Phenotypic variability in fatal familial insomnia (D178N-129M) genotype

Zerr, Inga; Giese, Armin; Windl, Otto; Kropp, Stefan; Schulz‐Schaeffer, Walter; Riedemann, Christian; Skworc, K.; Bodemer, Monika; Kretzschmar, Hans A.; Poser, S.

doi:10.1212/wnl.51.5.1398

Cited by 67 publications

(67 citation statements)

References 15 publications

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“…36 Cases reported to the CJD surveillance unit in Germany were less clinically distinct than the first reported FFI families in that none were clinically diagnosed as FFI due to an absence of obvious insomnia and no positive family history was obtained in 4/9. 78 Pocchiari et al 18 noted that of patients presenting with overt sleep disturbance to a CJD unit, 4/9 had sporadic CJD, 1/9 had a V210I mutation, but none had D178N. Of the 72 case reports reviewed here, the median age of onset was 50 (range 20 -71) and median duration of disease was 11 months (range 5 months -4 years).…”

Section: Prion Disease Genetics S Meadmentioning

confidence: 75%

Prion disease genetics

2006

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Prion diseases have stimulated intense scientific scrutiny since it was proposed that the infectious agent was devoid of nucleic acid. Despite this finding, genetics has played a key role in understanding the pathobiology and clinical aspects of prion disease through the effects of a series of polymorphisms and mutations in the prion protein gene (PRNP). The advent of variant Creutzfeldt-Jakob disease has confirmed one of the most powerful human genetic susceptibility factors, as all tested patients have an identical genotype at polymorphic codon 129 of PRNP. This review will also consider the accrued reports of inherited prion disease and attempt a genotype-phenotype correlation. The prospects for detection of novel genetic susceptibility factors using mouse models and human genetic association studies will be explored.

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Section: Prion Disease Genetics S Meadmentioning

confidence: 75%

Prion disease genetics

2006

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“…The latter figure may be due to the high number of genetic studies performed in Italy even in apparently sporadic cases. It is widely accepted that a significant number of PRNP mutation carriers have no known family history of prion diseases, as is the case in our family 9 and others reported in the literature [11][12][13]. In our families a very high, if not complete, penetrance is suggested, although this was not specifically addressed.…”

Section: Discussionmentioning

confidence: 62%

Familial Prion Diseases in the Basque Country (Spain)

Zarranz

Digón²,

Atarés³

et al. 2004

Neuroepidemiology

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In 1995, a surveillance system for prion diseases was set up in the Basque Country, an autonomous region in northern Spain (2.1 million inhabitants). In the period from January 1993 to December 2003, we diagnosed 21 patients with familial prion diseases prospectively and another 4 patients retrospectively. They represent 35% of all the cases referred to the epidemiological registry. Two main possible explanations for this unusual high incidence of familial prion diseases are proposed: first, comprehensive case ascertainment by public health neurologists; second, a probable cluster of the D178N mutation within families of Basque origin related to a still unconfirmed common ancestor. Further genetic and genealogical studies should resolve this issue.

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“…The SRTM analysis generates BPs by modeling the time activity curve (TAC) of a preset reference region and comparing it voxel‐wise in the whole scan 34. The identification of a reference region with 11C‐(R)‐PK11195‐PET can be particularly challenging, since the delivery of the tracer is homogeneous across the whole‐brain, hindering the delineation of an anatomically defined region 35, 36. This methodological caveat led to the development of automated clustering algorithms able to select pseudo‐reference regions, that is, clusters of voxels sharing a specific TAC 35, 37.…”

Section: Methodsmentioning

confidence: 99%

“…The D178N mutation can trigger different clinico‐pathological syndromes, either thalamic‐dominant FFI or CJD, depending on a methionine‐valine polymorphism at PRNP codon‐129 8, 9, 10. FFI syndrome is almost exclusively associated with methionine in the mutated allele (D178N‐129M),9 but not all the carriers of the D178N‐129M mutation develop an FFI phenotype 11, 12. Additionally, methionine/valine polymorphism in the normal allele appears relevant for disease progression and severity, with FFI D178N‐129 M/M patients presenting with a more rapid decline compared to D178N‐129 M/V cases 9.…”

Section: Introductionmentioning

confidence: 99%

An in vivo ¹¹C‐PK PET study of microglia activation in Fatal Familial Insomnia

Iaccarino

Presotto

Bettinardi

et al. 2017

Ann Clin Transl Neurol

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ObjectivePostmortem studies reported significant microglia activation in association with neuronal apoptosis in Fatal Familial Insomnia (FFI), indicating a specific glial response, but negative evidence also exists. An in vivo study of local immune responses over FFI natural course may contribute to the understanding of the underlying pathogenesis.MethodsWe included eight presymptomatic subjects (mean ± SD age:44.13 ± 3.83 years) carrying the pathogenic D178N‐129met FFI mutation, one symptomatic patient (male, 45 yrs. old), and nine healthy controls (HC) (mean ± SD age: 44.00 ± 11.10 years.) for comparisons. 11C‐(R)‐PK11195 PET allowed the measurement of Translocator Protein (TSPO) overexpression, indexing microglia activation. A clustering algorithm was adopted to define subject‐specific reference regions. Voxel‐wise statistical analyses were performed on 11C‐(R)‐PK11195 binding potential (BP) images both at the group and individual level.ResultsThe D178N‐129met/val FFI patient showed significant 11C‐(R)‐PK11195 BP increases in the midbrain, cerebellum, anterior thalamus, anterior cingulate cortex, orbitofrontal cortex, and anterior insula, bilaterally. Similar TSPO increases, but limited to limbic structures, were observed in four out of eight presymptomatic carriers. The only carrier with the codon 129met/val polymorphism was the only one showing an additional TSPO increase in the anterior thalamus.InterpretationIn comparison to nonprion neurodegenerative diseases, the observed lack of a diffuse brain TSPO overexpression in preclinical and the clinical FFI cases suggests the presence of a different microglia response. The involvement of limbic structures might indicate a role for microglia activation in these key pathologic regions, known to show the most significant neuronal loss and functional deafferentation in FFI.

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Phenotypic variability in fatal familial insomnia (D178N-129M) genotype

Abstract: The clinical presentation in patients with FFI may vary to a great extent. Genotyping of the patients was crucial in providing laboratory confirmation of the diagnosis of FFI, even when there was no family history of a prion disease.

Cited by 67 publications

References 15 publications

Prion disease genetics

Prion disease genetics

Familial Prion Diseases in the Basque Country (Spain)

An in vivo ¹¹C‐PK PET study of microglia activation in Fatal Familial Insomnia

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Phenotypic variability in fatal familial insomnia (D178N-129M) genotype

Abstract: The clinical presentation in patients with FFI may vary to a great extent. Genotyping of the patients was crucial in providing laboratory confirmation of the diagnosis of FFI, even when there was no family history of a prion disease.

Cited by 67 publications

References 15 publications

Prion disease genetics

Prion disease genetics

Familial Prion Diseases in the Basque Country (Spain)

An in vivo 11C‐PK PET study of microglia activation in Fatal Familial Insomnia

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An in vivo ¹¹C‐PK PET study of microglia activation in Fatal Familial Insomnia