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The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia
Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J et al.. Annals of neurology, 2004-02-01
Topic: Brain proteins, microglia and lab models
Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships. We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity. The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to alpha-synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the alpha-synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis. The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls. The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function. Our data show that, in addition to the previously described hereditary alpha-synucleinopathies, dementia with Lewy bodies is related to mutation of alpha-synuclein.
Key findings
- The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to alpha-synuclein and ubiquitin in cortical and subcortical areas.
- Sequencing of the alpha-synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis.
- The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls.
- The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function.
- Our data show that, in addition to the previously described hereditary alpha-synucleinopathies, dementia with Lewy bodies is related to mutation of alpha-synuclein.
Why it matters
In one Spanish family with autosomal dominant parkinsonism, dementia and visual hallucinations, this study found a novel E46K mutation in the alpha-synuclein gene and Lewy bodies in cortical and subcortical areas. It links this mutation to dementia with Lewy bodies, not to treating, curing or preventing Alzheimer's disease.
Study details
- Evidence strengthLow
How this study scored 59/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Annals of neurology) |
| Journal's citation record | 3 / 4 | Annals of Neurology: journal h-index 437 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2004 — older than 20 years, still counted |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (pubmed indexes it as a clinical or observational study) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 7 / 7 | Cited 2,742 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 114.2 citations a year over 24 year(s) since 2004 |
| Impact for its field and year | 6 / 6 | Cited 57.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 28 other studies in this library |
| Still being cited | 4 / 4 | Cited 258 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Justo Garcı́a de Yébenes: h-index 48 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Universidad Autónoma de Madrid: institution h-index 709 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 14755719) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 59 / 100 | — |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Zarranz, J. J., Alegre, J., Gómez-Esteban, J. C., Lezcano, E., Ros, R., Ampuero, I., et al. (2004). The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Annals of neurology. https://doi.org/10.1002/ana.10795
Vancouver
Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, Ampuero I, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Annals of neurology. 2004. doi:10.1002/ana.10795. PMID: 14755719.
BibTeX
@article{zarranz2004-14755719,
author = {Zarranz, J. J. and Alegre, J. and Gómez-Esteban, J. C. and Lezcano, E. and Ros, R. and Ampuero, I. and Vidal, L. and Hoenicka, J. and others},
title = {{The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia}},
journal = {Annals of neurology},
year = {2004},
doi = {10.1002/ana.10795},
pmid = {14755719},
url = {https://doi.org/10.1002/ana.10795}
}
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