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    • To the best of our knowledge only

    2022-11-18

    To the best of our knowledge, only 3 cases of an E196K mutation have been described since it was first identified in 2000 [15], [16], [17], although 5 cases, accounting for 1.1% of all genetic TSE cases, were reported with no precise data on the clinical phenotypes in the EUROCJD collaborative surveillance project [1]. The clinical pattern of these 3 patients and ours is reported in Table 1. As in our case, no autopsies were performed in these previously described cases. Consequently, in the absence of neuropathological confirmation, these patients can only be classified as having probable genetic TSA. Interestingly, one of the clinical characteristics is age at onset, which ranged from 66 to 80 years. This is slightly higher than that observed in most cases of genetic TSE [2], [18]. The initial clinical presentation was atypical in the majority of cases as patients exhibited behavioral and/or depressive manifestations. In our case, the patient experienced difficulties in using his computer keyboard several months before his admission for a stroke. This was retrospectively interpreted as apraxia of tool use since ideomotor apraxia was found in the second neurological evaluation. The patient also exhibited a sleep disorder, and rapidly developed behavioral abnormalities after his admission to hospital. Myoclonus was subsequently observed during the course of the disease in all cases. Even though cerebellar ataxia is a major criterion for the diagnosis of sporadic CJD [19], it has been reported in only one patient. In our observation, the unilateral left cerebellar syndrome was certainly due to infarction of the ipsilateral cerebellar hemisphere. Similarly, the absence of periodic activity on the electroencephalograph found in our patient is a constant feature of the disease. The duration of the disease (less than 18 months) is consistent with other genetic TSE except for GSS disease, which has been identified as having the longest duration [1]. Only 1 of the 3 previously reported patients had a known family history of a similar neurological disease [15]. The absence of a family history, as observed in our patient, has been reported in 47% of all genetic TSA [1]. Finally, homozygosity for either methionine (3 cases/4) or valine (1/4) was identified at choline fenofibrate australia 129. It is known that codon 129 affects susceptibility to all categories of prion disease or can modify its phenotype [20], [21], [22]. In EUROCJD, 67.9% of genetic TSE patients were methionine–methionine whereas 25.8% were methionine–valine [1]. Contrary to our patient and the 3 others described in the literature, one case with the PRNP E196K mutation was heterozygote at codon 129 has been reported [1]. From a pathophysiological point of view, it has been established that the E196K mutation is located sequentially adjacent to the third alpha helix of PrP, and could consequently eliminate the salt bridge that establishes a link between the first and third alpha helix [15], [23]. As a result, stability would be reduced, which would promote a possible conformational change of the mutant PrP and then accumulation of the protein within the brain [15]. This assumption, however, remains speculative. To conclude, our case underlines that a specific phenotype of patients with genetic TSE may exist, according to the mutation involved. Further observations are needed to confirm the atypical initial clinical picture, i.e. mainly abnormal behavioral manifestations, of patients with the very uncommon PRNP E196K mutation.
    The high mobility group (HMG) proteins are non-histone chromosomal proteins known as “architectural transcription factors” because of their ability to facilitate gene transcription via binding and modifying specific structures of DNA or chromatin , , , , . There are three subfamilies of HMG proteins: HMGA (formerly designated as HMG-I/Y, HMGI-C), HMGB1/B2 (formerly HMG1/2), and HMGN1/N2 (formerly HMG14/17) , . Among the HMG proteins, HMGN1 and N2 are the only nuclear proteins that recognize specifically the 146-bp nucleosomal core particle and they have a higher affinity toward nucleosomes than double-stranded DNA , . In addition, the association between HMGN1/N2 and nucleosome core particle is not dependent on DNA sequence . The binding of HMGN proteins to individual nucleosome unfolds chromatin fiber and increases the accessibility of the transcription factors to the nucleosomal DNA thereby facilitating transcription and replication from chromatin templates . The HMGN1 protein was also shown to be able to increase the rate of repair of UV-light damaged DNA in chromatin .