EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations
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- 作者：Veerle RC Eggens (1)
Peter G Barth (2)
Jikke-Mien F Niermeijer (2)
Jonathan N Berg (3)
Niklas Darin (4)
Abhijit Dixit (5)
Joel Fluss (6)
Nicola Foulds (7)
Darren Fowler (8)
Tibor Hortobágyi (9)
Thomas Jacques (10)
Mary D King (11)
Periklis Makrythanasis (12)
Adrienn Máté (13)
James AR Nicoll (14)
Declan O’Rourke (11)
Sue Price (15)
Andrew N Williams (15)
Louise Wilson (16)
Mohnish Suri (5)
Laszlo Sztriha (17)
Marit B Dijns-de Wissel (1)
Mia T van Meegen (1)
Fred van Ruissen (1)
Eleonora Aronica (18)
Dirk Troost (18)
Charles BLM Majoie (19)
Henk A Marquering (19) (20)
Bwee Tien Poll-Thé (2)
Frank Baas (1) - 关键词：Pontocerebellar hypoplasia ; Neurodegeneration ; EXOSC3 gene ; Genotype ; phenotype correlations
- 刊名：Orphanet Journal of Rare Diseases
- 出版年：2014
- 出版时间：December 2014
- 年：2014
- 卷：9
- 期：1
- 全文大小：373 KB
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Peter G Barth (2)
Jikke-Mien F Niermeijer (2)
Jonathan N Berg (3)
Niklas Darin (4)
Abhijit Dixit (5)
Joel Fluss (6)
Nicola Foulds (7)
Darren Fowler (8)
Tibor Hortobágyi (9)
Thomas Jacques (10)
Mary D King (11)
Periklis Makrythanasis (12)
Adrienn Máté (13)
James AR Nicoll (14)
Declan O’Rourke (11)
Sue Price (15)
Andrew N Williams (15)
Louise Wilson (16)
Mohnish Suri (5)
Laszlo Sztriha (17)
Marit B Dijns-de Wissel (1)
Mia T van Meegen (1)
Fred van Ruissen (1)
Eleonora Aronica (18)
Dirk Troost (18)
Charles BLM Majoie (19)
Henk A Marquering (19) (20)
Bwee Tien Poll-Thé (2)
Frank Baas (1)
1. Department of Genome Analysis, Academic Medical Centre, Amsterdam, the Netherlands
2. Division of Pediatric Neurology, Emma’s Children’s Hospital, Academic Medical Centre, Amsterdam, the Netherlands
3. Division of Pathology and Neuroscience, University of Dundee, Dundee, UK
4. Department of Paediatrics, University of Gothenburg, The Queen Silvia’s Children Hospital, Gothenburg, Sweden
5. Clinical Genetics, Nottingham City Hospital, Nottingham, UK
6. Pediatric Neurology, Children’s Hospital, Geneva, Switzerland
7. Clinical Genetics Service, Southampton University Hospitals Trust, Southampton, UK
8. Paediatric Pathology, University Hospital Southampton NHS Trust, Southampton, UK
9. Department of Neuropathology, Institute of Pathology, University of Debrecen, Debrecen, Hungary
10. Neural Development Unit, UCL Institute of Child Health and the Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
11. Paediatric Neurology, Childrens University Hospital, Temple St, Dublin, Ireland
12. Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
13. Department of Neurosurgery, University of Szeged, Szeged, Hungary
14. Clinical and Experimental Sciences, University of Southampton, Southampton, UK
15. Virtual Academic Unit, Child Development Centre, Northampton, Northants, UK
16. Clinical Genetics, Great Ormond Street Hospital, London, UK
17. Department of Paediatrics, University of Szeged, Szeged, Hungary
18. Department of (Neuro)Pathology, Academic Center, University of the Netherlands, Amsterdam, the Netherlands
19. Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands
20. Department of Biomedical Engineering and Physics, AMC, Amsterdam, the Netherlands - ISSN：1750-1172
文摘
Background 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. Methods 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. Results 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. Conclusions 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.