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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arch Neurol. Author manuscript; available in PMC 2012 April 16.
Published in final edited form as:
PMCID: PMC3326586

Clinical Characterization of a Kindred with a Novel Twelve Octapeptide Repeat Insertion in the Prion Protein Gene



To report the clinical, electroencephalographic, and neuroradiologic findings in a kindred with a novel insertion in the prion protein gene (PRNP).


Clinical description of a kindred.


Mayo Clinic Alzheimer’s Disease Research Center (Rochester).


Two pathologically-confirmed cases and their relatives.

Main outcome measures

Clinical features, electroencephalographic patterns, magnetic resonance imaging abnormalities, genetic analyses and neuropathological features.


The proband presented with clinical and neuroimaging features of atypical frontotemporal dementia (FTD) and ataxia. Generalized tonic-clonic seizures developed later in her course, and electroencephalography revealed spike and wave discharges but no periodic sharp wave complexes. Her affected sister and father also exhibited FTD-like features, and both experienced generalized tonic-clonic seizures and gait ataxia late in their course. Genetic analyses in the proband identified a novel defect in PRNP with one mutated allele carrying a 288 base pair insertion (BPI) consisting of 12 octapeptide repeats. Neuropathologic examination of the sister and proband revealed PrP-positive plaques and widespread tau-positive tangles.


This kindred has a unique combination of clinical and neuropathologic features associated with the largest BPI identified to date in PRNP, and underscores the need to consider familial prion disease in the differential diagnosis of a familial FTD-like syndrome.

Keywords: frontotemporal dementia, FTD, nonfluent aphasia, Gerstmann–Straüssler–Scheinker syndrome (GSS), Creutzfeldt-Jakob disease (CJD), prion, PRNP


Numerous point mutations and insertions in the prion protein gene (PRNP) have been identified in the familial human prion disorders - Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), and Gerstmann–Straüssler–Scheinker syndrome (GSS) syndrome 1. The phenotypes associated with each genetic alteration have varied across and within families, but the duration of symptoms has tended to be several years compared to a year or less that is more typical of sporadic CJD. Although many cases develop dementia, and some are initially diagnosed as probable Alzheimer’s disease (AD), few cases have presented clinically with features of frontotemporal dementia (FTD) or progressive nonfluent aphasia (PNFA).

Several octapeptide base pair insertions (BPI) in PRNP have been identified, ranging from 24 to 216 base pairs 123. Compared to patients with other PRNP mutations, patients with BPI tend to have an earlier age of onset and longer duration of illness, and are less likely to have cerebellar signs, myoclonus, or extrapyramidal signs 1. Seizures have been reported in CJD patients with BPI 7, 8, 10, 11, 13, 14 and other familial CJD subtypes, but the specific electroencephalographic (EEG) findings are rarely described (other than the absence of periodic sharp wave complexes). Specific findings on MRI in the BPI cases have not been described in detail, nor do many reports include data on 14-3-3 protein and neuron specific enolase (NSE) levels in the cerebrospinal fluid (CSF). The PrP immuno-staining patterns in the BPI cases include fine granular and occasional perivacuolar preponderance, fleecy or blurred staining pattern in the cortex, and “Kuru” and multicentric plaques 1.

In this paper, we report the antemortem findings in a kindred associated with a novel BPI, and compare and contrast the findings in this kindred with those in other kindreds with familial prion disease and BPIs.

Subjects and Methods

Antemortem data

The proband was referred to for evaluation of atypical dementia and was followed in the Mayo Alzheimer’s Disease Research Center (Rochester) as part of an Institutional Review Board (IRB) approved protocol. She underwent comprehensive neurobehavioral examinations and the clinical, electroencephalographic, and radiologic data were reviewed and analyzed. Magnetic resonance imaging (MRI) was performed using a 1.5 Tesla GE scanner, and images of the brain were obtained in the sagittal, axial, and coronal planes. All available clinical data regarding the only other affected relatives—her sister and father—were also reviewed.

Pathological and genetic data

The neuropathologic material of the proband’s sister was examined following consent from next of kin. The proband died years later, and her tissue was examined similarly with consent from next of kin. Genetic analyses were performed on the proband.



The pedigree of this family is shown in Figure 1.

Figure 1
Pedigree. Shaded symbols reflect patients with dementia, diagonal lines over symbols reflect deceased patients, “c” refers to current age, “d” refers to the age of death, “o” refers to the age of onset of ...

Clinical, Laboratory, and Neuroimaging Data

Case I.1

The proband’s father died when he was 53 years old due to a pulmonary embolism. He had a history of cognitive decline for 10 years prior to his death, personality and behavioral changes were obvious over the final five years of his life, and he experienced several generalized tonic-clonic seizures late in his course. He was known to get lost in his house and had a craving for sweets. Gait impairment and frequent falls evolved in the final two years of his illness. An autopsy was performed elsewhere, but this did not include examination of the brain.

Case II.1

The proband’s sister died at 51 years after a seven-year history of cognitive and behavioral decline. Her family described her as having slowness of thought since childhood, requiring repeated instructions in school and everyday activities, but she did graduate from high school. Her illness was characterized by a change in personality, inappropriate comments, restless behavior, and a tendency to seek out food. Four years prior to her demise a clinical diagnosis of Alzheimer’s dementia was made. During the course of her illness she had three generalized tonic clonic seizures. Gait ataxia was a late manifestation.

Case II.2

The proband’s other older sister is 57 years old and has no neurologic symptoms.

Case II.3

The proband was a right-handed woman who was brought by her healthy sister to our institution for evaluation of a six-year history of cognitive decline and gait impairment, which began at age 45. Her initial symptoms were difficulties in signing her name followed by the inability to find the right words to express herself. These changes included a decrease in the overall amount of verbal output, a decrease in the initiation of speech, and use of brief and unelaborated sentences during conversation. She would inconsistently count and sing along with others, sometimes verbally responding to yes/no questions, occasionally saying a phrase spontaneously, and she infrequently would talk in single word or short phrases while on the phone. When she did speak, her speech was clear, although delays in answering were apparent. She would not initiate common activities of daily living (i.e., dressing, eating), but she would eat when cued to (i.e., a fork placed in her right hand).

She had also exhibited changes in her behavior and personality over the preceding three years. Her behavior was noted to be more childish with inappropriate grinning and laughing at home and in restaurants. She exhibited repetitive and ritualistic behavior. She became more withdrawn, apathetic, and intermittently impulsive but lacked insight into these and other changes. Her attention to personal care declined. She also experienced difficulties with balance and gait over the preceding three years. Generalized body jerks and occasional limb posturing had evolved over the prior year. She had been significantly dependent on her healthy sister for most activities of daily living for two years. Her medical history was remarkable for rheumatoid arthritis that was diagnosed three years previously. Her arthritic symptoms had improved with methotrexate and prednisone. She also had a history of hypertension and hyperlipidemia. Her medications included hydrochlorothiazide, verapamil, atorvastatin, methotrexate, folic acid, prednisone, naproxen sodium, lisinopril and coenzyme Q.

On her initial examination at our institution, standard language evaluation was not possible because of her significant cognitive impairment. Her spontaneous activities consisted primarily of smiling, laughter, and an infantile-appearing touching or hiding of her face while smiling or laughing. She did not follow any simple one-step commands (e.g., “Close your eyes”), even on imitation, and she was unable to confirm with yes-no answers the identity of simple line drawings of objects. She failed to correctly orient a card of large-print words presented to her. She did not initiate any verbal or nonverbal communicative interaction with the clinician or her family members throughout the evaluation. Her spontaneous utterances were brief and unelaborated (e.g., “yeah”), and perseverative or echolalic, but accurate phonemically. She had difficulty performing automatic speech tasks (e.g., reciting the alphabet), although she did sing a few lines of “Happy Birthday” and “Jingle Bells” with adequate melody and lyrics, along with her sister. Oral mechanism examination failed to identify asymmetry or weakness, but there was some spontaneous dystonic posturing of the lips and, perhaps, tongue. Her articulation was mildly imprecise, dystonic perioral and lingual movements were evident during speech, and loudness was reduced. Voice quality and resonance were normal. Her overall speech pattern was suggestive of a mixed hypokinetic-hyperkinetic (dystonic) dysarthria. There was no evidence of apraxia of speech. Her overall pattern of responding was not clearly indicative of any focal aphasia; although she obviously had prominent difficulties with communication, they seemed more attributable to widespread impairment in cognitive and affective functioning.

No cranial nerve deficits were noted. She had mild generalized paratonia but no cogwheel rigidity or tremor. She had marked truncal ataxia: she was unable to walk without assistance. To the extent that she could follow instructions for examining limb motor and cerebellar functions, there was no significant weakness or dysmetria. Her reflexes were symmetrically brisk with flexor plantar responses. A bilateral grasp reflex was present. Skeletal changes involving small joints of the hand due to rheumatoid arthritis were also noted.

All blood, serum and urine studies for infectious, inflammatory, metabolic, and paraneoplastic disorders, and inborn errors of metabolism, were negative or normal except that the erythrocyte sedimentation rate was elevated to 44 mm/1 hr (normal 0–29 mm/1 hr), rheumatoid factor was elevated at 1360 IU/ml (normal <15 IU/ml), and the anti-gliadin antibody (IgA) was 66 U/ml (normal <50 U/ml). A skin biopsy was negative for evidence of storage disease and ultrathin sections studied by electron microscopy were normal. Cerebrospinal fluid cell count, glucose, proteins, lactate, IgG index and synthesis rate were normal and bacterial culture, cryptococcal antigen, polymerase chain reaction for JC virus and Trophermyma whippleii were negative. The CSF 14-3-3 protein was normal and the neuron specific enolase was mildly elevated at 39.5 ng/ml (normal <20ng/ml). The CSF amyloid-β42 (Aβ42; 255 pg/ml) and total tau (1921 pg/ml) protein levels were consistent with a diagnosis of Alzheimer’s dementia 24. Her brain MRI (Figures 2A and 2B) showed generalized hemispheric atrophy which was more prominent in the frontal lobes compared to the parietal and occipital lobes. In addition, significant atrophy was present in the corpus callosum and midline cerebellum. Her EEG showed diffuse, generalized theta and delta frequency slowing. Superimposed on the slow background were generalized spike and sharp wave discharges (Figure 3A), with marked activation of the generalized spike and wave discharges with photic stimulation (Figure 3B). She was initially started on nightly clonazepam to minimize the chance of nocturnal seizures. Weeks later she experienced multiple partial seizures and generalized tonic-clonic seizures which were refractory to clonazepam and gabapentin, but were better managed with levetiracetam. She remained bedbound, rigid and variably responsive for the terminal six months of her life, and died at age 52.

Figure 2
A. Coronal T1-weighted (top row) and axial fluid attenuation inversion recovery (FLAIR) (bottom row) MR images of case II.3. Note the severe symmetric bifrontal atrophy with mild atrophy of the amygdalae and hippocampi. While there is increased signal ...
Figure 3
A. Electroencephalogram showing diffuse slowing with generalized spike and sharp wave discharges. B. There is marked activation of the generalized spike and wave discharges with photic stimulation.

Generations III and IV

Subjects and treating clinicians have intentionally remained blind to the genetic status of the members of generation III and IV. The children of the affected subjects in generation II have been reviewed annually for five or more years, except for III.1 (first seen in 2008) and III.4, whom we have not met. Their ages range from 25 to 39. Four of the seven members of generation III are described as “slow” by the family, yet only one (III.3) has a below-normal scores in tests indicative of baseline intellectual function. Two of the four have recent declines in tests of executive (III.4) or visuospatial function (III.5), both of whom report concomitant behavioral and cognitive changes. All four have subtle bifrontal and cerebellar atrophy on serial MRI scans25.

Neuropathologic Data

The pathologic findings in Case II.1 and Case II.3 were very similar: bilateral frontal atrophy was present, but the mesial temporal structures showed no significant atrophy. Both cases had striking dense multicentric plaques that were negative for Aβ40 and Aβ42, but positive for PrP. The plaques were particularly frequent in the cerebellar cortex. There were also numerous tau-positive neurofibrillary tangles (NFT) and neuropil threads in the neocortex. There were no Lewy bodies or Pick bodies. Case II.3 also had findings suggestive of subacute leptomeningeal acanthamoeba infection. Neuropathologic characterization of these two cases will be reported in detail elsewhere.

Genetic Data

No mutations were present in presenilin 1 (PSEN1) or microtubule associated protein tau (MAPT), but sequence analysis of the proband’s PRNP gene showed a mutated allele carrying a 288 base pair insertion (BPI) consisting of 12 octapeptide repeats. No such insertions were present on testing 100 control samples.


The clinical and pathologic features in this kindred contrast with other reported CJD cases with BPI. All three affected members of this kindred had cognitive and behavioral changes more consistent with FTD 26 than AD 27 or CJD 28. Dementia is usually present in CJD with BPI, but most reports have not included the specific cognitive and behavioral features that permit comparisons to the “modern” syndromic terminology of FTD, PNFA, corticobasal syndrome, etc. The speech and language features in the proband were not entirely consistent with the PNFA syndrome, but were abnormal nonetheless. Gait ataxia is not typical of FTD, and this clinical feature in all three cases represented a clue to a disorder not usually considered within the FTD spectrum.

Elevations in 14-3-3 and NSE levels are common in sporadic CJD, but there is minimal data on values in familial prion disorders, and increases in CSF 14-3-3 or NSE are not specific to prion disorders. Despite the long duration of symptoms in the proband (six years from onset of symptoms to the time her CSF was examined), the mildly elevated NSE did suggest a prion disorder. The low CSF Aβ42 and high total tau observed in the proband is typical of AD - a false-positive result that reinforces the observation that such findings must be interpreted with caution when the clinical syndrome is not typical of AD. How common very high total CSF tau results are in familial CJD cases is not known.

The MRI findings in CJD cases with BPI have not been well-characterized. Symmetric bifrontal atrophy was present on MRI in the proband. There were no abnormal signal changes on fluid attenuation inversion recovery (FLAIR) or diffusion-weighted images. Clinical or electrophysiologic evidence of epileptiform activity was present in all affected members of this kindred. Seizures have been reported in the P301S MAPT mutation 29 but rarely if ever in the other MAPT mutations. Furthermore, seizures and particularly the spike and wave pattern on EEG are uncommon in the familial prion disorders. While we cannot exclude the possibility of another etiology for the seizures and EEG findings, we suspect the EEG pattern and seizures are related to the underlying prion disorder. This constellation of antemortem findings is therefore unique to this kindred.

The pathologic findings in both cases are more in keeping with the few other familial prion disorders with BPI of eight octapeptide repeats or more, in which the pathologic phenotype shares many similarities with GSS 30, 31. We suspect that the topographic involvement of pathology in the bifrontal regions explains the FTD-like clinical and radiologic features, and involvement in the cerebellum explains the gait ataxia. If one can surmise the topographic evolution of pathology in cases like these based on their evolution of symptoms and findings, it appears that significant frontal pathology occurs prior to the development of significant cerebellar pathology. This sequence of evolution can also occur in GSS due to point mutations in PRNP 32, potentially leading to diagnostic confusion with the disorders more typically associated with FTD.

The cases in this kindred therefore exemplify that a familial prion disorder should be considered in the setting of an autosomal dominant FTD-like syndrome, particularly if gait ataxia or generalized tonic-clonic seizures are present and if no mutations are present on PSEN1 and MAPT testing.

Figure 4
A. PRNP octarepeat nomenclature with nucleotide composition of all octarepeats observed in the proband’s mutated allele. B. PRNP gene with the relative position and order of the five octarepeats seen in the wild type allele. C. Position and composition ...


These research activities were supported by grants P50 AG16574 and PO1 AG07216 from the National Institute on Aging and R01 NS065782 from the National Institute of Neurological Disorders and Stroke. We are particularly thankful to the patients and their relatives for participating in this research.


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