Defining diagnostic cutoffs in neurological patients for serum very long chain fatty acids (VLCFA) in genetically confirmed X-Adrenoleukodystrophy

Rattay, Tim W.; Rautenberg, Maren; Sohn, A.; Hengel, Holger; Traschütz, Andreas; Röben, Benjamin; Hayer, Stefanie N.; Schüle, Rebecca; Wiethoff, Sarah; Zeltner, Lena; Haack, Tobias B.; Cegan, Alexander; Schöls, Lüdger; Schleicher, Erwin

doi:10.1038/s41598-020-71248-8

Cited by 15 publications

(18 citation statements)

References 27 publications

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“…Since the cloning of the ABCD1 gene in 1993 and its association with X-ALD [ 30 ], ABCD1 function has been attributed to the transport of saturated and monounsaturated VLCFAs across the peroxisomal membrane for further degradation by β-oxidation. Accumulation of saturated and monounsaturated VLCFAs indeed occurs in the plasma and tissues of X-ALD patients, and is used for diagnosis [ 31 , 32 ]. Due to its importance, studies concerning the structure, function, and defects of ABCD1 have never ceased.…”

Section: Structure Function and Mechanism Of Transportmentioning

confidence: 99%

Peroxisomal ABC Transporters: An Update

Tawbeh

Gondcaille

Trompier

et al. 2021

IJMS

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ATP-binding cassette (ABC) transporters constitute one of the largest superfamilies of conserved proteins from bacteria to mammals. In humans, three members of this family are expressed in the peroxisomal membrane and belong to the subfamily D: ABCD1 (ALDP), ABCD2 (ALDRP), and ABCD3 (PMP70). These half-transporters must dimerize to form a functional transporter, but they are thought to exist primarily as tetramers. They possess overlapping but specific substrate specificity, allowing the transport of various lipids into the peroxisomal matrix. The defects of ABCD1 and ABCD3 are responsible for two genetic disorders called X-linked adrenoleukodystrophy and congenital bile acid synthesis defect 5, respectively. In addition to their role in peroxisome metabolism, it has recently been proposed that peroxisomal ABC transporters participate in cell signaling and cell control, particularly in cancer. This review presents an overview of the knowledge on the structure, function, and mechanisms involving these proteins and their link to pathologies. We summarize the different in vitro and in vivo models existing across the species to study peroxisomal ABC transporters and the consequences of their defects. Finally, an overview of the known and possible interactome involving these proteins, which reveal putative and unexpected new functions, is shown and discussed.

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Section: Structure Function and Mechanism Of Transportmentioning

confidence: 99%

Peroxisomal ABC Transporters: An Update

Tawbeh

Gondcaille

Trompier

et al. 2021

IJMS

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“…In particular, the recent availability of next generation sequencing has deeply revolutioned the scenario of INMD, compared to only a few years ago, when the diagnostic algorithms were based on the sequencing gene by gene (e.g., Sanger), based on clinical, neurophysiology, biochemical and morphological evaluations [ 1 ]. In this scenario, serum biomarkers retain an important role in both the diagnosis and follow-up of INMD [ 7 , 8 , 9 , 10 ]. Many lab abnormalities commonly evaluated in routine blood examinations have been reported “typical” of certain INMD [ 8 , 11 , 12 ], but their role is sometimes underestimated in current clinical practice [ 13 ].…”

Section: Background and Aimsmentioning

confidence: 99%

“…An alternative and more accurate biomarker to detect the elevated serum VLCFA is the use of 1-hexacosanosyl-2-lyso-sn-3-glycero-phosphatidylcholine (26:0-lyso-PC) in DBS and it could be useful for newborn screening and diagnosis in women [ 153 ]. A recent study suggests new optimized cutoff values for both ratios C24:0/C22:0 and C26:0/C22:0, in combination with standard lipid profile considered that low-density lipid concentrations strongly correlate to all VLCFA [ 9 ].…”

Section: Axonal Neuropathiesmentioning

confidence: 99%

“…An alternative and more accurate biomarker to detect the elevated serum VLCFA is the use of 1-hexacosanosyl-2lyso-sn-3-glycero-phosphatidylcholine (26:0-lyso-PC) in DBS and it could be useful for newborn screening and diagnosis in women [153]. A recent study suggests new optimized cutoff values for both ratios C24:0/C22:0 and C26:0/C22:0, in combination with standard lipid profile considered that low-density lipid concentrations strongly correlate to all VLCFA [9]. Fabry disease (FD) is an X-linked inborn error of glycosphingolipid catabolism due to deficiency of α-galactosidase A (α-Gal A) leading accumulation of globotriaosylceramide in body fluids and lysosomes of vascular endothelium [154].…”

Section: Multisystemic Diseasesmentioning

confidence: 99%

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Inherited Neuromuscular Disorders: Which Role for Serum Biomarkers?

et al. 2021

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Inherited neuromuscular disorders (INMD) are a heterogeneous group of rare diseases that involve muscles, motor neurons, peripheral nerves or the neuromuscular junction. Several different lab abnormalities have been linked to INMD: sometimes they are typical of the disorder, but they usually appear to be less specific. Sometimes serum biomarkers can point out abnormalities in presymtomatic or otherwise asymptomatic patients (e.g., carriers). More often a biomarker of INMD is evaluated by multiple clinicians other than expert in NMD before the diagnosis, because of the multisystemic involvement in INMD. The authors performed a literature search on biomarkers in inherited neuromuscular disorders to provide a practical approach to the diagnosis and the correct management of INMD. A considerable number of biomarkers have been reported that support the diagnosis of INMD, but the role of an expert clinician is crucial. Hence, the complete knowledge of such abnormalities can accelerate the diagnostic workup supporting the referral to specialists in neuromuscular disorders.

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“…X-linked ALD results in aberrant accumulation of VLCFA in the cytosol due to impaired peroxisomal β-oxidation. X-linked ALD leads to progressive demyelination (Berger et al, 2014; van Geel et al, 2001; Rattay et al, 2020; Wiesinger et al, 2013). Loss of myelin reduces the ability of the nerves to transfer information and triggers neuroinflammation.…”

Section: Structural Elucidation Of the Human Aldp In Nucleotides Free Statementioning

confidence: 99%

Structure insights of the human peroxisomal ABC transporter ALDP

Jia

Zhang

Lei

et al. 2021

Preprint

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Adrenoleukodystrophy protein (ALDP) is responsible for the transport of free very-long-chain fatty acids (VLCFAs) and corresponding CoA-esters across the peroxisomal membrane. ALDP belongs to the ATP-binding cassette sub-family D, which is also named as ABCD1. Dysfunction of ALDP leads to peroxisomal metabolic disorder exemplified by X-linked adrenoleukodystrophy (ALD). Hundreds of ALD-causing mutations are identified on ALDP. However, the pathogenic mechanisms of these mutations are restricted to clinical description due to limited structural information. Furthermore, ALDP plays a role in myelin maintenance, which is tightly associated with axon regeneration. Here we report the cryo-electron microscopy (cryo-EM) structure of human ALDP with nominal resolution of 3.4 angstrom in nucleotide free state. The structure of ALDP exhibits a typical assembly of ABC transporters. The nucleotide binding domains (NBDs) displays a ligand free state. ALDP exhibits an inward-open conformation to the cytosol. A short helix is located at the peroxisomal side, which is different from other three members of ABCD transporters. The two transmembrane domains (TMDs) of ALDP form a cavity, in which two lipid-like densities can be recognized as the head group of an coenzyme-A ester of a lipid. This structure provides a framework for understanding the working mechanism of ALDP and classification of the disease-causing mutations.

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Defining diagnostic cutoffs in neurological patients for serum very long chain fatty acids (VLCFA) in genetically confirmed X-Adrenoleukodystrophy

Cited by 15 publications

References 27 publications

Peroxisomal ABC Transporters: An Update

Peroxisomal ABC Transporters: An Update

Inherited Neuromuscular Disorders: Which Role for Serum Biomarkers?

Structure insights of the human peroxisomal ABC transporter ALDP

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