Pontocerebellar hypoplasia type 2: a neuropathological update

Abstract

Pontocerebellar hypoplasia type 2 (PCH-2; MIM 277470), an autosomal recessive neurodegeneration with fetal onset, was studied in six autopsies with ages at death ranging between 1 and 22 years. Three patients were distantly related. A case of olivopontocerebellar hypoplasia (OPCH; MIM 225753) was studied for comparison. Typical findings are: short cerebellar folia with poor branching ("hypoplasia"), relative sparing of the vermis, sharply demarcated areas of full thickness loss of cerebellar cortex probably resulting from regression at an early stage of development, segmental loss of dentate nuclei with preserved islands and reactive changes, segmental loss in the inferior olivary nucleus with reactive changes, loss of ventral pontine nuclei with near absence of transverse pontine fibers and sparing of spinal anterior horn cells. Variable findings are: cystic cerebellar degeneration, found in two, with vascular changes limited to the cerebellum in one. Comparison to olivopontocerebellar hypoplasia (OPCH) strongly suggests a continuum of pathology between this disorder and PCH-2. Immunohistochemical evaluation of the endoplasmic reticulum stress response is negative. We conclude that the neuropathological findings in PCH-2 are sufficiently specific to enable an unequivocal diagnosis based on neuropathology.

Fig. 1

MRI of patient 6 at 2 months. a Midsagittal inversion recovery sequence: flat aspect of ventral pons and moderate vermal hypoplasia. b Coronal T2-weighted image: severe hypoplasia of the cerebellar hemispheres (arrows) together filling only a fraction of the posterior fossa

Fig. 2

Pedigree linking patients 4, 5 and 6 in the present report; IX, 1 and IX, 3 were reported before [5]

Fig. 3

Hypoplastic folia. Stains, synaptophysin. Sagittal sections of cerebellar hemispheres are seen on the left and detailed views on the right. Stunted folial growth with decreased number of folial branches. a, b Male, 8 years, with accidental death and normal findings on autopsy (control); c, d case 4; e, f case 6; g, h case 5. Marker bars on the left 1 cm, and on the right 1 mm

Fig. 4

Vermis cerebelli, case 5. Stains, a HE, b GFAP, c neurofilament protein, d vimentin. a–c Adjacent sections with circumscript segments of loss of all layers and glial reaction. Arrows in (a) point to circumscript areas of lost cortex. d Sharply demarcated foci and replacing bands of astrocytes possibly modified Bergmann cells. Marker bar in (d) = 500 μm

Fig. 5

Cerebellar hemispheric cortex with segmental lesions. Stains, a, h synaptophysin, b–d vimentin, e, g, i GFAP, f MAP-2. Case 6: opposing arrows mark lesions with loss of all cortical layers (a) and glial replacement (b). c, d Case 5: segment of whole thickness loss of cortex is replaced by a single layer of evenly spaced astrocytes, their topography compatible with modified Bergmann cells. e, f, g Case 4: segmental loss of cortex with glial replacement marked by opposing arrows; in (f) higher magnification shows a group of remaining isolated granule cells. h, i Case 2: segmental loss of cortex on top of a folium in moderately hypoplastic cortex. Marker bars: a–c, e, g–i = 0.5 mm, d = 0.25 mm, f = 50 μm

Fig. 6

Flocculus. Cerebellar hemispheric cortex, case 2, synaptophysin. Floccular cortex shows broader folial cores and denser granule cell population than other parts of the cortex

Fig. 7

Dentate nucleus, case 6. MAP-2. Loss of normal outline with remaining dentate neurons clustered in “islands”. Marker bar = 1 mm

Fig. 8

Dentate nucleus, details. Stains: a MAP-2, b MBP, c, d calbindin, e synaptophysin, f SMI31. a Case 6: fine vacuolation surrounding neurons. b Case 1: myelinated fibers separate individual neurons and their surrounding vacuoles. c, d Cases 6, 1: some vacuoles are decorated by antibody; e Case 2: concentration of vesicles (dots) indicates high synaptic density on soma and dendrites of surviving neuron. f Case 1: thickened axons in hilus of dentate nucleus. Marker bars = 100 μm

Fig. 9

Cerebellar cyst, case 5. a Vimentin, c HLA-DR. a Collapsed cyst seamed by astroglial reaction. b T1-weighted axial image of posterior fossa of patient at 1 month age shows the cysts in expanded state. c Macrophage reaction on the inside of the cyst

Fig. 10

Regressive changes, case 3. Stains: a GFAP, b HLA-DR, c double labeling for HLA-DR (green) and ubiquitine (red), confocal laser microscopy, d ubiquitin. a Transverse cerebellar section with cortical and subcortical gliosis, loss of the subcortical and central cerebellar structure, in part cystic, broken cortical lining in places suggest segmental lesions similar to other cases before ultimate decay; b abundance of reactive macrophages, predominantly in and surrounding blood vessels with thickened vessel walls; c ubiquitin is mostly restricted to vessel wall and macrophages are partly positive for ubiquitin; d neuron of nucleus magnus raphes (pontine tegmentum) with cytoplasmic inclusion and positivity extending into the neurite. Marker bars: b = 200 μm, c = 50 μm

Fig. 11

Inferior olivary nucleus. Stains: a–c MAP-2, d vimentin. case 6 and 5: segmental loss of inferior olivary nucleus with intact dorsal (a) and medial (b) accessory nuclei. c Case 3. Complete loss of nucleus, including accessory nuclei, only sparse isolated neurons remaining, indicated by arrowheads; inset shows magnified solitary olivary neuron. d Case 3. Outline of lost lateral leaf reveals mature folding. Marker bars = 0.5 mm

Fig. 12

OPCH, case 7. Stains: a, e synaptophysin, b vimentin, c, d, f MAP-2. a Whole mount transverse section of cerebellum and medulla oblongata: denuded hemispheric cerebellar cortex and striking preservation of nodulus and flocculi. b Hemispheric cortex lined by a single row of fibrous astrocytes. c “Empty” cerebellar cortex, arrows indicate some remaining neurons. d Higher magnification of c, arrowhead indicates bipolar neuron, possibly basket cell; arrow indicates malpositioned Purkinje cell. e Overview of cerebellar hemisphere, arrows at residues of dentate nucleus. f Single residual island of dentate nucleus with well-developed neurons. Marker bars: b 200 mμ, c 1 mm, d 100 mμ, e 1 mm, f 100 mμ

Fig. 13

OPCH, case 7. Stain, synaptophysin. Medulla oblongata with olivary nuclei. Inferior olivary nucleus with complete lack of folding. Lateral and medial leaves with segmental defects. Medial accessory olive is preserved in its dorsal part and shows discontinuities in its ventral part. Marker bar 0.5 mm