Pontocerebellar hypoplasia (PCH) represents a group of autosomal-recessive progressive neurodegenerative disorders of prenatal onset. Eleven PCH subtypes are classified according to clinical, neuroimaging and genetic findings. Individuals with PCH type 9 (PCH9) have a unique combination of postnatal microcephaly, hypoplastic cerebellum and pons, and hypoplastic or absent corpus callosum. PCH9 is caused by biallelic variants in AMPD2 encoding adenosine monophosphate deaminase 2; however, a homozygous AMPD2 frameshift variant has recently been reported in two family members with spastic paraplegia type 63 (SPG63). We identified homozygous or compound heterozygous AMPD2 variants in eight PCH-affected individuals from six families. The eight variants likely affect function and comprise one frameshift, one nonsense and six missense variants; seven of which were novel. The main clinical manifestations in the eight new patients and 17 previously reported individuals with biallelic AMPD2 variants were postnatal microcephaly, severe global developmental delay, spasticity, and central visual impairment. Brain imaging data identified hypomyelination, hypoplasia of the cerebellum and pons, atrophy of the cerebral cortex, complete or partial agenesis of the corpus callosum and the "figure 8" shape of the hypoplastic midbrain as consistent features. We broaden the AMPD2-related clinical spectrum by describing one individual without microcephaly and absence of the characteristic "figure 8" shape of the midbrain. The existence of various AMPD2 isoforms with different functions possibly explains the variability in phenotypes associated with AMPD2 variants: variants leaving some of the isoforms intact may cause SPG63, while those affecting all isoforms may result in the severe and early-onset PCH9.
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Acknowledgements We are grateful to the families who contributed to this study. We would like to thank Inka Jantke for skillful technical assistance and Jelena Bircic and Anna Podolska for help with WES data interpretation and segregation analysis in family 1. This work was supported by grants from the Deutsche Forschungsgemeinschaft (KO 4576/1–2 to F.K. and KU 1240/10–1 to K.K.), the Department of Health Research [project “Clinical and molecular characterization of leukodystrophies in Indian children” (V.25011/379/2015-GIA/HR)], and the EU 7th Framework Programme (FP7) under the project DESIRE (N602531 to R.G.).
Conflict of Interest K.L.H. was and S.T. is employed by and receive a salary from Ambry Genetics; whole-exome sequencing is among its commercially available tests. D.H. is employed by and receives a salary from MVZ Labor Leipzig. R.G. has received travel funding and honoraria for Advisory Board activities from Eisai, Inc., Novartis, and Zogenix; has received travel funding from UCB; has served on the editorial boards of Epilepsia, Progress in Epileptic Disorders, Neuro-pediatrics, the Journal of Child Neurology, Seizure, BMC Medical Genetics, Topics in Epilepsy, the Journal of Pediatric Epilepsy, Epileptic Disorders, the European Neurological Journal, Neurology, and the Journal of Embryology and Developmental Biology; receives publishing royalties from Cambridge University Press, Lippincott Williams and Wilkins, John Libbey Eurotext, and Oxford University Press; and has received research support from the European Union, Tuscany Region Research Department, EC, Italian Ministry of Health and, and the Pisa Foundation. The other authors report no disclosures relevant to the manuscript.