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. 2015 Jun 25:3:37.
doi: 10.1186/s40478-015-0214-2.

Distinct pathological phenotypes of Creutzfeldt-Jakob disease in recipients of prion-contaminated growth hormone

Ignazio Cali  1   2 , Cathleen J Miller  3 , Joseph E Parisi  4 , Michael D Geschwind  5 , Pierluigi Gambetti  6 , Lawrence B Schonberger  7
Affiliations

Distinct pathological phenotypes of Creutzfeldt-Jakob disease in recipients of prion-contaminated growth hormone

Ignazio Cali et al. Acta Neuropathol Commun. .

Abstract

Introduction: The present study compares the clinical, pathological and molecular features of a United States (US) case of growth hormone (GH)-associated Creutzfeldt-Jakob disease (GH-CJD) (index case) to those of two earlier referred US cases of GH-CJD and one case of dura mater (d)-associated CJD (dCJD). All iatrogenic CJD (iCJD) subjects were methionine (M) homozygous at codon 129 (129MM) of the prion protein (PrP) gene and had scrapie prion protein (PrP(Sc)) type 1 (iCJDMM1).

Results: The index subject presented with ataxia, weight loss and changes in the sleep pattern about 38 years after the midpoint of GH treatment. Autopsy examination revealed a neuropathological phenotype reminiscent of both sCJDMV2-K (a sporadic CJD subtype in subjects methionine/valine heterozygous at codon 129 with PrP(Sc) type 2 and the presence of kuru plaques) and variant CJD (vCJD). The two earlier cases of GH-CJDMM1 and the one of dCJDMM1 were associated with neuropathological phenotypes that differed from that of the index case mainly because they lacked PrP plaques. The phenotype of the earlier GH-CJDMM1 cases shared several, but not all, characteristics with sCJDMM1, whereas dCJDMM1 was phenotypically indistinguishable from sCJDMM1. Two distinct groups of dCJDMM1 have also been described in Japan based on clinical features, the presence or absence of PrP plaques and distinct PK-resistant PrP(Sc) (resPrP(Sc)) electrophoretic mobilities. The resPrP(Sc) electrophoretic mobility was, however, identical in our GH-CJDMM1 and dCJDMM1 cases, and matched that of sCJDMM1.

Conclusions: Our study shows that receipt of prion-contaminated GH can lead to a prion disease with molecular features (129MM and PrP(Sc) type 2) and phenotypic characteristics that differ from those of sporadic prion disease (sCJDMM1), a difference that may reflect adaptation of "heterologous" prion strains to the 129MM background.

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Figures

Fig. 1
Fig. 1
Brain MRIs of index case. a-e: MRI was normal at 4 months without clear evidence of restricted diffusion on DWI sequence (a), but progressed to restricted diffusion in the right caudate head (solid arrows) and more subtle cortical (dashed arrows) and possible superior vermis (dotted arrows) involvement at 10 months (b, DWI; c, ADC map), with progression to bilateral asymmetric caudate and more evident cerebellar vermis involvement at 11.5 months (d, DWI; e, ADC map)
Fig. 2
Fig. 2
Histopathology and immunohistochemistry of the index US GH-CJD patient. a-h: Histopathology. a-c: Spongiform degeneration (SD) selectively affecting the deeper layers of the cingulate gyrus (a; bracket), the hippocampal gyrus (b) and more severely the basal ganglia (c). c-d: Reactive astrogliosis (circles) in basal ganglia (c) and midbrain substantia nigra (d); arrows in the inset (dashed square) indicate intraneuronal vacuole formation. e: A kuru plaque in the frontal cortex reminiscent of the florid plaques observed in vCJD. f: A different type of plaque, apparently core-free, was detected in the cortical (f, parietal cortex) and subcortical brain regions. (not shown) g: A ballooned neuron. h: Kuru plaques (arrows) in the cerebellar granular layer. i-q: Immunohistochemistry. i: Laminar PrP immunostaining of the insula. j: Kuru plaque (circles) and plaque-like (squares) PrP immunostaining in the cerebellar granular and molecular layers, and peri-cellular PrP (“stellate”) (arrow) in the molecular layer. k: Large PrP aggregates (circle) and peri-cellular PrP immunostaining (“stellate” cells) (arrow) in proximity of one sulcus in the frontal cortex (dotted line delimiting the sulcus). i: Intense PrP immunostaining of the hippocampus. m: “Brush stroke-like” PrP immunostaining in the molecular layer of the cerebellum. n-o: Higher magnification of the PrP-immunostained “stellate” cells in the cerebellar molecular layer of the present case (n) and in one vCJD case (o). p-q: Intense PrP staining of the dentate nucleus (p) and along processes around the perikaryon of a neuron of the frontal cortex (q). Scale bar of inset in d: 50 μm; antibody: 3F4
Fig. 3
Fig. 3
Histopathology and immunohistochemistry of GH-CJDMM1 (cases 2 and 3), dCJDMM1 (case 4) and sCJDMM1. Histopathology (rows i-ii) and PrP immunohistochemistry (row iii). i: No spongiform degeneration (SD) (case 2) and fine SD (cases 3, 4 and sCJDMM1). ii: Focal SD (cases 2, 4 and sCJDMM1) and ubiquitous SD (case 3). Insets contain magnified regions delimited by rectangles in the main figure. iii: “Brush stroke-like” PrP immunostaining pattern (cases 2, 3, 4 and sCJDMM1). Scale bar of insets in ii: 100 μm; mol. L.: molecular layer; grl. L.: granular layer; antibody in iii: 3F4
Fig. 4
Fig. 4
Western blot of the PK-resistant PrPSc. Brain homogenates from the frontal cortex (FC) and the cerebellum (CE) of (a) the index case, (b) GH-CJDMM1 (case 2), dCJDMM1 (case 4) and (a and b) control cases sCJDMV2-K and sCJDMM1 were treated with 10 U/ml PK (~200 μg/ml) prior immunoblotting with antibodies (i) 3 F4, (ii) Tohoku-2, or (iii) 3 F4- and Tohoku-2-merged immunoreactivities. i: The unglycosylated resPrPSc from the index case co-migrated at ~20 kDa with the corresponding resPrPSc type 1 of sCJDMM1 and with a ~20 kDa fragment of sCJDMV2-K (arrow). The asterisk in i-iii indicates the unglycosylated resPrPSc type 2. ii: Only the resPrPSc associated with sCJDMV2-K (asterisk) reacted with Tohoku-2 confirming that it belongs to type 2. Tohoku-2 immunoreacted also with a resPrPSc fragment of ~18.0 kDa and to a lower size fragment (indicated in a by the filled and empty arrowheads, respectively) in the cerebellum of sCJDMV2-K, but not with the resPrPSc ~20 kDa fragment. The dashed rectangle in ii-(a) is shown below at a longer exposure time. iii: Merged 3 F4 (green dye) and Tohoku-2 (red dye) immunoreactivities
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