What's new in pontocerebellar hypoplasia? An update on genes and subtypes

Abstract

Background: Pontocerebellar hypoplasia (PCH) describes a rare, heterogeneous group of neurodegenerative disorders mainly with a prenatal onset. Patients have severe hypoplasia or atrophy of cerebellum and pons, with variable involvement of supratentorial structures, motor and cognitive impairments. Based on distinct clinical features and genetic causes, current classification comprises 11 types of PCH.

Main text: In this review we describe the clinical, neuroradiological and genetic characteristics of the different PCH subtypes, summarize the differential diagnosis and reflect on potential disease mechanisms in PCH. Seventeen PCH-related genes are now listed in the OMIM database, most of them have a function in RNA processing or translation. It is unknown why defects in these apparently ubiquitous processes result in a brain-specific phenotype.

Conclusions: Many new PCH related genes and phenotypes have been described due to the appliance of next generation sequencing techniques. By including such a broad range of phenotypes, including non-degenerative and postnatal onset disorders, the current classification gives rise to confusion. Despite the discovery of new pathways involved in PCH, treatment is still symptomatic. However, correct diagnosis of PCH is important to provide suitable care and counseling regarding prognosis, and offer appropriate (prenatal) genetic testing to families.

Keywords: Genetics; Pediatric neurology; Pontocerebellar hypoplasia.

Fig. 1

Simplified representation of main characteristic symptoms in PCH and similar conditions. DSD = Disorder of Sex Development, CC = Corpus callosum, MEB = Muscle-eye-brain disease, WWS = Walker Warburg syndrome, CDG1A = Congenital disorder of Glycosylation type Ia, SCA = Spinocerebellar ataxia. Note that exceptions are possible in most categories due to large phenotypic variability. *The strongest correlation of a dragonfly configuration of the cerebellum and dystonia is with PCH2A. In other PCH2 subtypes, that are all very rare, cerebellar hypoplasia may be less profound and extrapyramidal movement disorders absent. In PCH2E, brain MRI is initially normal; cerebellar atrophy becomes apparent in the first year of life. In addition, osteoporosis and scoliosis were reported in PCH2E.** (Relative) sparing of the pons can also be seen in milder affected patients with other PCH subtypes

Fig. 2

MR images in different PCH subtypes. a-b. Coronal (a) and midsagittal (b) image of severely affected PCH1B patient (age 3 weeks, homozygous for the p. G31A mutation in EXOSC3), showing severe hypoplasia of cerebellar hemisphere with relative sparing of the vermis (indicated by arrowhead). The ventral pons is reduced in size but not completely flattened (indicated by arrow). c-d. Coronal (c) and midsagittal (d) image of PCH1B patient (age 2,5 months) with milder EXOSC3 mutations(the patient is homozygous for the p.D132A mutation). Cerebellar hypoplasia is very mild, with bilateral hyperintensities in the hili of the dentate nucleus. Size and shape of the ventral pons are normal. e-f. Coronal (e) and midsagittal (f) image of PCH2A patient (age 7 days, homozygous for the TSEN54, p.A307S mutation) with severe flattening of cerebellar hemispheres with relative sparing of the vermis (indicated by arrowhead) resulting in the ‘dragonfly’ configuration typical of PCH2A. This pattern is also seen in some PCH1 patients, as shown in 1A. The ventral pons is reduced in size but not completely flattened. g-h. Coronal (g) and midsagittal (h) image of PCH4 patient (age 6 weeks, compound heterozygous for the p. A307S mutation and a frameshift mutation in the TSEN54 gene). Note severe flattening of pons and severe hypoplasia of the cerebellum without sparing of the vermis and profound supratentorial atrophy (indicated by asterisks). i-j. Coronal (i) and midsagittal (j) image of a PCH6 patient (age 6 months, compound heterozygous for mutations in the RARS2 gene) with strikingly rapid progression of supratentorial atrophy (indicated by asterisks) and relatively slight atrophy of cerebellar hemispheres with normal pons and brainstem. k-l. Coronal (k) and midsagittal (l) image of a PCH7 patient (age 8 months, with biallelic mutations in the TOE1 gene), showing severe pontocerebellar hypoplasia, equally affecting hemispheres and vermis. Note very thin corpus callosum and profound ventriculomegaly (indicated by asterisks and ^, respectively). m-n. Coronal and midsagittal image of a PCH9 patient (age 2 years, homozygous for a mutation in the AMPD2 gene), showing characteristic ‘figure 8’ shaped brainstem and corpus callosum agenesis (indicated by a circle and arrowhead, respectively).o-p. Coronal and midsagittal image of a control

Fig. 3

Schematic representation of main pathways involved in PCH. A. Schematic and simplified representation of tRNA splicing by the TSEN complex and CLP1. B. Schematic figure of the exosome complex including EXOSC3, located in the RNA binding cap, and EXOSC8, located in the core ring. The exosome complex processes mRNA, rRNA and presumably tRNA. C. Upper: charging of tRNA-Arg by RARS2. Lower: conversion of Sec-tRNA-Ser to Sec-tRNA-Sec by SEPSECS

Fig. 4

Pie-chart showing proportions of PCH patients per PCH pathway. Patient numbers are estimated based on published reports and reviews and depicted between brackets