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Article ; Online: Attitudes of Patients with Adrenoleukodystrophy towards Sex-Specific Newborn Screening.

Yska, Hemmo A F / Henneman, Lidewij / Barendsen, Rinse W / Engelen, Marc / Kemp, Stephan

International journal of neonatal screening

2023 Volume 9, Issue 3

Abstract: Newborn screening (NBS) for X-linked adrenoleukodystrophy (ALD) can identify affected individuals before the onset of life-threatening manifestations. Some countries have decided to only screen boys (sex-specific screening). This study investigates the ... ...

Abstract	Newborn screening (NBS) for X-linked adrenoleukodystrophy (ALD) can identify affected individuals before the onset of life-threatening manifestations. Some countries have decided to only screen boys (sex-specific screening). This study investigates the attitudes of individuals with ALD towards sex-specific NBS for ALD. A questionnaire was sent to all patients in the Dutch ALD cohort. Invitees were asked who they thought should be screened for ALD: only boys, both boys and girls or neither. The motives and background characteristics of respondents were compared between screening preferences. Out of 108 invitees, 66 participants (61%), 38 men and 28 women, participated in this study. The majority (n = 53, 80%) favored screening both newborn boys and girls for ALD, while 20% preferred boys only. None of the respondents felt that newborns should not be screened for ALD. There were no differences in the background characteristics of the respondents between screening preferences. Our study revealed a diverse range of motivations underlying respondents' screening preferences. This study is one of the first to investigate the attitudes of patients towards sex-specific screening for ALD. The outcomes of this study can offer insights to stakeholders engaged in the implementation of NBS programs. ALD patients are important stakeholders who can provide valuable input in this process.
Language	English
Publishing date	2023-09-02
Publishing country	Switzerland
Document type	Journal Article
ISSN	2409-515X
ISSN (online)	2409-515X
DOI	10.3390/ijns9030051
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Article ; Online: Structure and Function of the

Mallack, Eric J / Gao, Kerry / Engelen, Marc / Kemp, Stephan

Cells

2022 Volume 11, Issue 2

Abstract: The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in ... ...

Abstract	The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in the
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily D, Member 1/chemistry ; ATP Binding Cassette Transporter, Subfamily D, Member 1/genetics ; Adrenoleukodystrophy/diagnosis ; Adrenoleukodystrophy/genetics ; Amino Acid Sequence ; Databases, Genetic ; Humans ; Infant, Newborn ; Mutation/genetics ; Neonatal Screening ; Structure-Activity Relationship
Chemical Substances	ABCD1 protein, human ; ATP Binding Cassette Transporter, Subfamily D, Member 1
Language	English
Publishing date	2022-01-14
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11020283
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Article ; Online: VUS: Variant of uncertain significance or very unclear situation?

Kemp, Stephan / Orsini, Joseph J / Ebberink, Merel S / Engelen, Marc / Lund, Troy C

Molecular genetics and metabolism

2023 Volume 140, Issue 1-2, Page(s) 107678

Abstract: The advancements in population screening, including newborn screening, enables the identification of disease-causing variants and timely initiation of treatment. However, screening may also identify mild variants, non-disease variants, and variants of ... ...

Abstract	The advancements in population screening, including newborn screening, enables the identification of disease-causing variants and timely initiation of treatment. However, screening may also identify mild variants, non-disease variants, and variants of uncertain significance (VUS). The identification of a VUS poses a challenge in terms of diagnostic uncertainty and confusion. X-linked adrenoleukodystrophy (ALD) serves as an illustrative example of this complex issue. ALD is a monogenic neurometabolic disease with a complex clinical presentation and a lack of predictive tests for clinical severity. Despite the success of ALD newborn screening, a significant proportion (62%) of missense variants identified through newborn screening exhibit uncertainty regarding their pathogenicity. Resolving this issue requires ongoing efforts to accurately classify variants and refine screening protocols. While it is undisputable that ALD newborn screening greatly benefits boys with the disease, the identification of VUS underscores the need for continuous research and collaboration in improving screening practices.
MeSH term(s)	Male ; Infant, Newborn ; Humans ; Adrenoleukodystrophy/diagnosis ; Neonatal Screening/methods ; Mutation, Missense
Language	English
Publishing date	2023-08-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1418518-0
ISSN	1096-7206 ; 1096-7192
ISSN (online)	1096-7206
ISSN	1096-7192
DOI	10.1016/j.ymgme.2023.107678
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Article: Endocrine dysfunction in adrenoleukodystrophy.

Engelen, Marc / Kemp, Stephan / Eichler, Florian

Handbook of clinical neurology

2021 Volume 182, Page(s) 257–267

Abstract: X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene and characterized by impaired very long-chain fatty acid beta-oxidation. Clinically, male patients develop adrenal failure and a progressive myelopathy in ...

Abstract	X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene and characterized by impaired very long-chain fatty acid beta-oxidation. Clinically, male patients develop adrenal failure and a progressive myelopathy in adulthood, although age of onset and rate of progression are highly variable. Additionally, 40% of male patients develop a leukodystrophy (cerebral ALD) before the age of 18 years. Women with ALD also develop a myelopathy but generally at a later age than men and with slower progression. Adrenal failure and leukodystrophy are exceedingly rare in women. Allogeneic hematopoietic cell transplantation (HCT), or more recently autologous HCT with ex vivo lentivirally transfected bone marrow, halts the leukodystrophy. Unfortunately, there is no curative treatment for the myelopathy. In the following chapter, the biochemistry, pathology, and clinical spectrum of ALD are discussed in detail.
MeSH term(s)	Adolescent ; Adrenoleukodystrophy/genetics ; Adrenoleukodystrophy/therapy ; Adult ; Fatty Acids ; Female ; Humans ; Male ; Mutation/genetics ; Spinal Cord Diseases
Chemical Substances	Fatty Acids
Language	English
Publishing date	2021-07-15
Publishing country	Netherlands
Document type	Journal Article ; Review
ISSN	0072-9752
ISSN	0072-9752
DOI	10.1016/B978-0-12-819973-2.00018-6
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Article ; Online: Evolution of adrenoleukodystrophy model systems.

Montoro, Roberto / Heine, Vivi M / Kemp, Stephan / Engelen, Marc

Journal of inherited metabolic disease

2021 Volume 44, Issue 3, Page(s) 544–553

Abstract: X-linked adrenoleukodystrophy (ALD) is a neurometabolic disorder affecting the adrenal glands, testes, spinal cord and brain. The disease is caused by mutations in the ABCD1 gene resulting in a defect in peroxisomal degradation of very long-chain fatty ... ...

Abstract	X-linked adrenoleukodystrophy (ALD) is a neurometabolic disorder affecting the adrenal glands, testes, spinal cord and brain. The disease is caused by mutations in the ABCD1 gene resulting in a defect in peroxisomal degradation of very long-chain fatty acids and their accumulation in plasma and tissues. Males with ALD have a near 100% life-time risk to develop myelopathy. The life-time prevalence to develop progressive cerebral white matter lesions (known as cerebral ALD) is about 60%. Adrenal insufficiency occurs in about 80% of male patients. In adulthood, 80% of women with ALD also develop myelopathy, but adrenal insufficiency or cerebral ALD are very rare. The complex clinical presentation and the absence of a genotype-phenotype correlation are complicating our understanding of the disease. In an attempt to understand the pathophysiology of ALD various model systems have been developed. While these model systems share the basic genetics and biochemistry of ALD they fail to fully recapitulate the complex neurodegenerative etiology of ALD. Each model system recapitulates certain aspects of the disorder. This exposes the complexity of ALD and therefore the challenge to create a comprehensive model system to fully understand ALD. In this review, we provide an overview of the different ALD modeling strategies from single-celled to multicellular organisms and from in vitro to in vivo approaches, and introduce how emerging iPSC-derived technologies could improve the understanding of this highly complex disorder.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily D, Member 1/genetics ; Adrenoleukodystrophy/epidemiology ; Adrenoleukodystrophy/genetics ; Adult ; Animals ; Biological Evolution ; Fatty Acids/metabolism ; Female ; Humans ; Male ; Models, Animal ; Models, Biological ; Mutation ; Sex Factors ; Spinal Cord Diseases/epidemiology
Chemical Substances	ABCD1 protein, human ; ATP Binding Cassette Transporter, Subfamily D, Member 1 ; Fatty Acids
Language	English
Publishing date	2021-01-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	438341-2
ISSN	1573-2665 ; 0141-8955
ISSN (online)	1573-2665
ISSN	0141-8955
DOI	10.1002/jimd.12357
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Article ; Online: Molecular Biomarkers for Adrenoleukodystrophy: An Unmet Need.

Honey, Madison I J / Jaspers, Yorrick R J / Engelen, Marc / Kemp, Stephan / Huffnagel, Irene C

Cells

2021 Volume 10, Issue 12

Abstract: X-linked adrenoleukodystrophy (ALD) is an inherited progressive neurometabolic disease caused by mutations in ... ...

Abstract	X-linked adrenoleukodystrophy (ALD) is an inherited progressive neurometabolic disease caused by mutations in the
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily D, Member 1/genetics ; Adrenoleukodystrophy/blood ; Adrenoleukodystrophy/diagnosis ; Adrenoleukodystrophy/genetics ; Adrenoleukodystrophy/pathology ; Biomarkers/blood ; Genetic Diseases, X-Linked/blood ; Genetic Diseases, X-Linked/diagnosis ; Genetic Diseases, X-Linked/genetics ; Genetic Diseases, X-Linked/pathology ; Humans
Chemical Substances	ATP Binding Cassette Transporter, Subfamily D, Member 1 ; Biomarkers
Language	English
Publishing date	2021-12-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10123427
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Article ; Online: Disruption of polyunsaturated fatty acid biosynthesis drives STING-dependent acute myeloid leukemia cell maturation and death.

Kanefsky, Joice / Basse, Mary / Sokei, Judith / di Martino, Orsola / Valin, Liana / Jaspers, Yorrick / Martinez, Esteban / Huhn, Jacklyn / Di Marcantonio, Daniela / Magee, Jeffrey A / Goldman, Aaron R / Tang, Hsin-Yao / Ferraro, Francesca / Kemp, Stephan / Wiest, David L / Sykes, Stephen M

The Journal of biological chemistry

2024 Volume 300, Issue 5, Page(s) 107214

Abstract: The role of polyunsaturated fatty acid (PUFA) biosynthesis in acute myeloid leukemia (AML) remains largely undefined. A comparative expression analysis of 35 genes encoding fatty acid biosynthesis enzymes showed that fatty acid desaturase 1 (FADS1) was ... ...

Abstract	The role of polyunsaturated fatty acid (PUFA) biosynthesis in acute myeloid leukemia (AML) remains largely undefined. A comparative expression analysis of 35 genes encoding fatty acid biosynthesis enzymes showed that fatty acid desaturase 1 (FADS1) was highly expressed across multiple AML subtypes relative to healthy controls and that elevated FADS1 expression correlates with worse overall AML patient survival. Functionally, shRNA-mediated inhibition of FADS1 reduced AML cell growth in vitro and significantly delayed leukemia onset in an AML mouse model. AML cell lines depleted of FADS1 arrested in the G1/S-phase of the cell cycle, acquired characteristics of myeloid maturation and subsequently died. To understand the molecular consequences of FADS1 inhibition, a combination of mass spectrometry-based analysis of complex lipids and gene expression analysis (RNA-seq) was performed. FADS1 inhibition caused AML cells to exhibit significant lipidomic remodeling, including depletion of PUFAs from the phospholipids, phosphatidylserine, and phosphatidylethanolamine. These lipidomic alterations were accompanied by an increase induction of inflammatory and stimulator of interferon genes (STING)-mediated type-1 interferon signaling. Remarkably, genetic deletion of STING largely prevented the AML cell maturation and death phenotypes mediated by FADS1 inhibition. Highlighting the therapeutic implications of these findings, pharmacological blockade of PUFA biosynthesis reduced patient-derived AML cell numbers ex vivo but not that of healthy donor cells. Similarly, STING agonism attenuated patient-derived-AML survival; however, STING activation also reduced healthy granulocyte numbers. Collectively, these data unveil a previously unrecognized importance of PUFA biosynthesis in leukemogenesis and that imbalances in PUFA metabolism can drive STING-mediated AML maturation and death.
Language	English
Publishing date	2024-03-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2024.107214
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Article ; Online: ABCD1 Transporter Deficiency Results in Altered Cholesterol Homeostasis.

Buda, Agnieszka / Forss-Petter, Sonja / Hua, Rong / Jaspers, Yorrick / Lassnig, Mark / Waidhofer-Söllner, Petra / Kemp, Stephan / Kim, Peter / Weinhofer, Isabelle / Berger, Johannes

Biomolecules

2023 Volume 13, Issue 9

Abstract: X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the peroxisomal transporter ABCD1, resulting in the accumulation of very long-chain fatty acids (VLCFA). Strongly affected cell types, such as ... ...

Abstract	X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the peroxisomal transporter ABCD1, resulting in the accumulation of very long-chain fatty acids (VLCFA). Strongly affected cell types, such as oligodendrocytes, adrenocortical cells and macrophages, exhibit high cholesterol turnover. Here, we investigated how ABCD1 deficiency affects cholesterol metabolism in human X-ALD patient-derived fibroblasts and CNS tissues of Abcd1-deficient mice. Lipidome analyses revealed increased levels of cholesterol esters (CE), containing both saturated VLCFA and mono/polyunsaturated (V)LCFA. The elevated CE(26:0) and CE(26:1) levels remained unchanged in LXR agonist-treated Abcd1 KO mice despite reduced total C26:0. Under high-cholesterol loading, gene expression of SOAT1, converting cholesterol to CE and lipid droplet formation were increased in human X-ALD fibroblasts versus healthy control fibroblasts. However, the expression of NCEH1, catalysing CE hydrolysis and the cholesterol transporter ABCA1 and cholesterol efflux were also upregulated. Elevated Soat1 and Abca1 expression and lipid droplet content were confirmed in the spinal cord of X-ALD mice, where expression of the CNS cholesterol transporter Apoe was also elevated. The extent of peroxisome-lipid droplet co-localisation appeared low and was not impaired by ABCD1-deficiency in cholesterol-loaded primary fibroblasts. Finally, addressing steroidogenesis, progesterone-induced cortisol release was amplified in X-ALD fibroblasts. These results link VLCFA to cholesterol homeostasis and justify further consideration of therapeutic approaches towards reducing VLCFA and cholesterol levels in X-ALD.
MeSH term(s)	Humans ; Mice ; Animals ; Adrenoleukodystrophy/genetics ; Adrenoleukodystrophy/metabolism ; ATP Binding Cassette Transporter, Subfamily D, Member 1/genetics ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/metabolism ; Fatty Acids/metabolism ; Homeostasis ; Cholesterol
Chemical Substances	ATP Binding Cassette Transporter, Subfamily D, Member 1 ; ATP-Binding Cassette Transporters ; Fatty Acids ; Cholesterol (97C5T2UQ7J) ; ABCD1 protein, human ; Abcd1 protein, mouse
Language	English
Publishing date	2023-08-31
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom13091333
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Article ; Online: The impact of bed rest on human skeletal muscle metabolism.

Cell reports. Medicine

2024 Volume 5, Issue 1, Page(s) 101372

Abstract: Insulin sensitivity and metabolic flexibility decrease in response to bed rest, but the temporal and causal adaptations in human skeletal muscle metabolism are not fully defined. Here, we use an integrative approach to assess human skeletal muscle ... ...

Abstract	Insulin sensitivity and metabolic flexibility decrease in response to bed rest, but the temporal and causal adaptations in human skeletal muscle metabolism are not fully defined. Here, we use an integrative approach to assess human skeletal muscle metabolism during bed rest and provide a multi-system analysis of how skeletal muscle and the circulatory system adapt to short- and long-term bed rest (German Clinical Trials: DRKS00015677). We uncover that intracellular glycogen accumulation after short-term bed rest accompanies a rapid reduction in systemic insulin sensitivity and less GLUT4 localization at the muscle cell membrane, preventing further intracellular glycogen deposition after long-term bed rest. We provide evidence of a temporal link between the accumulation of intracellular triglycerides, lipotoxic ceramides, and sphingomyelins and an altered skeletal muscle mitochondrial structure and function after long-term bed rest. An intracellular nutrient overload therefore represents a crucial determinant for rapid skeletal muscle insulin insensitivity and mitochondrial alterations after prolonged bed rest.
MeSH term(s)	Humans ; Insulin Resistance/physiology ; Bed Rest/adverse effects ; Muscle, Skeletal/metabolism ; Energy Metabolism/physiology ; Glycogen/metabolism
Chemical Substances	Glycogen (9005-79-2)
Language	English
Publishing date	2024-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2023.101372
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Article ; Online: Method for Measurement of Peroxisomal Very Long-Chain Fatty Acid Beta-Oxidation and De Novo C26:0 Synthesis Activity in Living Cells Using Stable-Isotope Labeled Docosanoic Acid.

van de Beek, Malu-Clair / Dijkstra, Inge M E / Kemp, Stephan

Methods in molecular biology (Clifton, N.J.)

2017 Volume 1595, Page(s) 45–54

Abstract: Peroxisomes are present in virtually every eukaryotic cell type with the exception of the mature erythrocyte. In higher eukaryotes, one of the main functions of peroxisomes is lipid metabolism by means of beta-oxidation of very long-chain fatty acids ( ... ...

Abstract	Peroxisomes are present in virtually every eukaryotic cell type with the exception of the mature erythrocyte. In higher eukaryotes, one of the main functions of peroxisomes is lipid metabolism by means of beta-oxidation of very long-chain fatty acids (VLCFA; ≥22 carbon atoms). A dysfunction in peroxisomal VLCFA beta-oxidation results in elevated VLCFA levels in cells, tissue, and plasma. Here, we describe a straightforward and sensitive method to measure peroxisomal beta-oxidation capacity in living cells using stable-isotope labeled docosanoic acid (D
MeSH term(s)	Cell Culture Techniques ; Cells, Cultured ; Fatty Acids/metabolism ; Fibroblasts/metabolism ; Humans ; Isotopes ; Lipid Metabolism ; Oxidation-Reduction ; Peroxisomes/metabolism
Chemical Substances	Fatty Acids ; Isotopes ; behenic acid (H390488X0A)
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-6937-1_5
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