Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia

Yasmin Namavar, Peter G. Barth, Paul R. Kasher, Fred Van Ruissen, Knut Brockmann, Günther Bernert, Karin Writzl, Karen Ventura, Edith Y. Cheng, Donna M. Ferriero, Lina Basel-Vanagaite, Veerle R.C. Eggens, Ingeborg Krägeloh-Mann, Linda De Meirleir, Mary King, John M. Graham, Arpad Von Moers, Nine Knoers, Laszlo Sztriha, Rudolf KorinthenbergWilliam B. Dobyns, Frank Baas*, Bwee Tien Poll-The

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

180 Scopus citations


Pontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P<0.0005) between TSEN54 mutations and a dragonfly-like cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. Mutations in TSEN54 are clinically associated with dyskinesia and/or dystonia and variable degrees of spasticity, in some cases with pure generalized spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype of more perinatal symptoms, ventilator dependency and early death. In addition, we present ten new mutations in TSEN54, TSEN2 and RARS2. Furthermore, we show that pontocerebellar hypoplasia type 1 together with elevated cerebrospinal fluid lactate may be caused by RARS2 mutations.

Original languageEnglish
Pages (from-to)143-156
Number of pages14
Issue number1
StatePublished - Jan 2011
Externally publishedYes


FundersFunder number
Medical Research CouncilG0601943
Universiteit van Amsterdam


    • RARS2
    • TSEN
    • neurogenetics
    • neuroimaging
    • pontocerebellar hypoplasia


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