Differential Diagnosis in Neurology

16.4. Prion Disease

• General considerations:
  • Prion protein (PrP) exists in normal healthy brain:
    • Coded by the host genome
    • Located on chromosome 20; PRNP gene
  • Exists in two isoform:
    • PPC cellular isoform (host protein):
      • Exists in normal brain
      • Proteinase sensitive PrP (sen)
    • PrP sc (scrapie) isoform (altered protein):
      • Proteinase resistant form
    • The function of cellular (normal) isoform of PrP is unknown:
      • PrP is a normal constituent of the neuronal cell membrane
      • Transported along axons and accumulates at the neuromuscular junction
      • Polymorphism at the codon 12 q of the PrP gene (val–val):
        • Increased cognitive impairment in the elderly
        • 129 homozygosity at codon 12 q for sporadic form
        • Val/val at codon 129 for the iatrogenic and acquired form
        • Met/met at codon 129 for the new variant
  • Hereditary form of prion disease:
    • Transmission of a mutant PrP gene:
      • Produces an altered protein
      • 10–15% of prion diseases are hereditary
    • Infection with the altered protein:
      • Introduction into normal host brain causes:
        • Conversion of the normal host PrP into the abnormal PrP isoform
        • Alpha helix of the normal protein is converted to the beta sheet
        • The process facilitated by another protein
        • Evidence of efficient prion convulsion is a short incubation time
        • Prion strain properties are enciphered in the tertiary structure of PrP sc
        • This influences the molecular interactions between the normal and disease specific isoform
  • Mutations in the PrP gene:
    • Chromosome 20
    • Cause conformational changes of the PrPc protein:
      • Shift from the normal alpha helix to a beta sheet
      • Affects the degree of glycosylation of the PrPc protein
  • Secondary tertiary structure of PrP sc determines:
    • Size of protein
    • Differences
    • Different mutations cause different pathologic changes:
      • Spongiosis
      • Amyloidosis
      • Neurofibrillary degeneration
      • Congophilic angiopathy
      • Gliosis
      • Neuronal loss
    • The tertiary structure of the PrP sc fragment causes the different pathologies
  • Prion protein (PrP sc) fragments are:
    • Neurotoxic
    • Fibrillogenic
    • In a beta sheet secondary structure
    • Proteinase resistant

Creutzfeldt–Jacob Disease

• General considerations:
  • Average of 1 case/million people
  • 10% have family history of presenile dementia that is not CJD
  • Prolonged incubation > 20 years have been noted in infectious etiologies
  • Human transmission described from:
    • Corneal transplant
    • EEG electrodes
    • Dural graft
    • Growth hormone
  • Invariably fatal
• Clinical features:
  • Rapidly developing dementia with myoclonus
  • Early stages:
    • Gait ataxia
    • Visual disturbances
    • Personality change
    • Dizziness
  • Later stages:
    • Aphasia
    • Apraxia
    • Confusion
    • Stupor
    • Myoclonic jerks usually occur 2–3 months from onset of the disease
  • In 5–10% of patients the illness may last > 2 years

Classification Scheme of Classic Form by the Underlying PrP Polymorphism at Codon 129

• General considerations:
  • PrPsc type 1:
    • Met codon 129:
      • Usual CJD presentation of dementia and myoclonus (CJD-M/M1)
      • Size of the protease resistant core 21 kD
  • PrP sc type II:
    • Size of the protease resistant core 19 kD
    • Met1/met (CJD M/M2):
      • Longer disease duration and lack of myoclonus
    • Met/Val:
      • Related to variant with Kuru plaques (CJD-M/V)
    • Val/Val:
      • Ataxia and late dementia (CJD-V/V)
    • CJD with M/V and V/V polymorphism at 129:
      • Less pathology in the neocortex
      • Involve primarily the deep nuclei and cerebellum
• EEG findings:
  • Distinction repetitive sharp waves
  • Intervals of 1–2 Hz (periodic complexes)
  • Progressive slow background
• MRI:
  • Increased diffusion in the cortex
  • T2 weighted lesions in the pulvinar
• Pathology:
  • Cerebral atrophy
  • Spongiosis:
    • Vacuoles within the neuropil that contain membrane fragments
    • Gliosis
    • Neuronal loss
    • Abnormal fibrils
    • Pathological changes are to a different degree and combination of:
      • Fragment size
      • Tertiary structure of the protein
  • Type I/II coexist 33% of the time

Pathologic Distribution of Involvement by Polymorphism of Codon 129

• Met/Met at codon 129:
  • Mild
  • Occipital lobe
  • Low PrP sc load
  • Few focal PrP sc amyloid deposits
  • No amyloid plaques
• Met/Val at codon 129:
  • Multiple lesions throughout the brain
  • Parahippocampal gyrus particularly involved
  • Numerous plaques
• Val/Val at codon 129:
  • Younger age at onset (<55 years of age)
  • Longer disease duration (11.5 years)
  • Hippocampal formation and basal ganglia are severely involved
  • Focal non-amyloid deposits
  • Rare amyloid plaques
• Unusual mutations:
  • E 200 K or V2101 associated with familial CJD
  • 178 ASP to ASN associated with FFI (fatal familia insomnia) and familial CJD

Kura

• General considerations:
  • Transmitted amongst the Fiore people in New Guinea high lands in the past by ritual cannibalism
• Clinical features:
  • Gait ataxia early
  • Hypotonia
  • Chorea
  • Dysarthria
  • Dementia in late stages

Gerstmann–Straussler–Scheinker Syndrome (GSS)

• General considerations:
  • AD
  • Six different point mutations of PRNP gene at codon 129:
    • 102, 105, 117, 145, 198, 217
    • On chromosome 20
• Clinical features:
  • Onset in 3rd to 6th decade
  • Ataxia
  • Extrapyramidal signs
  • Spastic paraparesis
  • Progressive dementia
  • Death within five years of onset

Variant GSS (Missense Mutation at Codon 105 (P105L)

• Clinical features:
  • Spastic paraparesis
  • Dementia
  • Age at onset 38 to 50
  • Severe gait disturbance
  • Involuntary movements

Classic GSS (P102L)

• General considerations:
  • Missense mutation at codon 102 (P102L)
  • Cerebellar ataxia and dementia
  • Polymorphism at codon 129 and 219
  • Babinski's signs noted early
  • Leg pain and dysesthesias:
    • Loss of ankle reflexes
  • Some patients:
    • Axonal neuropathy
    • Motor neuron disease
• Pathology:
  • PrP amyloid plaque deposition:
    • Cerebral and cerebellar cortex
    • Involvement of the spinal grey posterior horn
    • Deep grey matter
    • Dentate nucleus

Fatal Familial Insomnia

• General characteristics:
  • AD hereditary prion disease:
    • Sporadic form
  • Mutation are at codon 178 and 129 of the PRNP gene:
    • The mutations are not dual
    • Mutation is at codon 178, but the phenotype is CJD unless there is a methionine at codon 129
• Clinical features:
  • Intractable insomnia
  • Delirium, confusion, hallucinations
  • Psychosis
  • Dysautonomia (autonomic hyperactivity)
  • Myoclonus
  • Dysarthria
  • Ataxia
  • Memory impairment
  • Onset anytime in adulthood
• Laboratory evaluation:
  • Consistent glycosylation pattern
• Pathology:
  • Tonsillar biopsy for PrP sc
  • Protein 14-3-3 in CSF
  • Neuronal loss and gliosis in thalamus:
    • Anterior ventral nuclei
    • Mediodorsal thalamic nuclei
  • Lesions in:
    • Inferior olives
    • Some spongiform changes in cortical areas

New Variant Prion Disease

• General characteristics:
  • Early reports from the UK
• Clinical features:
  • Young adults are affected
  • Usual duration of illness is 14 months
  • After six months ataxia is present
  • Cognitive impairment
  • Psychiatric symptoms
  • Paraesthesias and dysesthesias of the limb
  • Persistent limb pain
  • Visual symptoms
  • Involuntary movements (dystonia and chorea more prominent than myoclonus)
• MRI:
  • Bilateral high signal on T2 weighted images in the pulvinar

Focal Cortical Degenerations with Dementia

• Frontal lobe:
  • Left hemisphere:
    • Progressive nonfluent aphasia
    • Hereditary disinhibition dysphasic dementia
    • Primary progressive aphasia
    • Semantic aphasia and associative agnosia
• Heidenhain variant of CJD (occipital lobe)
• Parietal Pick's disease
• Motor neuron disease:
  • Primary lateral sclerosis (motor cortex)
  • ALS with frontal dementia
• Corticobasal ganglionic degeneration:
  • Frontal and parietal lobe atrophy
• Posterior cortical atrophy:
  • AD
  • SCG
  • CJ Heidenhain variant
  • Posterior lobar atrophy

Thalamic Dementia

• Associated with MND
• Familial multi system atrophy (MSA)
• Familial fatal insomnia (FFI)
• Thalamic degeneration of Shulman