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

Eggens VR, Barth PG, Niermeijer JM, Berg JN, Darin N, Dixit A, Fluss J, Foulds N, Fowler D, Hortobágyi T, Jacques T, King MD, Makrythanasis P, Máté A, Nicoll JA, O'Rourke D, Price S, Williams AN, Wilson L, Suri M, Sztriha L, Dijns-de Wissel MB, van Meegen MT, van Ruissen F, Aronica E, Troost D, Majoie CB, Marquering HA, Poll-Thé BT, Baas F - Orphanet J Rare Dis (2014)

Bottom Line: EXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes.Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genome Analysis, Academic Medical Centre, Amsterdam, the Netherlands. f.baas@amc.uva.nl.

ABSTRACT

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.

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Related in: MedlinePlus

Pons abnormalities in patient with p.G31A mutation. Luxol/PAS staining of the pons shows small pons and reduction of transverse pontine fibres (B) and pontine neurons (D) in a patient with a homozygous p.G31A mutation (patient 1) compared to age matched control (A and C). Scale bar A and B=0.5cm, C and D=100μm. VP=ventral pons; T=tegmentum.
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Figure 3: Pons abnormalities in patient with p.G31A mutation. Luxol/PAS staining of the pons shows small pons and reduction of transverse pontine fibres (B) and pontine neurons (D) in a patient with a homozygous p.G31A mutation (patient 1) compared to age matched control (A and C). Scale bar A and B=0.5cm, C and D=100μm. VP=ventral pons; T=tegmentum.

Mentions: Autopsy was performed on one patient with a p.G31A mutation (patient 1). No MRI was made of this patient, but post mortem results showed atrophy of cerebellar hemispheres, inferior and middle cerebellar peduncles. The cerebellar hemispheres were poorly developed and presented a smooth surface. Histological analysis showed a reduced number of Purkinje cells and a fragmented dentate nucleus. The number of transverse pontine fibres and pontine neurons was reduced compared to control tissue (Figure 3).


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

Eggens VR, Barth PG, Niermeijer JM, Berg JN, Darin N, Dixit A, Fluss J, Foulds N, Fowler D, Hortobágyi T, Jacques T, King MD, Makrythanasis P, Máté A, Nicoll JA, O'Rourke D, Price S, Williams AN, Wilson L, Suri M, Sztriha L, Dijns-de Wissel MB, van Meegen MT, van Ruissen F, Aronica E, Troost D, Majoie CB, Marquering HA, Poll-Thé BT, Baas F - Orphanet J Rare Dis (2014)

Pons abnormalities in patient with p.G31A mutation. Luxol/PAS staining of the pons shows small pons and reduction of transverse pontine fibres (B) and pontine neurons (D) in a patient with a homozygous p.G31A mutation (patient 1) compared to age matched control (A and C). Scale bar A and B=0.5cm, C and D=100μm. VP=ventral pons; T=tegmentum.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3928094&req=5

Figure 3: Pons abnormalities in patient with p.G31A mutation. Luxol/PAS staining of the pons shows small pons and reduction of transverse pontine fibres (B) and pontine neurons (D) in a patient with a homozygous p.G31A mutation (patient 1) compared to age matched control (A and C). Scale bar A and B=0.5cm, C and D=100μm. VP=ventral pons; T=tegmentum.
Mentions: Autopsy was performed on one patient with a p.G31A mutation (patient 1). No MRI was made of this patient, but post mortem results showed atrophy of cerebellar hemispheres, inferior and middle cerebellar peduncles. The cerebellar hemispheres were poorly developed and presented a smooth surface. Histological analysis showed a reduced number of Purkinje cells and a fragmented dentate nucleus. The number of transverse pontine fibres and pontine neurons was reduced compared to control tissue (Figure 3).

Bottom Line: EXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes.Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genome Analysis, Academic Medical Centre, Amsterdam, the Netherlands. f.baas@amc.uva.nl.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus