Familial Cjd Variant With E200k-129m >> Mutation in the Prp Gene

Creutzfeldt–Jakob disease (CJD) is characterised by speedily progressive dementia, myoclonus, ataxia, visual disturbances and motor dysfunction. Neuropathological exam shows diffuse spongiosis, neuronal loss, gliosis and a variable degree of amyloid plaque degradation composed of protease‐resistant prionic protein (PrP^RES) in several locations, including the brain stem. The most frequent clinical presentations are dementia, ataxia or visual symptoms. Virtually of the cases are sporadic. Simply 10–15% are familial, and the most frequent point mutation is E200K. The form of disease, investigation results and neuropathology are similar to those of the desultory form of CJD. The typical clinical presentation of E200K is a rapidly progressive dementia with myoclonus and pyramidal, cerebellar or extrapyramidal signs.¹ We report a familial case with an unusual onset, with deafness and polyneuropathy.

A 53‐yr‐former man presented with subacute progressive bilateral hypoacusis, with tinnitus in the left ear. He was a frequent diver and the symptoms were attributed to barotrauma. During the following months, his hypoacusis worsened and he progressively developed bilateral stocking‐type paresthaesia and gait instability. On test, he was warning and cooperative, although communication was mildly affected because of the hypoacusis. He showed emotional lability; his spoken communication was tedious just fluent, and he was partially disoriented in fourth dimension. Extrinsic ocular move, cranial fretfulness and muscular strength were normal. Lower limbs showed mild hypertonia, right extensor plantar response, stocking‐type hypoaesthaesia and hypopallaesthaesia, and moderate gait clutter. An audiometric examination showed bilateral neurosensorial hypoacusis, and nerve conduction studies showed a mixed axonal polyneuropathy. Computed tomography and magnetic resonance imaging of the brain were normal and the electroencephalograph (EEG) showed non‐specific changes.

These symptoms led to an initial suspicion of a paraneoplastic disorder, and an examination for malignant illness was started. At this moment, we learnt that the patient's mother had died of neuropathologically confirmed CJD; hence we conducted a CSF 14‐iii‐three‐protein detection exam, which was positive. Serial EEGs showed repeated non‐specific changes. Brain stem auditory evoked potentials (BAEPs) could not be performed, owing to lack of patient collaboration.

During the following ii weeks, myoclonus appeared and rapidly generalised, mental status deteriorated and progressive clutter bars the patient to bed. He died of respiratory infection 10 months after onset of symptoms.

Neuropathological examination showed neuronal loss, microspongiosis and astroglial and microglial proliferation predominantly in the isocortex, entorhinal cortex, and hippocampal CA1 region, striatum, amygdala and cerebellar cortex. Punctate, synaptic‐similar deposits of PrP^RES in the cerebral and cerebellar cortices were found, likewise every bit scattered large PrP^RES deposits in the granular layer of the cerebellum. The mesencephalon did non prove spongiosis, but gliosis in colliculum and periaqueductal grey matter were detected.

Marked neuronal loss and gliosis in the vestibular and cochlear nuclei were observed, associated with PrP^RES deposition (fig 1​ ). Western blot of PrP^RES showed a three‐band pattern, with an unglycated fragment migrating at 21 kDa, corresponding to PrP^RES type 1. Genetic sequencing of PrP showed the presence of the E200K mutation in heterozygosis. No insertions or deletions were found in the 51–91 region. The patient was heterozygotic for the M/V polymorphism at codon 129.

Figure 1 (A) Frontal cortex with moderate neurone loss, neuronal vacuoles and spongiform change. (B) Ventral cochlear nucleus showing the almost absence of large neurones. (C) Punctate PrPres immunostaining in the lateral vestibular nucleus. Paraffin sections (A,B) Haematoxylin and eosin staining; c: PrP^RES immunohistochemistry. Scale bar = 25 μm.

Only ii cases of CJD with deafness at onset accept been published: i sporadic, associated with symptoms suggestive of polyneuropathy,ⁱⁱ and the other familial, with the E200K mutation and typical features.³ Other cases have been reported as presenting with auditory agnosia or with cortical deafness, and early interest of the acoustic pathway was already detected through demonstration of progressive BAEP deterioration in patients with CJD who did not present deafness in the course of the disease.

The start instance was that of a 71‐twelvemonth‐old adult female who presented with a sudden change in hearing and aural fullness, and a vague feeling of imbalance.ⁱⁱ Hearing loss and gait instability worsened rapidly Audiometry showed bilateral neurosensorial hearing loss, and BAEPs were initially normal. She afterward adult signs of polyneuropathy and mental deterioration, left homonynous hemianopsia and decreased vibratory and pinprick sensation. The second case was that of a 46‐year‐one-time Italian adult female with the E200K mutation, who had speedily worsening hearing loss.³ Three weeks later she developed an unstable gait, and her condition chop-chop progressed to bilateral deafness, clutter, myoclonus, pyramidal and extrapyramidal dysfunction, and mental deterioration. She died half dozen months after the onset of the illness. Magnetic resonance imaging scans showed high signal areas, more often than not in the caudate and putamen, EEGs showed periodic sharp‐wave complexes, and protein 14‐iii‐three was nowadays in the cerebrospinal fluid. Audiometric investigation showed bilateral sensorineural hearing loss, and BAEP abnormalities from the beginning seemed to confirm early encephalon stem involvement. The grade of the affliction, clinical features and EEG recordings were like to those of the sporadic grade of CJD.

Accumulation of PrP in the brain stem has been found to be an early pathological outcome in desultory CJD, but these deposits are non necessarily associated with clinical symptoms or neuronal loss, and the encephalon stem seems to remain relatively resistant to the pathological process of sporadic CJD.⁴ Neuropathological changes in brain stalk structures take been described in sporadic and familial CJD, associated with singular onset, with gaze disorders and with fatal familial insomnia. Unfortunately, necropsy was not possible in the two patients with early deafness, and to our cognition specific involvement of cochlear and vestibular nuclei has non been reported previously

Western blot of PrP showed a type 1 pattern in our example. This is the pattern usually observed in desultory CJD M/Thousand homozygotic at codon 129, and it has also been described in patients with the E200K mutation associated with the allele 129M in the mutated chromosome.⁵ It is not known whether the glycation pattern of aberrant PrP has an influence on phenotype. In our patient too, who was M/V homozygotic, the codon 129 status of the mutated allele was not investigated.

This case illustrates the phenotypic variability of presentation of CJD, and describes the specific involvement of brain stalk auditive nuclei in a patient with hypoacusis as the initial manifestation, thereby reflecting early encephalon stem involvement.

Footnotes

Funding: This work was supported by the Eu project Neuroprion.

Competing interests: None alleged.

Informed consent was obtained for publication of the patient'due south details described in this report.

References

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2117778/

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