical phenotype of pontocerebellar hypoplasia type 7 with compound heterozygous variants of TOE1

“…PCH is a rare autosomal recessive hereditary neurological degenerative disease that has a typical prenatal onset [ 17 ]. The common features of PCH include pons and cerebellum atrophy, progressive microcephaly, different degrees of ventricular dilation, severe cognitive impairment, motor disorders, and seizures.…”

IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency

“…Patients usually present developmental delay, feeding problems and motor abnormalities, with the most severe cases showing regression and early death due to respiratory problems (van Dijk et al , 2018). Current classification comprises 17 types of PCH which are distinguished by the genetic diagnosis, brain imaging and clinical features (Zakaria et al , 2023). Functional annotation of PCH associated genes suggest impaired protein synthesis, RNA or energy metabolism as the underlaying pathogenic mechanism (van Dijk et al ., 2018).…”