Prominent psychiatric features and early onset in an inherited prion disease with a new insertional mutation in the prion protein gene

Abstract

In five generations of the French M-E kindred, 11 members are now known to be or have been affected by a form of spongiform encephalopathy previously recorded as Gerstmann-Sträussler-Scheinker disease. Mean age at onset was 28 years (range 21-34 years). In six instances, these patients were hospitalized in psychiatric institutions with various diagnoses, the most frequent being mania or mania-like symptoms. Dementia occurred progressively after a lengthy course. Histological studies showed atrophy of the cerebellar molecular layer, which contained kuru and multicentric plaques labelled with anti-prion protein antibodies. Spongiosis was not prominent and remained largely limited to the periphery of plaques; it was more marked in the thalamus, where plaques were scarce. A 192 base pair (bp) insert (eight extra repeats of 24 bp) in the octapeptide coding region of the prion protein gene (PRNP) within a codon-129 methionine allele was found in four symptomatic subjects. Early age at onset, the prominence of psychiatric symptoms and the long course of the disease are noticeable clinical features in this family with an inherited prion disease due to a new insertional mutation in PRNP.

Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation

“…[10][11][12] The neuropathological features of IPD with 8-OPRI include varying degrees of spongiosis, cell loss, and astrocytosis in different areas of the brain, 7,9,10 and the presence of prion protein (PrP) plaques in the cerebellum. 8,13,14 Brain homogenates from one subject in each of the Che and M-E families were injected into monkeys. 7,8 Only in the first case was transmission achieved a minority of inherited prion diseases (IPD) are caused by four to 12 extra octapeptide repeat insertions (OPRI) in the prion protein gene (PRNP).…”

“…Two of them were unrelated French families (M-E and Che families) displaying some features of GSS. [5][6][7][8] The third family was a Dutch kindred (A family) displaying predominantly hypokinesia and dementia. 9 The fourth family was a 3 generation Swedish kindred in which 4 of 7 affected subjects had chorea, initially attributed to Huntington's disease (HD).…”

Neuron Dysfunction Is Induced by Prion Protein with an Insertional Mutation via a Fyn Kinase and Reversed by Sirtuin Activation inCaenorhabditis elegans

“…The various constructs, human wild-type PrP, mutated PrP with 8 additional octarepeat (PHGGGWGQ) expansion, and GFP, were cloned into the EcoRV-EcoRI site of the P mec-7 plasmid, pPD118.44 (gifts from Andy Fire, Washington University, St. Louis, MO), to create P mec-7 GFP and P mec-7 PrP constructs. The normal Wt-PrP and the mutated PG13-PrP constructs were derived from human DNA (Laplanche et al, 1999). Primers used to amplification of human PrP were as follows: PrP-f, 5Ј-CCGGATATCCGGATGGCGAACCTTG-GCTGCTGGA-3Ј; PrP-r, 5Ј-CGGGAATTCCGGTCATCATCATCC-CACTATCAGGAAGATG-3Ј.…”

“…These mutations may direct the folding of the protein toward the PrP Sc conformation, and could initiate a self-conversion process (Leliveld et al, 2006). We previously identified a peculiar French family with early age at onset, prominence of psychiatric symptoms, lengthy clinical course, and a neuropathological phenotype of Gerstmann-Sträussler-Scheinker syndrome associated with eight extra octarepeats in PrP (PG13-PrP) (Laplanche et al, 1999). Here, we expressed PG13-PrP in nematode touch receptor neurons to establish a model of prion neurotoxicity.…”

Prion disease genetics

“…16 Other clinicians have ascribed psychiatric symptoms in IPD to the early stages of a neurodegenerative disease (eg Rodriguez et al 27 and Laplanche et al 61 ). The presence of personality disorders with such an early onset may indicate a role for the normal function of PrP in the healthy brain that is abrogated by certain mutations.…”