Rare causes of dystonia-parkinsonism with cognitive impairment, behavioral abnormalities, and voiceless whispering stereotypies: Describing the long-term evolution of the neurological phenotype in a patient with the PSEN2 Ile149Thr variant

Romito, Luigi Michele; Prioni, Sara; Braccia, Arianna; Catania, Marcella; Elia, Antonio Emanuele; Dondi, Francesco; Lucchini, Silvia; Bertagna, Francesco; Piacentini, Sylvie H.M.J.; Eleopra, Roberto; Di Fede, Giuseppe

doi:10.1016/j.jns.2023.120846

Cited by 2 publications

(1 citation statement)

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“…In addition to informing clinical care for people with suspected ADAD-causing variants and the conduct of ongoing clinical trials in ADAD, understanding the link between altered γ-secretase function and the pathogenicity of PSEN2 variants is particularly critical as there are many variants reported in PSEN2 that are reported as questionably pathogenic, unclassified, or of uncertain significance. In addition to AD, variants in PSEN2 have also been linked with other neurological disorders not classically associated with mutations in the PSEN1 (as reviewed by Cai and colleagues (16)), such as dementia with Lewy bodies (34), frontotemporal dementia (35), and Parkinson's disease dementia (36,37). In this context, the systematic evaluation of PSEN2 variants may help to refute or support the pathological significance of individual variants in clinical and research settings, particularly when limited family history is available.…”

Section: Introductionmentioning

confidence: 99%

The pathogenicity ofPSEN2variants is tied to Aβ production and homology toPSEN1

Liu,

Schultz,

Saba

et al. 2024

Preprint

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INTRODUCTIONThough recognized as a potential cause of Autosomal Dominant Alzheimer’s Disease, the pathogenicity of manyPSEN2variants remains uncertain. We compared Aβ production across all missensePSEN2variants in the Alzforum database and, when possible, to correspondingPSEN1variants.METHODSWe expressed 74PSEN2variants, 21 of which had homologousPSEN1variants with the same amino acid substitution, in HEK293 cells lacking PSN1/2. Aβ production was compared to age at symptom onset (AAO) and between homologousPSEN1/2variants.RESULTSAβ42/40 and Aβ37/42 ratios were associated with AAO acrossPSEN2variants, strongly driven byPSEN2variants withPSEN1homologs.PSEN2AAO was 18.3 years later compared toPSEN1homologs. Aβ ratios fromPSEN1/2homologs were highly correlated, suggesting a similar mechanism of γ-secretase dysfunction.DISCUSSIONThe existence of aPSEN1homolog and patterns of Aβ production are important considerations in assessing the pathogenicity of previously-reported and newPSEN2variants.

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Section: Introductionmentioning

confidence: 99%

The pathogenicity ofPSEN2variants is tied to Aβ production and homology toPSEN1

Liu,

Schultz,

Saba

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1

Liu,

Schultz,

Saba

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONThough recognized as a potential cause of autosomal dominant Alzheimer's disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared amyloid beta (Aβ) production across all missense PSEN2 variants in the AlzForum database and, when possible, to corresponding PSEN1 variants.METHODSWe expressed 74 PSEN2 variants, 21 of which had known, homologous PSEN1 pathogenic variants with the same amino acid substitution, in HEK293 cells lacking presenilin 1/2. Aβ production was compared to age at symptom onset (AAO) and between PSEN1/2 homologs.RESULTSAβ42/40 and Aβ37/42 ratios correlated with AAO across all PSEN2 variants, strongly driven by the subset of PSEN2 variants with PSEN1 homologs. Aβ production across PSEN1/2 homologs was highly correlated. PSEN2 AAO correlated with AAO in PSEN1 homologs but was an average of 18.3 years later.DISCUSSIONThe existence of a PSEN1 homolog and patterns of Aβ production are important considerations in assessing the pathogenicity of previously reported and new PSEN2 variants.Highlights There were associations between the patterns of amyloid beta (Aβ) production across presenilin 2 (PSEN2) variants and age at symptom onset (AAO). PSEN2 variants for which there is a known, corresponding variant in presenilin 1 (PSEN1) are more likely to have abnormal Aβ production patterns that strongly correlate with AAO, compared to those that lack a known PSEN1 counterpart (“non‐homologous PSEN2 variants”). Most PSEN2 variants lacking PSEN1 counterparts had Aβ42/40 ratios close to those of wild‐type PSN2, arguing against their pathogenicity. Homologous PSEN1 and PSEN2 variants had correlated Aβ42/40 and Aβ37/42 ratios, indicating that the corresponding amino acid substitution in each presenilin may have largely similar biochemical effects on γ‐secretase processivity.

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Rare causes of dystonia-parkinsonism with cognitive impairment, behavioral abnormalities, and voiceless whispering stereotypies: Describing the long-term evolution of the neurological phenotype in a patient with the PSEN2 Ile149Thr variant

Cited by 2 publications

References 10 publications

The pathogenicity ofPSEN2variants is tied to Aβ production and homology toPSEN1

The pathogenicity ofPSEN2variants is tied to Aβ production and homology toPSEN1

The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1

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