Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia

Abstract

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.

Figure 1

Study design.

Figure 2

Examples of MRI scores of cerebellum. (A and B) Cerebellar hemisphere score 1: dragonfly type, with flat cerebellar hemispheres and a relatively spared cerebellar vermis (coronal sections, T₂-weighted, 9 months). Mild atrophy of the cerebral cortex with visible sulci. Homozygous for common TSEN54 mutation. (C) Cerebellar hemisphere score 2: butterfly type, with hypoplastic cerebellar hemispheres. Decrease in size of the vermis is proportional to the diminution in size of the hemispheres (coronal section, T₁-weighted, 7 years). In addition, cerebellar cortical atrophy is seen, as well as mild atrophy of the cerebral cortex with visible sulci. No mutation identified. (D) Cerebellar hemisphere score 3: postnatal atrophy-like on the right side, combined with mild cerebellar hypoplasia on the left (coronal section, T₂-weighted, 10 months). In addition there is cerebral cortical atrophy with visible sulci. Heterozygote for uncommon TSEN54 mutation (p.G124V) plus heterozygote for common TSEN54 mutation.

Figure 3

Progressive microcephaly in patients with the common mutation. Frontal-occipital circumference was measured in 38 cases (61 measurements). Measurements of individual patients are connected within the first 3 years of life to illustrate rates of progression. Reference measurements were used from Roche et al. (1987).

Figure 4

Typical MRI seen in the common mutation group. Flat ventral surface of the pons, cerebellar hemispheric and mild vermal hypoplasia. In this case without significant folial atrophy (sagittal sections, T₂-weighted, 9 months). The corpus callosum is too thin. Homozygous for common TSEN54 mutation.

Figure 5

Additional findings in patients with the common mutation (A). Neocortical atrophy (sagittal view, T₂-weighted, 9 months). Homozygous for common TSEN54 mutation. (B and C) Cerebellar vermal (B) and hemispheric cyst (C). Mid and lateral sagittal sections from Patient Am1b II.1 (T₁-weighted Inversion Recovery, 12 months). Homozygous for common TSEN54 mutation.

Figure 6

Typical findings in severe mutation group (pontocerebellar hypoplasia type 4 phenotype). (A) Showing flat lower surface of the pons and more severe involvement of vermis with extreme hypoplasia and moderate atrophy (midsagittal section, T₂-weighted, 31+5 weeks). Heterozygote for nonsense mutation in TSEN54 (p.R353GfsX81) plus heterozygote for common TSEN54 mutation. (B) Coronal image shows extremely small and flattened cerebellar hemispheres. The inferior vermis projects slightly below the hemispheres. Small appendages below the vermis possibly represent tonsils or flocculi, in this case (coronal view, T₁-weighted, 31+5 weeks). Heterozygote for nonsense mutation in TSEN54 (p.R353GfsX81) plus heterozygote for common TSEN54 mutation. (C) Increased extracerebral space, wide-open sylvian fossa and shallow frontal sulci indicating delay in neocortical maturation (axial T₂-weighted, 31+5 weeks). Heterozygote for nonsense mutation in TSEN54 (p.R353GfsX81) plus heterozygote for common TSEN54 mutation.