Cerebellar dysfunction in a family harboring the PSEN1 mutation co-segregating with a Cathepsin D variant p.A58V

Ehling, Rainer; Nosková, Lenka; Stránecký, Viktor; Hartmannová, Hana; Přistoupilová, Anna; Hodaňová, Kateřina; Benke, Thomas; Kovács, Gábor G.; Ströbel, Thomas; Niedermüller, Ulrike; Wagner, M.; Nachbauer, Wolfgang; Janecke, Andreas R.; Budka, Herbert; Boesch, Sylvia; Kmoch, Stanislav

doi:10.1016/j.jns.2013.01.017

Cited by 19 publications

(11 citation statements)

References 31 publications

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“…Recently, a family presenting with early-onset dementia, cerebellar dysfunction, and cerebellar Aβ deposits was identified. However, aside from carrying a PS1 S170F mutation, the affected patients carried variant A58V of cathepsin D (32). Furthermore, E280A-FAD has shown previously altered Tau phosphorylation in the cerebellum causing pTau deposition (12).…”

Section: Figurementioning

confidence: 99%

Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

Sepulveda‐Falla¹,

Barrera-Ocampo²,

Hagel³

et al. 2014

J. Clin. Invest.

114

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Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A-associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca 2+ channels IP3Rs and CACNA1A were downregulated, and Ca 2+ -dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/ mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca 2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration.

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Section: Figurementioning

confidence: 99%

Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

Sepulveda‐Falla¹,

Barrera-Ocampo²,

Hagel³

et al. 2014

J. Clin. Invest.

114

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“…Thereupon, sequencing of PSEN1 revealed the S170F mutation, which was later confirmed in his sister (III.2). The pathogenic nature of the S170F mutation has been established before in several familial as well as sporadic cases [41,42,43,44,45]. …”

Section: Resultsmentioning

confidence: 99%

“…This mutation results in an amino acid change from serine (TCT) to phenylalanine (TTT) at codon 170 on exon 6 of the PSEN1 gene encoding the transmembrane domain III of presenilin-1, where many pathogenic mutations are found to cluster [28]. The pathogenic nature of the S170F mutation has been established before in several reported familial as well as sporadic cases: it was first demonstrated in a North American family with 3 affected family members in 2 generations [44], another family from Austria with 5 cases spanning 3 generations [45] as well as single sporadic cases from Great Britain and Poland with de novo mutations [41,42] and 1 patient in Italy with an incomplete family history [43]. Altogether, data from 15 patients (9 women) with more detailed clinical information in 10 are currently available; a comparative summary of findings associated with the S170F mutation can be found in Table 2.…”

Section: Discussionmentioning

confidence: 99%

“…The apolipoprotein E allele, for instance, was analysed in 3 patients, who were homozygous for the “neutral” type (E3/E3). Furthermore, Ehling et al [45] reported 3 patients where the S170F mutation co-segregated with a variant of the cathepsin D gene. The relevance of this finding remains unclear, considering that all patients inherited the cathepsin D variant from their (unaffected) father.…”

Section: Discussionmentioning

confidence: 99%

“…Observations in patients harbouring this mutation have been described - with considerable differences across reports - in consecutive publications since 2005 [41,42,43,44,45]. The most consistent findings associated with this mutation are a very early onset of dementia in the late twenties and cerebellar ataxia as a prominent non-cognitive symptom whereas the degree of variability of genotype-phenotype correlations in S170F carriers remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic Variability in Autosomal Dominant Familial Alzheimer Disease due to the S170F Mutation of Presenilin-1

et al. 2018

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Background: In rare cases, patients with Alzheimer disease (AD) present at an early age and with a family history suggestive of an autosomal dominant mode of inheritance. Mutations of the presenilin-1 (PSEN1) gene are the most common causes of dementia in these patients. Early-onset and particularly familial AD patients frequently present with variable non-amnestic cognitive symptoms such as visual, language or behavioural changes as well as non-cognitive, e.g. motor, symptoms. Objective: To investigate the phenotypic variability in carriers of the PSEN1 S170F mutation. Methods: We report a family with 4 patients carrying the S170F mutation of whom 2 underwent detailed clinical examinations. We discuss our current findings in the context of previously reported S170F cases. Results: The clinical phenotype was consistent regarding initial memory impairment and early onset in the late twenties found in all S170F patients. There were frequent non-amnestic cognitive changes and, at early stages of the disease, indications of a more pronounced disturbance of visuospatial abilities as compared to face and object recognition. Non-cognitive symptoms most often included myoclonus and cerebellar ataxia. A review of the available case reports indicates some phenotypic variability associated with the S170F mutation including different constellations of symptoms such as parkinsonism and delusions. Conclusion: The variable clinical findings associated with the S170F mutation highlight the relevance of atypical phenotypes in the context of research and under a clinical perspective. CSF sampling and detection of Aβ species may be essential to indicate AD pathology in unclear cases presenting with cognitive and motor symptoms at a younger age.

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Application of Exome Sequencing to Mendelian Disorders and the Emergence of Personalised Medicine

Raszek

2013

Encyclopedia of Life Sciences

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Since the introduction of next‐generation sequencing, the field of genomic medicine has expanded rapidly. Whole‐exome sequencing (WES) can sequence thousands of functional genes at a time and has become the tool of choice for the discovery of causative genetic variants, especially for Mendelian diseases. This approach also expands the knowledge of novel mutations of established genes linked to a particular disease, and helps to uncover the complex interplay between modifier variants that contribute to a disease phenotype. For these reasons, WES can perform diagnoses that would be difficult to accomplish with traditional methods, particularly for diseases that exhibit a broad genetic or phenotypic heterogeneity. Together, these trends already have begun to influence the quality of patient care and appear to fulfil the promise of personal medicine. The article summarises recent literature that highlights these trends, and discusses the limitations and ethical considerations surrounding this new technology. Key Concepts: Next‐generation sequencing is driving the emergence of personalised medicine. Superiority of WES as a diagnostic tool over traditional genetic methods is apparent, especially for diseases that are genetically and phenotypically heterogenous. WES utility is a rapidly expanding field of genetic aetiology. The underlying genetic complexity of monogenic diseases might have been underappreciated. The clinical manifestation of monogenic diseases is driven by a complex interplay of a multitude of genetic modifiers. The incidentalome remains an important ethical issue, but important steps forward have been taken with the work of Dr. Berg and collaborators commencing in 2011. The rapidly expanding field of genomics faces important technical limitations: storage space and analysis capability. Important ethical questions need to be addressed with regard to the use of NGS technology; this includes rights to data access and issues regarding follow‐up data reanalysis.

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Cerebellar dysfunction in a family harboring the PSEN1 mutation co-segregating with a Cathepsin D variant p.A58V

Cited by 19 publications

References 31 publications

Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

Phenotypic Variability in Autosomal Dominant Familial Alzheimer Disease due to the S170F Mutation of Presenilin-1

Application of Exome Sequencing to Mendelian Disorders and the Emergence of Personalised Medicine

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