Prion-Related Diseases Clinical Presentation

Updated: Jun 02, 2021
  • Author: Deepak K Gupta, MD; Chief Editor: Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM  more...
  • Print


Several different forms of prion disease exist (see Table 1 below).  One of the first human prionoses to be described is called kuru. [53, 54, 55] This is an illness of the Fore people living in the highlands of New Guinea that is thought to be linked to ritualistic cannibalism. Presumably, this illness originated with the consumption of an initial patient with sporadic CJD. Kuru was once the major cause of death among Fore women; however, the disease has virtually disappeared with the end of cannibalistic rituals. Similar to scrapie, patients clinically present with difficulty walking and they develop progressive signs of cerebellar dysfunction. Death occurs approximately 1 year following onset of symptoms.

The neuropathology of kuru, in common with all prionoses to a variable extent, includes widespread spongiform change and astrocytosis, as well as neuronal loss affecting the cerebral hemispheres and cerebellum. More intraneuronal vacuolation is observed in kuru compared to CJD (see below). In about 70% of cases, amyloid plaques are found, with amyloid deposition being a common, but not invariable, accompaniment of the prionoses. Gajdusek's detailed description of this illness led Hadlow to suggest that kuru might be the human representation of scrapie. [4] This in turn inspired Gajdusek and his team to test whether kuru was also transmissible. In 1966, they first showed kuru was transmissible to chimpanzees, after a long incubation. [56] Gajdusek was awarded the Noble Prize in 1976 for this work.

Table 1. Prion-Related Diseases, Hosts, and Mechanism of Transmission (Open Table in a new window)







Sporadic CJD


Spontaneous PrPC to PrPSc conversion or somatic mutation

Iatrogenic CJD


Infection from prion-containing material, eg, dura mater, electrode

Familial CJD


Mutations in the PrP gene



Infection from BSE



Mutations in the PrP gene



D178N mutation in the PrP gene, with M129 polymorphism

Sporadic fatal insomnia


Spontaneous PrPC to PrPSc conversion or somatic mutation



Infection in susceptible sheep



Infection from contaminated food



Infection from sheep or cattle in food


Mule, deer, elk


Feline spongiform encephalopathy


Infection from contaminated food

Exotic ungulate encephalopathy

Nyala, oryx, kudu

Infection from contaminated food

By far the most common human prion disease is CJD, accounting for about 85% of all human prion disease. CJD was initially described by Jacob in 1921 [57] ; ironically, the case reported by Creutzfeldt a year earlier is probably unrelated to the disease that carries his name. Clinically, CJD is characterized by a rapidly progressive dementia associated with myoclonic jerks, as well as a variable constellation of pyramidal, extrapyramidal, and cerebellar signs. The EEG findings typically show distinctive changes of high-voltage slow (1-2 Hz) and sharp wave complexes on an increasingly slow and low-voltage background. CJD is found throughout the world, with an incidence of about 1 case per million population. In addition to extensive cortical spongiosis, gliosis, and neuronal loss, 10% of CJD cases have amyloid plaques. [5] Ten percent of cases of CJD are familial, with an autosomal dominant pattern of inheritance linked to mutations in the PrP gene. [58]

Creutzfeldt-Jakob disease

Sporadic CJD is characterized by a rapidly progressive multifocal neurological dysfunction, myoclonic jerks, a terminal state of global severe cognitive impairment, and death in about 8 months.

About 40% of patients with sporadic CJD present with rapidly progressive cognitive impairment, 40% with cerebellar dysfunction, and the remaining 20% with a combination of both. These may be preceded by symptoms of peripheral neuropathy in patients with certain strains of sCJD. This is thought to be due to PrP(Sc) deposition, however, variable involvement of the PNS suggests that tropism is strain-dependent. [59]

The clinical picture rapidly expands to include behavioral abnormalities, higher cortical dysfunction, cortical visual abnormalities, cerebellar dysfunction, and both pyramidal and extrapyramidal signs.

Almost all patients with sporadic CJD develop myoclonic jerks that involve either the entire body or a limb. These myoclonic jerks can occur spontaneously or can be precipitated by auditory or tactile stimulation.

During the course of sporadic CJD, most patients develop a characteristic picture on EEG with periodic or pseudoperiodic paroxysms of sharp waves or spikes on a slow background. These periodic complexes have a sensitivity and specificity of 67% and 87% respectively on a single EEG. However, if repeated recordings are obtained, more then 90% of patients show periodic EEG abnormalities. [60]

When evaluating a patient for possible sporadic CJD, the clinician should be guided by published case definitions; they are as follows:

  • Definite CJD

    • Characteristic neuropathology

    • Protease-resistant PrP by Western blot

  • Probable CJD

    • Progressive dementia

    • Typical findings on EEG

    • At least 2 of the following - Myoclonus, visual impairment, cerebellar signs, pyramidal or extrapyramidal signs, or akinetic mutism

  • Possible CJD

    • Progressive dementia

    • Atypical findings on EEG or EEG not available

    • At least 2 of the following - Myoclonus, visual impairment, cerebellar signs, pyramidal or extrapyramidal signs, or akinetic mutism

    • Duration less than 2 years

Gerstmann-Sträussler-Scheinker disease

Gerstmann-Sträussler-Scheinker disease was described in a large kindred in 1936. [61]

Patients with this illness present with a slowly progressive limb and truncal ataxia, as well as dementia. Death occurs 3–8 years following presentation.

The prominent involvement of the brainstem often leads to symptoms suggestive of olivopontocerebellar degeneration. The pattern of inheritance is autosomal dominant and is caused by mutations of the PrP gene. The neuropathology of GSS is remarkable in that extensive and invariable amyloid deposition occurs, in addition to the typical spongiform change, gliosis, and neuronal loss. Interestingly, in several kindreds of GSS, extensive neurofibrillary tangle (NFT) formation is found. [62] NFTs are an essential feature of Alzheimer disease, but are also observed in other neurodegenerative conditions.

Another variation of autosomal dominantly inherited human prionoses has been termed prion protein congophilic angiopathy (ie, prion protein cerebral amyloid angiopathy [PrP-CAA]), which is characterized by cerebral vessel amyloid deposition and the presence of NFT. [63] Cerebral amyloid angiopathy (CAA) is also an essential feature of Alzheimer disease. Both these variants of prionoses further link the pathogenesis of Alzheimer disease and the prion-related diseases.

Fatal familial insomnia

Patients with FFI present with intractable insomnia, dysautonomia (ie, hyperthermia, hypertension, tachycardia, tachypnea, hyperhidrosis), dementia, and motor paralysis; however, the phenotypic expression is very variable even within the same family. [64] The age of onset is also variable, ranging from 18-60 years. Although presentation may vary drastically between individual patients, it is important to be aware that early FFI may present with neuro-ophthalmological abnormalities, including excessive saccadic intrusions. [65] Once symptoms begin, the course ranges from 6 months to 3 years. Because of the diversity of clinical presentations of this disorder, genotyping is very important for definitive diagnosis. Neuropathologically, marked atrophy of the anterior ventral and mediodorsal thalamic nuclei occurs because of neuronal loss and gliosis. Unlike other prionoses, spongiform change can be a minor feature or can be absent altogether.

All patients with FFI have a missense mutation at codon 178 of the PrP gene where Asn is replaced by Asp, coupled with a Met at the polymorphic codon 129. [66] The somewhat divergent clinical and neuropathological features of FFI, in comparison to other human prionoses, highlight the wide spectrum of disease associated with PrP dysfunction and suggest that other human illnesses have yet to be recognized as prionoses.

Fatal familial insomnia and Creutzfeldt-Jakob disease are associated with a D178N mutation of the PRNP gene located on chromosome 20. D178N mutation changes the aspartate to asparagine at codon 178. In this disease, the mutant chromosome encodes methionine in the polymorphism of codon 129. The cortex is spared but the thalamus is particularly susceptible to this type of prion disease; therefore, fatal insomnia is situated at the extreme end of a spectrum of prion diseases with frequent psychiatric presentations. [67]

There is an unusual incidence of this disease in Basque Country (Spain). Oliveros et al report a patient with postmortem diagnosis of fatal insomnia who had a phenotypic presentation of catatonia and they stress the importance of considering this disease in catatonia nonresponsive to ECT. [68]

Variant Creutzfeldt-Jakob disease

A recent epidemic of a new prionosis has occurred; BSE has led to more then 160,000 cattle deaths in the United Kingdom. [69] This new disease is thought to be caused by meat and bone meal dietary supplements to cattle that were contaminated with scrapie-infected sheep and other cattle with BSE. Extensive evidence suggests that BSE has also led to a new type of CJD, called variant CJD (vCJD). [70] The first cases of vCJD were reported in 1995, when CJD was found in 2 British teenagers. [71, 72]

Only 4 cases of sporadic CJD have been reported previously among teenagers; the peak incidence of onset of sporadic CJD is in people aged 60-65 years. In addition to the early age, these cases had distinctive neuropathology that included so-called florid amyloid plaques, which are reminiscent of kuru-associated PrP amyloid plaques. [73, 74] Significantly, such florid amyloid plaques are also a feature of chronic wasting disease. [75]

As of February 2006, 159 cases of vCJD have been diagnosed in Great Britain (see The National Creutzfeldt-Jakob Disease Surveillance Unit). The latest numbers from other countries as of November 2005 are 15 in France, 3 from Ireland, 2 in the United States, and one each from Canada, Italy, Japan, Netherlands, Portugal, Saudi Arabia, and Spain (see Centers for Disease Control and Prevention, Variant Creutzfeldt-Jakob Disease). Both of the US cases, 1 of the 3 in Ireland, and the single cases from Canada and Japan were likely exposed while living in the UK. The emergence of vCJD has raised the specter of an epidemic of prion-related disease among the British population (and possibly a wider population) similar to that of BSE in cattle.



Physical signs and symptoms vary with the type of prion disease. vCJD differs from sporadic CJD in that psychiatric abnormalities and sensory symptoms are much more common at presentation of vCJD.

  • Mental status and/or neuropsychological examination

    • This shows a rapidly worsening global cognitive status. The most common initial symptoms are cognitive impairment and ataxia.

    • Many fewer common variations exist, such as presentations with initial cortical blindness (ie, Heidenhain variant). Involuntary arm levitation as a manifestation of alien-limb syndrome may also be a rare first or exclusive manifestation of CJD. [76]
    • In sporadic CJD, an important and almost universal physical feature is the presence of myoclonus. However, it appears relatively late in the course of the disease, and reliance on this clinical finding may delay recognition and diagnosis of CJD in affected patients. [77]

    • Cerebellar findings are present in all patients with vCJD, while about 40% of those with sporadic CJD have cerebellar dysfunction.

In 2009, Kahn et al reported a patient with inherited prion disease who sustained fractures that were successfully managed conservatively with unusual results, such as accelerated healing, akin to that seen in traumatic head injuries. Local growth factors, inflammatory cytokines, and endogenous bone morphogenic proteins have all been implicated in head injuries and the authors propose that similar factors may be responsible in prion disease, common to both conditions. [78]



Prion-related diseases are unique in that they can be related to infectious, sporadic, or familial causes (see Pathophysiology).

Infectious causes

Kuru, a form of prion disease, occurred among the Fore people of the Eastern Highlands of New Guinea and was related to ritualistic cannibalism. The disease is believed to have started with the ingestion of body parts of a patient with sporadic CJD, followed by a serial passage of the disease.

Many cases of iatrogenic CJD have been reported. In clinical practice, CJD has been transmitted by surgical instruments, EEG electrodes, corneal transplants, dura mater grafts, human pituitary-derived gonadotrophins, and human-derived growth hormone. Concerns that vCJD could be transmitted by blood transfusion have been borne out with 3 documented cases. One study identified 119 cases of iatrogenic CJD from 1443 individuals treated with human cadaver-sourced growth hormone (hGH) in France, with a 2-fold higher incidence in men. [79] It is recommended that for high-risk procedures such as cerebral surgery, craniotomy surgery, orthopedic spinal surgery, and ophthalmic surgery that medical instruments are appropriately treated with established inactivation methods. [80] Informing patient contacts about iatrogenic CJD can be particularly challenging, with many patients expressing significant concern about the potential for developing disease, despite reassurance that this is rare. This discussion may be facilitated by face-to-face meetings, a help line, and clinical followup. [81]

vCJD in humans is presumed to have been caused by ingestion of beef products contaminated with BSE. BSE is presumed to have started because of the practice of supplementing the diets of calves and dairy cows with meat and bone products. These meat and bone products are thought to have been contaminated with scrapie material (from sheep) and/or with material from cattle with a sporadic form of bovine prion disease.

A number of cases of apparent sporadic CJD have occurred in the United States among young individuals (< 30 y). The incidence of sporadic CJD among such young individuals has historically been about 1 case per billion population. In the years 1979-1996, 4 cases of sporadic CJD were reported in the United States among individuals younger than 30 years. In the years 1997-2000, 5 cases have occurred in the United States among young patients. Two of these individuals came from adjacent counties in Michigan (ages at onset were 26 and 28 y), and 3 cases occurred among individuals who were known hunters of deer and/or elk. [82]

Over the same period, a major outbreak of CWD occurred among the deer and elk populations in many western states, which has now spread to at least 10 states (see Chronic Wasting Disease Alliance). CWD is a form of prion disease that occurs naturally in the deer and elk population; however, the pathology has many similarities to BSE, including the presence of florid plaques. [75] Significantly, transmission studies of CWD PrPSc in the laboratory have shown that it can cross the species barrier from deer to human PrP at about the same efficiency as the BSE prion agent. [83] These observations have led to the speculation that limited transmission of CWD to humans has occurred recently in the United States.

Findings indicated that transgenic mice that express the deer/elk prion protein can be infected with intracerebral injection of muscle tissue from symptomatic cervids, [84] which raises concerns about infectivity of meat products from these animals. Also, a nonhuman primate developed prion disease after intracerebral injection with brain material from symptomatic deer. [85]

Case reports of accidental occupational exposures are also reported in the literature. For example, an employee at a prion research laboratory who worked with frozen sections of brain of transgenic mice infected with a sheep-adapted form of BSE died of CJD less than ten years after puncturing her finger with forceps used to handle the samples. [86]

Familial causes

The cause of familial forms of prion disease is related to mutations in the PrP gene. A number of mutations in the PrP gene are linked to autosomal dominant forms of prion disease. The image below is a representation of the human PrP gene, PRNP.

Prion-related diseases. A representation of the hu Prion-related diseases. A representation of the human proteinaceous infectious particle, or PrP, gene. Mutations associated with inherited prionoses are shown above the gene, while polymorphisms are shown below the gene. A polymorphism at codon 129 (M versus V) is common in white populations, while a polymorphism at codon 219 (E versus K) is common in Japanese populations. The locations of the 4 putative helical regions, H1-H4, correspond to residues 109-122, 129-141, 178-191, and 202-218, respectively. This diagram does not illustrate all of the alpha-helical regions. A diagonal striped area represents the region of octarepeats, spanning residues 51-91. Octarepeats of 16, 32, 40, 48, 56, 64, or 72 amino acids at codons 67, 75, or 83 are indicated by the rectangle above the octarepeat region. These inserts are associated with familial Creutzfeldt-Jakob disease (CJD).

A signal peptide of 22 amino acids (dotted area) is cleaved at the amino terminus (N-terminus) synthesis, and a further sequence at the carboxyl terminus (dotted area) is removed during the addition of a glycosyl-phosphatidylinositol anchor (GPI).

Mutations associated with inherited prionoses are shown above the gene, while polymorphisms are shown below the gene. A polymorphism at codon 129 (M versus V) is common in white populations, while a polymorphism at codon 219 (E versus K) is common in Japanese populations.

The locations of the 4 putative helical regions are indicated by the boxes labeled H1 through H4, corresponding to residues 144-154, 179-193, and 200-218, respectively.

The diagonal striped area represents the region of octarepeats, spanning residues 51-91. Octarepeats of 16, 32, 40, 48, 56, 64, or 72 amino acids at codons 67, 75, or 83 are indicated by the rectangle above the octarepeat region. These inserts are associated with familial CJD.

Mutations at codons 102, 105, and 117 have been associated with GSS, while mutations at codons 198 and 217 are found in pedigrees with GSS and NFTs.

PrP-CAA has been linked to a point mutation at codon 145 that results in a stop codon. Familial CJD has been associated with mutations at codons 178, 180, 200, 210, and 232.

Interestingly, kindreds with FFI have the same D178N mutation as 178 familial CJD kindreds; however, the FFI phenotype is associated with a Met at codon 129, whereas the mutated allele in 178 CJD patients has a Val at the polymorphic codon 129.

Sporadic causes

Sporadic CJD is the most common form of prion disease.

It probably arises as a spontaneous conformational change in PrPC to a PrPSc form. The PrPSc form is then self-propagating, inducing more PrPC to convert to the PrPSc form.

The risk of transmission depends on both the type of procedure and the type of tissue involved, with brain, spinal cord, and eye having the highest risk.

To study the association between medical procedures and sporadic Creutzfeldt-Jakob disease (sCJD), Hamaguchi et al analyzed medical procedures (any surgical procedure, neurosurgery, ophthalmic surgery, and blood transfusion) for patients registered by the CJD Surveillance Committee in Japan from 1999–2008. The study included 753 patients with sCJD and 210 controls and patients who underwent neurosurgical or ophthalmic surgical procedures at the same hospital. No evidence was found that prion disease was transmitted through the investigated medical procedures before the onset of sCJD. After the onset of sCJD, 4.5% of the patients with sCJD underwent operations, and no special precautions against transmission of prion diseases were taken. The authors have not identified patients with prion disease attributed to these operations and conclude that surgical procedures or blood transfusion has little effect on the incidence of sCJD. [87]

However, recent evidence suggests that the risk of iatrogenic transmission may be higher than previously thought. Postmortem quantitative analyses of prion seeding activity in the esophagus of patients with CJD have been shown to reach levels comparable to the central nervous system, indicating a potential risk associated with endoscopic examination and procedures. [88] While still at substantially lower levels when compared to brain tissue, prion seeding activity has also been identified in skin biopsies of sCJD patients, suggesting that future research may be warranted to determine the risk of iatrogenic transmission associated with minor surgical procedures involving the skin. [89] Additionally, iatrogenic transmission of CJD via corneal transplant has recently emerged as a concern, with statistical analyses suggesting that the 10 reported global cases likely under-represents the true number of deaths by CJD among corneal transplant patients. [90]

Transfusion transmission of the prion, the agent of variant Creutzfeldt-Jakob disease (vCJD), is now established. Subjects infected through food may transmit the disease through blood donations.