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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Orphanet Journal of Rare Diseases 1/2014

EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations

Orphanet Journal of Rare Diseases > Ausgabe 1/2014
Veerle RC Eggens, Peter G Barth, Jikke-Mien F Niermeijer, Jonathan N Berg, Niklas Darin, Abhijit Dixit, Joel Fluss, Nicola Foulds, Darren Fowler, Tibor Hortobágyi, Thomas Jacques, Mary D King, Periklis Makrythanasis, Adrienn Máté, James AR Nicoll, Declan O’Rourke, Sue Price, Andrew N Williams, Louise Wilson, Mohnish Suri, Laszlo Sztriha, Marit B Dijns-de Wissel, Mia T van Meegen, Fred van Ruissen, Eleonora Aronica, Dirk Troost, Charles BLM Majoie, Henk A Marquering, Bwee Tien Poll-Thé, Frank Baas
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1750-1172-9-23) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare to have no competing interests.

Authors’ contribution

VRCE collected and analysed the data and wrote the manuscript. PGB had a valuable contribution in writing and revising the manuscript. FvR, MBD-dW and MTvM performed molecular genetic analysis. PGB, JFN and BTP-T analysed MRI scans and were closely involved in discussions. JNB, ND, AD, JF, NF, DF, TH, TJ, MK, PM, AM, JARN, DO’R, SP, ANW, LW, MS and LS provided clinical information. EA, DT, TJ and TH provided post mortem tissue and stainings. CBM and HAM were involved in neuroradiological analysis. FB coordinated the study and the writing of the manuscript. All authors read, revised and approved the final manuscript.



Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1.


We selected a cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. Patients in this cohort were referred with a tentative diagnose PCH type 1, 2, 4, 7 or unclassified PCH. Genetic analysis of the EXOSC3 gene was performed using Sanger sequencing. Clinical data, MR images and autopsy reports of patients positive for EXOSC3 mutations were analyzed.


EXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes. Identified mutations included a large deletion, nonsense and missense mutations. Examination of clinical data reveals a prolonged disease course in patients with a homozygous p.D132A mutation. MRI shows variable pontine hypoplasia in EXOSC3 mediated PCH, where the pons is largely preserved in patients with a homozygous p.D132A mutation, but attenuated in patients with other mutations. Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele.


EXOSC3 mediated PCH shows clear genotype-phenotype correlations. A homozygous p.D132A mutation leads to PCH with possible survival into early puberty, and preservation of the pons. Compound heterozygosity for a p.D132A mutation and a nonsense or p.Y109N allele, a homozygous p.G31A mutation or a p.G135E mutation causes a more rapidly progressive course leading to death in infancy and attenuation of the ventral pons.
Our findings imply a clear correlation between genetic mutation and clinical outcome in EXOSC3 mediated PCH, including variable involvement of the pons.
Additional file 1:Supplementary methods.(DOC 32 KB)
Authors’ original file for figure 1
Authors’ original file for figure 2
Authors’ original file for figure 3
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