Pontocerebellar Hypoplasia Type 9: A New Subtype

Case Study: Pontocerebellar hypoplasia (PCH) comprises a group of autosomal recessive neurodegenerative disorders with mostly prenatal onset. Clinical hallmarks are severe global developmental delay as well as specific neurologic symptoms depending on the subtype of PCH. Treatment is symptomatic and affected individuals often die during the neonatal period or infancy.

All currently reported PCH subtypes share common neuroradiological characteristics such as hypoplasia of the cerebellum and pons, progressive microcephaly, and a variable degree of cerebral involvement.

The genetic heterogeneity of the disorder and its low incidence make molecular genetic diagnosis challenging. Mutations of the transfer RNA (tRNA) splicing endonuclease complex have been reported for the subtypes PCH 2, 4 and 5, and of the mitochondrially encoded arginyl-tRNA synthetase for PCH6, while vaccinia-related kinase 1 is mutated in the minority of PCH1. Finally, the recently reported PCH9 type is causally related to mutations in the AMPD2 gene. All these genes are crucial for the pathogenesis of PCH by regulating RNA and thus protein synthesis.

We report the case of a 4-year-old boy of consanguineous parents with PCH. Clinically, a retardation of motor and cognitive development, dysphagia, early-onset tetraspasticity, as well as hypoacusis were found. MR imaging demonstrated hypoplasia of both pons and cerebellum together with white matter defects and agenesis of the corpus callosum. Exome sequencing detected a homozygous AMPD2 mutation (c.1648G > A and p.Glu550Lys) predicted as putatively pathogen by PolyPhen-2 and SIFT. On the basis of the clinical and radiological findings as well as the results of molecular genetic testing, the diagnosis of PCH9 could thus be established.

The growing knowledge of the underlying genetic defects of PCH widens the clinical spectrum of the disease by novel phenotypic features. Although it might soon be possible to establish many PCH diagnoses by molecular genetic testing, we hope our case contributes to a more precise clinical characterization of PCH9.

Keywords: pontocerebellar hypoplasia, neurodegenerative disorder, global developmental delay.