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Eur J Hum Genet. 2018 May;26(5):695-708. doi: 10.1038/s41431-018-0098-2. Epub 2018 Feb 20.

Clinical and genetic spectrum of AMPD2-related pontocerebellar hypoplasia type 9.

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Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
University Medical Center Hamburg-Eppendorf, Bioinformatics Core, Hamburg, Germany.
Division of Genetics and Metabolism, Departments of Pediatrics and Genetics, Cell Biology & Development, University of Minnesota, Minneapolis, MN, USA.
Institute of Human Genetics, University of Ulm, Ulm, Germany.
Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Praxis für Humangenetik, MVZ Labor Leipzig, Leipzig, Germany.
Klinikum Oldenburg, Zentrum für Kinder- und Jugendmedizin, Klinik für Neuropädiatrie und angeborene Stoffwechselerkrankungen, Oldenburg, Germany.
Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.
Division of Neuropaediatrics, Development and Rehabilitation, University Children's Hospital Bern, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
IRCCS Stella Maris, Pisa, Italy.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.


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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