Brain Morphometry in Pontocerebellar Hypoplasia Type 2

Objective: Pontocerebellar hypoplasia type 2 (PCH2) is caused by a defect in the TSEN54 gene and leads to severe and early disruption of brain development, especially of cerebellum and pons. The aim of this article was to quantify the growth of several brain structures during brain development in children with PCH2.

Methods: A total of 32 magnetic resonance images (MRI) of 24 children with PCH2 (age range, 0.02-17 years.) were analyzed volumetrically and compared with images of 34 typically developing children (age range, 0.02-17 years.) with similar age and gender distribution (derived from National Institutes of Health MRI study of normal brain development). All children with PCH2 had the p.A307S mutation in the TSEN54 gene.

Images of the children with PCH2 were available either on film (n = 12) or in digital format (n = 20). To quantify all images volumetrically, images on film were digitalized. First, manual brain masks were generated and then semi-automatically adjusted further using intensity thresholds. Volumes of cerebellum, brain stem, and area of pons, as well as cerebral volume and volume of frontal lobes were measured. For validation of the method part of the digital images of patients and controls were processed as images on film. Furthermore, intra- and inter-rater variability was tested.

Results: Children with PCH2 showed the reduced volume of all measured brain structures compared with healthy controls. The difference was largest in volumes of cerebellum, pons, and brain stem. In postnatal development, infratentorial structures increased only little in size, and this reduced growth was also seen in the longitudinal measures of four patients. Also, the supratentorial brain volume showed reduced growth compared with the healthy controls, the frontal lobe was not affected predominantly.

Validation of the method showed a high precision and reproducibility, also in measurements on film.

Conclusions: In a genetically very homogenous group of children with PCH2, standardized volumetric data were presented and compared with healthy controls. In addition to the infratentorial brain structures, also the supratentorial brain growth was reduced. Two mechanisms might contribute to this; on the one hand, a severe disruption of the cerebellar-cerebral networks caused by a primary cerebellar dysfunction, and on the other hand a postnatal neurodegeneration.