Thursday, November 19, 2009

Inherited Creutzfeldt–Jakob disease in a Dutch patient with a novel five octapeptide repeat insertion and unusual cerebellar morphology

J Neurol Neurosurg Psychiatry 2009;80:1386-1389 doi:10.1136/jnnp.2008.169359

Short report

Inherited Creutzfeldt–Jakob disease in a Dutch patient with a novel five octapeptide repeat insertion and unusual cerebellar morphology

C Jansen1, J C van Swieten2, S Capellari3, R Strammiello3, P Parchi3, A J M Rozemuller1 + Author Affiliations

1Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands 2Department of Neurology, Erasmus University Medical Centre, Rotterdam, The Netherlands 3Dipartimento di Scienze Neurologiche, Universit√† di Bologna, Bologna, Italy Correspondence to Dr C Jansen, Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, Heidelberglaan 100, PO Box 85500, 3508 GA, Utrecht, The Netherlands; Received 2 December 2008 Revised 22 February 2009 Accepted 5 March 2009 Abstract An atypical case of inherited Creutzfeldt–Jakob disease (CJD) is described in a 35-year-old Dutch woman, homozygous for methionine at codon 129 of the prion protein gene (PRNP). The clinical phenotype was characterised by slowly progressive cognitive decline and parkinsonism. Neuropathological findings consisted of scanty spongiosis and only faint to absent immunohistochemical staining for the abnormal prion protein, PrPSc, with patchy deposits in the cerebellar cortex. Purkinje cells were abnormally located in the molecular layer of the cerebellum. Western blot analysis showed the co-occurrence of PrPSc types 1 and 2 with an unusual distribution. Sequence analysis disclosed a novel 120 bp insertion in the octapeptide repeat region of the PRNP, encoding five additional R2 octapeptide repeats. These features define an unusual neuropathological phenotype and novel genotype, further expanding the spectrum of genotype–phenotype correlations in inherited prion diseases and emphasising the need to carry out pre-mortem PRNP sequencing in all young patients with atypical dementias.


METHODS Case history The patient presented with forgetfulness and difficulties in writing at the age of 35 years, after the birth of her second child. Her family noted that she had become increasingly absentminded and apathetic. Her clinical history was otherwise unremarkable. Her father had suffered from dementia and parkinsonism from the age of 45 years and died at the age of 55 years. At neurological examination, 2.5 years after the first symptoms, the patient was disoriented in time and place, and exhibited echolalia, perseveration and disturbed visual perception. She had a masked face with vertical gaze palsy, and increased tone of the extremities. Neuropsychological evaluation revealed an intact memory with acalculia, agraphia and apraxia. Brain MRI showed generalised cortical atrophy without evidence of hyperintensity or atrophy of either the caudate nucleus or the basal ganglia (fig 1A). The 14-3-3 test in CSF was negative. An electroencephalogram was not recorded. Genetic analysis revealed no abnormalities in the tau protein gene (MAPT), the Presenilin 1 gene (PSEN1) or the Huntingtin gene. Over the next 3 years, rigidity increased with the appearance of a slight tremor in her right hand, without any beneficial effect on levodopa and amantadin treatment. She increasingly developed dysarthria and swallowing problems, and suffered from anxiety and panic attacks. She was admitted to a nursing home where she died from bronchopneumonia at the age of 42 years, 92 months after the clinical onset of the disease.



Seventeen patients with six different 5-OPRI have been described so far in the literature.6 As in other inherited prion diseases, these disorders show a considerable degree of phenotypic variability, partly accounted for by the codon 129 Met/Val polymorphism. Age at onset in codon 129 heterozygous patients is usually later (58.0 years) than in codon 129 homozygous patients (42.3 years).6 Approximately half of these patients show a disease duration of more than 60 months. Although the clinical and pathological features of 5-OPRI mutations are relatively well known, genotype–phenotype correlation has not been clearly established, warranting the description of further genetic cases.

In this report, we describe a novel insertion mutation in PRNP, consisting of five extra R2 octapeptide repeats (R1-(R2)7- R3-R4). The clinical phenotype in our patient was characterised by slowly progressive cognitive decline, parkinsonism, anxiety and a long disease duration of 92 months. Neuropathological findings included scanty spongiosis and faint synaptic or even absent immunohistochemical staining, except for small patchy deposits in the cerebellar cortex, without the characteristic perpendicular orientation to the meningeal outline, as described in other patients with insertion mutations.8 12 An intriguing finding, although described before in three other patients with a 5-OPRI mutation,13 was the abnormal localisation of Purkinje cells in the molecular layer of the cerebellum. The type of abnormalities, combined with the absence of ataxia and significant cerebellar pathology, strongly suggest this defect as being longstanding and likely related to a developmental defect. Thus although largely speculative, the observation may suggest a role for PrPC in cerebellar neuronal migration or in the elimination of misplaced Purkinje cells during development which likely involve the programmed cell death machinery, as recently suggested.14 Furthermore, in the absence of a specific histopathological picture, the observation of misplacement of Purkinje cells in the molecular layer might be a helpful diagnostic clue prompting the suspicion of inherited prion disease with OPRI mutation.

Another interesting finding was the co-occurrence of PrPSc types 1 and 2 in brain homogenates, as demonstrated by immunoblotting. To our knowledge, this has only been described once before in a patient with one extra octapeptide repeat in PRNP, who showed widespread spongiosis and diffuse synaptic immunoreactivity in all cortical lobes.15 In light of the scanty spongiosis and faint immunohistochemical staining in the brain of our patient, the presence of type 2 protein is a peculiar finding, since in methionine homozygotes (MM) at codon 129, type 2 is usually associated with prominent spongiosis with confluent vacuoles and more consistent coarse and perivacuolar deposits of PrPSc in the cerebral cortex.11 Furthermore, type 2 in MM cases preferentially accumulates in the cerebral cortex11 whereas it was mainly detected in the striatum and cerebellum in the present case. The 5-OPRI mutation in this patient was probably inherited in an autosomal dominant pattern but a positive family history in patients with inherited prion disease is not obligate. In all patients with a clinical history of frontotemporal dementia or atypical dementia and abnormal localisation of Purkinje cells in the molecular layer of the cerebellum, inherited prion disease should always be considered and pre-mortem PRNP sequencing should be carried out.

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