Jørgen Frøkiær

A novel neurodegenerative spectrum disorder in patients with MLKL deficiency

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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A novel neurodegenerative spectrum disorder in patients with MLKL deficiency. / Faergeman, Soren L.; Evans, Hayley; Attfield, Kathrine E.; Desel, Christiane; Kuttikkatte, Subita Balaram; Sommerlund, Mette; Jensen, Lise Torp; Frokiaer, Jorgen; Friese, Manuel A.; Matthews, Paul M.; Luchtenborg, Christian; Brügger, Britta; Oturai, Annette Bang; Dendrou, Calliope A.; Fugger, Lars.

In: Cell Death and Disease, Vol. 11, 303, 05.2020.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Faergeman, SL, Evans, H, Attfield, KE, Desel, C, Kuttikkatte, SB, Sommerlund, M, Jensen, LT, Frokiaer, J, Friese, MA, Matthews, PM, Luchtenborg, C, Brügger, B, Oturai, AB, Dendrou, CA & Fugger, L 2020, 'A novel neurodegenerative spectrum disorder in patients with MLKL deficiency', Cell Death and Disease, vol. 11, 303. https://doi.org/10.1038/s41419-020-2494-0

APA

Faergeman, S. L., Evans, H., Attfield, K. E., Desel, C., Kuttikkatte, S. B., Sommerlund, M., Jensen, L. T., Frokiaer, J., Friese, M. A., Matthews, P. M., Luchtenborg, C., Brügger, B., Oturai, A. B., Dendrou, C. A., & Fugger, L. (2020). A novel neurodegenerative spectrum disorder in patients with MLKL deficiency. Cell Death and Disease, 11, [303]. https://doi.org/10.1038/s41419-020-2494-0

CBE

Faergeman SL, Evans H, Attfield KE, Desel C, Kuttikkatte SB, Sommerlund M, Jensen LT, Frokiaer J, Friese MA, Matthews PM, Luchtenborg C, Brügger B, Oturai AB, Dendrou CA, Fugger L. 2020. A novel neurodegenerative spectrum disorder in patients with MLKL deficiency. Cell Death and Disease. 11:Article 303. https://doi.org/10.1038/s41419-020-2494-0

MLA

Vancouver

Faergeman SL, Evans H, Attfield KE, Desel C, Kuttikkatte SB, Sommerlund M et al. A novel neurodegenerative spectrum disorder in patients with MLKL deficiency. Cell Death and Disease. 2020 May;11. 303. https://doi.org/10.1038/s41419-020-2494-0

Author

Faergeman, Soren L. ; Evans, Hayley ; Attfield, Kathrine E. ; Desel, Christiane ; Kuttikkatte, Subita Balaram ; Sommerlund, Mette ; Jensen, Lise Torp ; Frokiaer, Jorgen ; Friese, Manuel A. ; Matthews, Paul M. ; Luchtenborg, Christian ; Brügger, Britta ; Oturai, Annette Bang ; Dendrou, Calliope A. ; Fugger, Lars. / A novel neurodegenerative spectrum disorder in patients with MLKL deficiency. In: Cell Death and Disease. 2020 ; Vol. 11.

Bibtex

@article{d1ea5d799f9d4ef7808d3b63310be6e8,
title = "A novel neurodegenerative spectrum disorder in patients with MLKL deficiency",
abstract = "Mixed lineage kinase domain-like (MLKL) is the main executor of necroptosis, an inflammatory form of programmed cell death. Necroptosis is implicated in combating infections, but also in contributing to numerous other clinical conditions, including cardiovascular diseases and neurodegenerative disorders. Inhibition of necroptosis is therefore of therapeutic interest. Here we report two siblings both of whom over the course of 35 years developed a similar progressive, neurodegenerative spectrum disorder characterized by paresis, ataxia and dysarthria. Magnetic resonance imaging of their central nervous system (CNS) revealed severe global cerebral volume loss and atrophy of the cerebellum and brainstem. These brothers are homozygous for a rare haplotype identified by whole genome sequencing carrying a frameshift variant in MLKL, as well as an in-frame deletion of one amino acid in the adjacent fatty acid 2-hydroxylase (FA2H) gene. Functional studies of patient-derived primary cells demonstrated that the variant in MLKL leads to a deficiency of MLKL protein resulting in impairment of necroptosis. Conversely, shotgun lipidomic analysis of the variant in FA2H shows no impact on either the abundance or the enzymatic activity of the encoded hydroxylase. To our knowledge, this is the first report of complete necroptosis deficiency in humans. The findings may suggest that impaired necroptosis is a novel mechanism of neurodegeneration, promoting a disorder that shares some clinical features with primary progressive multiple sclerosis (PPMS) and other neurodegenerative diseases. Importantly, the necroptotic deficiency does not cause symptoms outside the nervous system, nor does it confer susceptibility to infections. Given the current interest in pharmacological inhibition of necroptosis by targeting MLKL and its associated pathways, this strategy should be developed with caution, with careful consideration of the possible development of adverse neurological effects.",
author = "Faergeman, {Soren L.} and Hayley Evans and Attfield, {Kathrine E.} and Christiane Desel and Kuttikkatte, {Subita Balaram} and Mette Sommerlund and Jensen, {Lise Torp} and Jorgen Frokiaer and Friese, {Manuel A.} and Matthews, {Paul M.} and Christian Luchtenborg and Britta Br{\"u}gger and Oturai, {Annette Bang} and Dendrou, {Calliope A.} and Lars Fugger",
year = "2020",
month = may,
doi = "10.1038/s41419-020-2494-0",
language = "English",
volume = "11",
journal = "Cell Death & Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - A novel neurodegenerative spectrum disorder in patients with MLKL deficiency

AU - Faergeman, Soren L.

AU - Evans, Hayley

AU - Attfield, Kathrine E.

AU - Desel, Christiane

AU - Kuttikkatte, Subita Balaram

AU - Sommerlund, Mette

AU - Jensen, Lise Torp

AU - Frokiaer, Jorgen

AU - Friese, Manuel A.

AU - Matthews, Paul M.

AU - Luchtenborg, Christian

AU - Brügger, Britta

AU - Oturai, Annette Bang

AU - Dendrou, Calliope A.

AU - Fugger, Lars

PY - 2020/5

Y1 - 2020/5

N2 - Mixed lineage kinase domain-like (MLKL) is the main executor of necroptosis, an inflammatory form of programmed cell death. Necroptosis is implicated in combating infections, but also in contributing to numerous other clinical conditions, including cardiovascular diseases and neurodegenerative disorders. Inhibition of necroptosis is therefore of therapeutic interest. Here we report two siblings both of whom over the course of 35 years developed a similar progressive, neurodegenerative spectrum disorder characterized by paresis, ataxia and dysarthria. Magnetic resonance imaging of their central nervous system (CNS) revealed severe global cerebral volume loss and atrophy of the cerebellum and brainstem. These brothers are homozygous for a rare haplotype identified by whole genome sequencing carrying a frameshift variant in MLKL, as well as an in-frame deletion of one amino acid in the adjacent fatty acid 2-hydroxylase (FA2H) gene. Functional studies of patient-derived primary cells demonstrated that the variant in MLKL leads to a deficiency of MLKL protein resulting in impairment of necroptosis. Conversely, shotgun lipidomic analysis of the variant in FA2H shows no impact on either the abundance or the enzymatic activity of the encoded hydroxylase. To our knowledge, this is the first report of complete necroptosis deficiency in humans. The findings may suggest that impaired necroptosis is a novel mechanism of neurodegeneration, promoting a disorder that shares some clinical features with primary progressive multiple sclerosis (PPMS) and other neurodegenerative diseases. Importantly, the necroptotic deficiency does not cause symptoms outside the nervous system, nor does it confer susceptibility to infections. Given the current interest in pharmacological inhibition of necroptosis by targeting MLKL and its associated pathways, this strategy should be developed with caution, with careful consideration of the possible development of adverse neurological effects.

AB - Mixed lineage kinase domain-like (MLKL) is the main executor of necroptosis, an inflammatory form of programmed cell death. Necroptosis is implicated in combating infections, but also in contributing to numerous other clinical conditions, including cardiovascular diseases and neurodegenerative disorders. Inhibition of necroptosis is therefore of therapeutic interest. Here we report two siblings both of whom over the course of 35 years developed a similar progressive, neurodegenerative spectrum disorder characterized by paresis, ataxia and dysarthria. Magnetic resonance imaging of their central nervous system (CNS) revealed severe global cerebral volume loss and atrophy of the cerebellum and brainstem. These brothers are homozygous for a rare haplotype identified by whole genome sequencing carrying a frameshift variant in MLKL, as well as an in-frame deletion of one amino acid in the adjacent fatty acid 2-hydroxylase (FA2H) gene. Functional studies of patient-derived primary cells demonstrated that the variant in MLKL leads to a deficiency of MLKL protein resulting in impairment of necroptosis. Conversely, shotgun lipidomic analysis of the variant in FA2H shows no impact on either the abundance or the enzymatic activity of the encoded hydroxylase. To our knowledge, this is the first report of complete necroptosis deficiency in humans. The findings may suggest that impaired necroptosis is a novel mechanism of neurodegeneration, promoting a disorder that shares some clinical features with primary progressive multiple sclerosis (PPMS) and other neurodegenerative diseases. Importantly, the necroptotic deficiency does not cause symptoms outside the nervous system, nor does it confer susceptibility to infections. Given the current interest in pharmacological inhibition of necroptosis by targeting MLKL and its associated pathways, this strategy should be developed with caution, with careful consideration of the possible development of adverse neurological effects.

UR - http://www.scopus.com/inward/record.url?scp=85084146817&partnerID=8YFLogxK

U2 - 10.1038/s41419-020-2494-0

DO - 10.1038/s41419-020-2494-0

M3 - Journal article

C2 - 32358523

AN - SCOPUS:85084146817

VL - 11

JO - Cell Death & Disease

JF - Cell Death & Disease

SN - 2041-4889

M1 - 303

ER -