INDEX

Publications Team ALD

Sex-specific newborn screening for X-Linked adrenoleukodystrophy.
Albersen M, van der Beek SL, Dijkstra IME, Alders M, Barendsen RW, Bliek J, Boelen A, Ebberink MS, Ferdinandusse S, Goorden SMI, Heijboer AC, Jansen M, Jaspers YRJ, Metgod I, Salomons GS, Vaz FM, Verschoof-Puite RK, Visser WF, Dekkers E, Engelen M, Kemp S.
J Inherit Metab Dis. 2022 Oct 18. doi: 10.1002/jimd.12571. Online ahead of print. PMID: 36256460

International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach.
Engelen M, van Ballegoij WJC, Mallack EJ, Van Haren KP, Köhler W, Salsano E, van Trotsenburg ASP, Mochel F, Sevin C, Regelman MO, Tritos NA, Halper A, Lachmann RH, Davison J, Raymond GV, Lund T, Orchard PJ, Kuehl JS, Lindemans CA, Caruso P, Turk BR, Moser AB, Vaz FM, Ferdinandusse S, Kemp S, Fatemi A, Eichler FS, Huffnagel IC.
Neurology. 2022 Sep 29:10.1212/WNL.0000000000201374. doi: 10.1212/WNL.0000000000201374. Online ahead of print. PMID: 36175155

Treatment of cerebral adrenoleukodystrophy: allogeneic transplantation and lentiviral gene therapy.
Gupta AO, Raymond G, Pierpont EI, Kemp S, McIvor RS, Rayannavar A, Miller B, Lund TC, Orchard PJ.
Expert Opin Biol Ther. 2022 Sep;22(9):1151-1162. PMID: 36107226

Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response.
Weinhofer I, Buda A, Kunze M, Palfi Z, Traunfellner M, Hesse S, Villoria-Gonzalez A, Hofmann J, Hametner S, Regelsberger G, Moser AB, Eichler F, Kemp S, Bauer J, Kühl JS, Forss-Petter S, Berger J.
Commun Biol. 2022 Sep 9;5(1):944. PMID: 36085307

Peroxisome Metabolism Contributes to PIEZO2-Mediated Mechanical Allodynia.
Gong Y, Laheji F, Berenson A, Qian A, Park SO, Kok R, Selig M, Hahn R, Sadjadi R, Kemp S, Eichler F.
Cells. 2022 Jun 4;11(11):1842. PMID: 35681537

Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy.
Mallack EJ, Gao K, Engelen M, Kemp S.
Cells. 2022 Jan 14;11(2):283. PMID: 35053399

Biochemical Studies in Fibroblasts to Interpret Variants of Unknown Significance in the ABCD1 Gene.
van de Stadt SIW, Mooyer PAW, Dijkstra IME, Dekker CJM, Vats D, Vera M, Ruzhnikov MRZ, van Haren K, Tang N, Koop K, Willemsen MA, Hui J, Vaz FM, Ebberink MS, Engelen M, Kemp S, Ferdinandusse S.
Genes (Basel). 2021 Nov 30;12(12):1930. PMID: 34946879

Molecular Biomarkers for Adrenoleukodystrophy: An Unmet Need.
Honey MIJ, Jaspers YRJ, Engelen M, Kemp S, Huffnagel IC.
Cells. 2021 Dec 6;10(12):3427. PMID: 34943935

iBRET Screen of the ABCD1 Peroxisomal Network and Mutation-Induced Network Perturbations.
Lotz-Havla AS, Woidy M, Guder P, Friedel CC, Klingbeil JM, Bulau AM, Schultze A, Dahmen I, Noll-Puchta H, Kemp S, Erdmann R, Zimmer R, Muntau AC, Gersting SW.
J Proteome Res. 2021 Sep 3;20(9):4366-4380. PMID: 34383492

Endocrine dysfunction in adrenoleukodystrophy.
Engelen M, Kemp S, Eichler F.
Handb Clin Neurol. 2021;182:257-267. PMID: 34266597

The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy.
Rodríguez-Pascau L, Vilalta A, Cerrada M, Traver E, Forss-Petter S, Weinhofer I, Bauer J, Kemp S, Pina G, Pascual S, Meya U, Musolino PL, Berger J, Martinell M, Pizcueta P.
Sci Transl Med. 2021 Jun 2;13(596):eabc0555. PMID: 34078742

Metabolic rerouting via SCD1 induction impacts X-linked adrenoleukodystrophy.
Raas Q, van de Beek MC, Forss-Petter S, Dijkstra IM, Deschiffart A, Freshner BC, Stevenson TJ, Jaspers YR, Nagtzaam L, Wanders RJ, van Weeghel M, Engelen-Lee JY, Engelen M, Eichler F, Berger J, Bonkowsky JL, Kemp S.
J Clin Invest. 2021 Apr 15;131(8):e142500. PMID: 33690217

MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines.
Mallack EJ, Turk BR, Yan H, Price C, Demetres M, Moser AB, Becker C, Hollandsworth K, Adang L, Vanderver A, Van Haren K, Ruzhnikov M, Kurtzberg J, Maegawa G, Orchard PJ, Lund TC, Raymond GV, Regelmann M, Orsini JJ, Seeger E, Kemp S, Eichler F, Fatemi A.
J Inherit Metab Dis. 2021 May;44(3):728-739. PMID: 33373467

Evolution of adrenoleukodystrophy model systems.
Montoro R, Heine VM, Kemp S, Engelen M.
J Inherit Metab Dis. 2021 May;44(3):544-553. PMID: 33373044

The variability conundrum in neurometabolic degenerative diseases.
van Karnebeek CDM, Richmond PA, van der Kloet F, Wasserman WW, Engelen M, Kemp S.
Mol Genet Metab. 2020 Dec;131(4):367-369. PMID: 33246824

Plasma NfL and GFAP as biomarkers of spinal cord degeneration in adrenoleukodystrophy.
van Ballegoij WJC, van de Stadt SIW, Huffnagel IC, Kemp S, Willemse EAJ, Teunissen CE, Engelen M.
Ann Clin Transl Neurol. 2020 Nov;7(11):2127-2136. PMID: 33047897

Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS-275.
Zierfuss B, Weinhofer I, Buda A, Popitsch N, Hess L, Moos V, Hametner S, Kemp S, Köhler W, Forss-Petter S, Seiser C, Berger J.
Ann Clin Transl Neurol. 2020 Nov;7(11):2161-2177. PMID: 32997393

Comparison of the Diagnostic Performance of C26:0-Lysophosphatidylcholine and Very Long-Chain Fatty Acids Analysis for Peroxisomal Disorders.
Jaspers YRJ, Ferdinandusse S, Dijkstra IME, Barendsen RW, van Lenthe H, Kulik W, Engelen M, Goorden SMI, Vaz FM, Kemp S.
Front Cell Dev Biol. 2020 Jul 29;8:690. doi: 10.3389/fcell.2020.00690. PMID: 32903870

Postural Body Sway as Surrogate Outcome for Myelopathy in Adrenoleukodystrophy.
van Ballegoij WJC, van de Stadt SIW, Huffnagel IC, Kemp S, van der Knaap MS, Engelen M.
Front Physiol. 2020 Jul 17;11:786. PMID: 32765293

Multi-Omic Approach to Identify Phenotypic Modifiers Underlying Cerebral Demyelination in X-Linked Adrenoleukodystrophy.
Richmond PA, van der Kloet F, Vaz FM, Lin D, Uzozie A, Graham E, Kobor M, Mostafavi S, Moerland PD, Lange PF, van Kampen AHC, Wasserman WW, Engelen M, Kemp S, van Karnebeek CDM.
Front Cell Dev Biol. 2020 Jun 25;8:520. PMID: 32671069

Adrenoleukodystrophy Newborn Screening in the Netherlands (SCAN Study): The X-Factor.
Barendsen RW, Dijkstra IME, Visser WF, Alders M, Bliek J, Boelen A, Bouva MJ, van der Crabben SN, Elsinghorst E, van Gorp AGM, Heijboer AC, Jansen M, Jaspers YRJ, van Lenthe H, Metgod I, Mooij CF, van der Sluijs EHC, van Trotsenburg ASP, Verschoof-Puite RK, Vaz FM, Waterham HR, Wijburg FA, Engelen M, Dekkers E, Kemp S.
Front Cell Dev Biol. 2020 Jun 17;8:499. PMID: 32626714

Spinal cord atrophy as a measure of severity of myelopathy in adrenoleukodystrophy.
van de Stadt SIW, van Ballegoij WJC, Labounek R, Huffnagel IC, Kemp S, Nestrasil I, Engelen M.
J Inherit Metab Dis. 2020 Jul;43(4):852-860. PMID: 32077106

Longitudinal diffusion MRI as surrogate outcome measure for myelopathy in adrenoleukodystrophy.
Huffnagel IC, van Ballegoij WJC, Vos JMBW, Kemp S, Caan MWA, Engelen M.
Neurology. 2019 Dec 3;93(23):e2133-e2143. PMID: 31719133

Disease progression in women with X-linked adrenoleukodystrophy is slow.
Huffnagel IC, Dijkgraaf MGW, Janssens GE, van Weeghel M, van Geel BM, Poll-The BT, Kemp S, Engelen M.
Orphanet J Rare Dis. 2019 Feb 7;14(1):30. PMID: 30732635

Progression of myelopathy in males with adrenoleukodystrophy: towards clinical trial readiness.
Huffnagel IC, van Ballegoij WJC, van Geel BM, Vos JMBW, Kemp S, Engelen M.
Brain. 2019 Feb 1;142(2):334-343. PMID: 30535170

The Natural History of Adrenal Insufficiency in X-Linked Adrenoleukodystrophy: An International Collaboration.
Huffnagel IC, Laheji FK, Aziz-Bose R, Tritos NA, Marino R, Linthorst GE, Kemp S, Engelen M, Eichler F.
J Clin Endocrinol Metab. 2019 Jan 1;104(1):118-126. PMID: 30252065

Comparison of C26:0-carnitine and C26:0-lysophosphatidylcholine as diagnostic markers in dried blood spots from newborns and patients with adrenoleukodystrophy.
Huffnagel IC, van de Beek MC, Showers AL, Orsini JJ, Klouwer FCC, Dijkstra IME, Schielen PC, van Lenthe H, Wanders RJA, Vaz FM, Morrissey MA, Engelen M, Kemp S.
Mol Genet Metab. 2017 Dec;122(4):209-215. PMID: 29089175

Lipid-induced endoplasmic reticulum stress in X-linked adrenoleukodystrophy.
van de Beek MC, Ofman R, Dijkstra I, Wijburg F, Engelen M, Wanders R, Kemp S.
Biochim Biophys Acta Mol Basis Dis. 2017 Sep;1863(9):2255-2265. PMID: 28666219

Adrenoleukodystrophy – neuroendocrine pathogenesis and redefinition of natural history.
Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M.
Nat Rev Endocrinol. 2016 Oct;12(10):606-15. PMID: 27312864

26:0-Carnitine Is a New Biomarker for X-Linked Adrenoleukodystrophy in Mice and Man.
van de Beek MC, Dijkstra IM, van Lenthe H, Ofman R, Goldhaber-Pasillas D, Schauer N, Schackmann M, Engelen-Lee JY, Vaz FM, Kulik W, Wanders RJ, Engelen M, Kemp S.
PLoS One. 2016 Apr 28;11(4):e0154597. PMID: 27124591

Pathogenicity of novel ABCD1 variants: The need for biochemical testing in the era of advanced genetics.
Schackmann MJ, Ofman R, van Geel BM, Dijkstra IM, van Engelen K, Wanders RJ, Engelen M, Kemp S.
Mol Genet Metab. 2016 Jun;118(2):123-7. PMID: 27067449

Hematopoietic cell transplantation does not prevent myelopathy in X-linked adrenoleukodystrophy: a retrospective study.
van Geel BM, Poll-The BT, Verrips A, Boelens JJ, Kemp S, Engelen M.
J Inherit Metab Dis. 2015 Mar;38(2):359-61. PMID: 25488625

X-linked adrenoleukodystrophy: pathogenesis and treatment.
Engelen M, Kemp S, Poll-The BT.
Curr Neurol Neurosci Rep. 2014 Oct;14(10):486. PMID: 25115486

Reply: Age-dependent penetrance among females with X-linked adrenoleukodystrophy.
Engelen M, Barbier M, Dijkstra IM, Schür R, de Bie RM, Verhamme C, Dijkgraaf MG, Aubourg PA, Wanders RJ, van Geel BM, de Visser M, Poll-The BT, Kemp S.
Brain. 2015 Feb;138(Pt 2):e326. PMID: 25149411

X-linked adrenoleukodystrophy in women: a cross-sectional cohort study.
Engelen M, Barbier M, Dijkstra IM, Schür R, de Bie RM, Verhamme C, Dijkgraaf MG, Aubourg PA, Wanders RJ, van Geel BM, de Visser M, Poll-The BT, Kemp S.
Brain. 2014 Mar;137(Pt 3):693-706. PMID: 24480483

Comment on the paper “Effect of statin treatment on adrenomyeloneuropathy with cerebral inflammation: a revisit”.
Engelen M, Ofman R, Dijkgraaf M, van Geel B, de Visser M, Wanders R, Poll-The BT, Kemp S.
Clin Neurol Neurosurg. 2013 Nov;115(11):2401-2. PMID: 24018110

X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management.
Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, Aubourg P, Poll-The BT.
Orphanet J Rare Dis. 2012 Aug 13;7:51. PMID: 22889154

Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation.
Engelen M, Schackmann MJ, Ofman R, Sanders RJ, Dijkstra IM, Houten SM, Fourcade S, Pujol A, Poll-The BT, Wanders RJ, Kemp S.
J Inherit Metab Dis. 2012 Nov;35(6):1137-45. PMID: 22447153

Bezafibrate for X-linked adrenoleukodystrophy.
Engelen M, Tran L, Ofman R, Brennecke J, Moser AB, Dijkstra IM, Wanders RJ, Poll-The BT, Kemp S.
PLoS One. 2012;7(7):e41013. PMID: 22911730

X-linked adrenomyeloneuropathy due to a novel missense mutation in the ABCD1 start codon presenting as demyelinating neuropathy.
Engelen M, van der Kooi AJ, Kemp S, Wanders RJ, Sistermans EA, Waterham HR, Koelman JT, van Geel BM, de Visser M.
J Peripher Nerv Syst. 2011 Dec;16(4):353-5. PMID: 22176151

Lovastatin in X-linked adrenoleukodystrophy.
Engelen M, Ofman R, Dijkgraaf MG, Hijzen M, van der Wardt LA, van Geel BM, de Visser M, Wanders RJ, Poll-The BT, Kemp S.
N Engl J Med. 2010 Jan 21;362(3):276-7. PMID: 20089986

Cholesterol-deprivation increases mono-unsaturated very long-chain fatty acids in skin fibroblasts from patients with X-linked adrenoleukodystrophy.
Engelen M, Ofman R, Mooijer PA, Poll-The BT, Wanders RJ, Kemp S.
Biochim Biophys Acta. 2008 Mar;1781(3):105-11. PMID: 18206987

Characterization of the human omega-oxidation pathway for omega-hydroxy-very-long-chain fatty acids.
Sanders RJ, Ofman R, Dacremont G, Wanders RJ, Kemp S.
FASEB J. 2008 Jun;22(6):2064-71. PMID: 18182499

X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism, ABC half-transporters and the complicated route to treatment.
Kemp S, Wanders RJ.
Mol Genet Metab. 2007 Mar;90(3):268-76. doi: 10.1016/j.ymgme.2006.10.001. Epub 2006 Nov 7.
PMID: 17092750

Omega-oxidation of very long-chain fatty acids in human liver microsomes. Implications for X-linked adrenoleukodystrophy.
Sanders RJ, Ofman R, Duran M, Kemp S, Wanders RJA.
J Biol Chem. 2006 May 12;281(19):13180-13187. doi: 10.1074/jbc.M513481200. Epub 2006 Mar 17.
PMID: 16547005

Gene redundancy and pharmacological gene therapy: implications for X-linked adrenoleukodystrophy.
Kemp S, Wei HM, Lu JF, Braiterman LT, McGuinness MC, Moser AB, Watkins PA, Smith KD.
Nat Med. 1998 Nov;4(11):1261-8. doi: 10.1038/3242.
PMID: 9809549

Editorial board of ALD info

Marc EngelenMarc Engelen received his MD from the University of Amsterdam, the Netherlands in 2002. He was trained as a neurologist and subsequently subspecialized in pediatric neurology at the Amsterdam University Medical Centers. In 2012, Dr. Engelen obtained a PhD on “Translational studies in Adrenoleukodystrophy”. He is currently a member of the medical staff of the Department of Neurology and the Department of Pediatrics at Amsterdam UMC. Marc has a special interest in peroxisomal disorders. In 2015, the Amsterdam UMC was designated the national expert center for this group of diseases. His research focuses on adrenoleukodystrophy and in 2019 he received a Vidi grant from NWO (Netherlands Organization for Scientific Research) to study the natural history of adrenoleukodystrophy and identify predictive biomarkers for the onset of cerebral adrenoleukodystrophy.

Rachel Salzman serves as Chief Scientific Officer of The Stop ALD Foundation (SALD), and has held this position since 2001. SALD is a non-profit Medical Research Organization dedicated to employing entrepreneurial approaches and innovative methodology towards effective therapies, cures, and prevention of adrenoleukodystrophy. The biomedical interests of the Foundation include gene therapy, hematopoietic stem cells, mesenchymal and other adult stem cells, genomics, and small molecules. Rachel also consults for large pharma and biotech in the field of drug development, including preclinical and clinical analysis in a variety of therapeutic areas. This consultancy includes advising veterinary pharmaceutical developers and food production industry on nutritional supplements, preventive healthcare, and animal housing conditions/other welfare practices. Prior to these roles, Rachel worked in private veterinary practice in both large and small animal medicine for over 10 years. She has a D.V.M. from Oklahoma State University and a B.S. from Rutgers University.

Virginie BonnamainVirginie Bonnamain currently serves as Clinical Scientist at Glycostem Therapeutics, where she manages clinical and project management activities for NK-cell based immunotherapy studies for oncology indications. Virginie has more than 12 years’ experience in Life Sciences R&D and project management, including 6 years in drug development, rare diseases and cell & gene therapy, acquired when working at various academic institutions (University of Nantes Medical School, Mount Sinai School of Medicine and the Cleveland Clinic) and at biotech companies. In particular, she worked as Clinical Project Manager for a gene therapy study for Adrenoleukodystrophy, and she also contributed to the development of a European academic Consortium for Adrenomyeloneuropathy, aimed at improving patient care and disease understanding. Virginie received a MSc in Biological & Medical Sciences in 2006 and a PhD in Neuroimmunology in 2009 from the University of Nantes, France. She published 18 scientific publications/book chapters.

Stephan KempStephan Kemp is an Associate Professor at the Amsterdam University Medical Centers (location AMC), University of Amsterdam, the Netherlands. He was trained as a translational researcher at Johns Hopkins University/ Kennedy Krieger Institute, Baltimore, Maryland, USA and obtained his PhD in 1999 at the University of Amsterdam. Dr Kemp has more >20 years of experience with adrenoleukodystrophy research and published >80 papers and book chapters on adrenoleukodystrophy. In 1999, together with Dr. Hugo Moser, he initiated the ALD database (www.x-ald.nl), which moved to www.adrenoleukodystrophy.info in 2017. He is scientific adviser of the Dutch ALD patient organisation and the Stop ALD Foundation, member of the Panel of Experts of Alex TLC (UK), member of the scientific board of the European Leukodystrophy Association (ELA) and a member of the board of directors of ALD Connect. Dr Kemp is the project leader of the SCAN study; the pilot for implementing ALD newborn screening in the Netherlands. In 2015, he received the AMC Societal Impact Award (ASIA). His research focuses on lipid metabolism and neurotoxicity.

Sitemap of the ALD website

The main language of adrenoleukodystrophy.info is English. But from an increasing number of pages translations in Español, Deutch, Français, or Nederlands are available.

English

Variants & Biochemistry
Variants in ABCD1
Large deletions
Virants statistics
Pseudogenes & Genetic Testing
Pathogenic variants & ALD Protein Stability
ALDP orthologs
ABCD proteins
Very long-chain fatty acids
Origin and Metabolism of VLCFA
Biochemical defect
ABCD1 coding region
The ABCD1 gene

Clinical & Diagnosis
Facts on ALD
Newborn screening
Guidelines for management
Diagnosis of ALD
Females with ALD
Clinical presentations
History of ALD
ALD Connect Educational Videos & Webinars
The ALD Connect Patient Portal

Treatment options
Hematopoietic stem cell transplantation
Gene Therapy for ALD
Lorenzo’s oil
Lovastatin in ALD
Adrenal insufficiency
The adrenal gland
Lorenzo Odone

Español

Ácidos Grasos de Cadena Muy Larga
Datos sobre la ALD
Cribado neonatal
Guía para el asesoramiento
Diagnóstico de ALD
Historia de ALD
Mujeres con ALD
Presentaciones clínicas
Trasplante de células madre hematopoyéticas
Terapia génica para la ALD
Aceite de Lorenzo
Lovastatina en ALD
Insuficiencia suprarrenal
La glándula suprarrenal
Lorenzo Odone

Deutch

Sehr langkettige Fettsäuren
Tatsachen zur ALD
Neugeborenenscreening
Genetik und genetische Beratung
Diagnose der ALD
Klinische Bilder

Français

Acides Gras à Très Longue Chaîne
Les faits sur l’ALD
Dépistage néonatal
Présentations cliniques
Les femmes ayant une ALD
Histoire de l’ALD
Thérapie Génique pour l’ALD
L’huile de Lorenzo
La lovastatine pour l’ALD
L’insuffisance surrénale
Lorenzo Odone

Nederlands

Zeer langketen vetzuren
Feiten over ALD
Hielprik screening
Vrouwen met ALD
Lovastatine en ALD
Gentherapie voor ALD
Behandeling van ALD

General

Hugo Moser
On Twitter
Editorial board
Sitemap
Acknowledgements
Disclaimer
Contact

Acknowledgements

ALD info is a community driven project. Its strength lies in the sharing of information and the collaboration with many ALD experts with different fields of expertise.

We are very thankful to the following persons:

Website

John Hirschbeck Memorial Fund (for funding the first version of the website).
Marcel Mattijssen (for funding the hosting of the website (1999 – 2003)).
Netherlands ALD Patient Organization (for funding several years of the hosting cost (2003 – 2012)).
Ted van Geest (GoedGedaan) (for sponsoring the hosting of the website (since 2012) and his continuous help with the website and all the other stuff that keeps a website functional & running).

Scientific contributions

Johanna Assies, M.D., Ph.D.
Wouter van Ballegoij, M.D.
Johannes Berger, Ph.D.
Virginie Bonnamain, Ph.D.
Marc Engelen, M.D., Ph.D.
Gabor Linthorst, M.D.
Ann Moser, B.A.
Hugo Moser, M.D.
Charles Peters, M.D.
Gerald Raymond, M.D.
Rachel Salzman, D.V.M. Rachel Salzman, DVM (CSO, The Stop ALD Foundation)
Steven J Steinberg, Ph.D.
Björn van Geel, M.D., Ph.D.
Paul Watkins, M.D., Ph.D.
for their scientific contributions.

Translations to French, German and Spanish

Nerea Montedeoca Vázquez (Biomedicine student)
Cyntia Amorosi, Ph.D.
Alfried Kohlschütter M.D.
Elise Saunier Vivar, Ph.D. (European Leukodystrophy Foundation, ELA)
Carmen Sever (ELA España)

Disclaimer

The purpose of the adrenoleukodystrophy website is to provide general educational information about ALD. We intend to cover as many aspects of ALD as possible. You should not use our website to diagnose or treat ALD. While we provide information, you should always consult your professional health care provider with any specific disease-related questions or problems you may have.

Contributors are responsible for the reliability of unreviewed data published on this website. While as much effort as possible has been made to ensure that the ABCD1 Variant Database is of high quality, the laboratories/investigators that have identified these variants make no warranty, expressed or implied, as to the accuracy of the information or its suitability for any specific purpose. Users should be very cautious for several reasons:

Unpublished variants may not be used for publication purposes without prior approval from the editor of the database and the laboratories/investigators that have identified and reported these variants.

This website uses the web analytics tool Matomo for website statistics.

Contact

For comments, questions or further information please contact:

Stephan Kemp, Ph.D.
Associate Professor & AMC Principal Investigator
Genetic Metabolic Diseases
Departments of Clinical Chemistry and Pediatrics
Amsterdam UMC – University of Amsterdam
Meibergdreef 9
1105 AZ, Amsterdam
The Netherlands
s.kemp [at_symbol] amsterdamumc.nl
Website: Team ALD

Facts on ALD

Authors: Marc Engelen, M.D., Ph.D., Rachel Salzman, D.V.M. (CSO, The Stop ALD Foundation), and Stephan Kemp, Ph.D.

Definition

Adrenoleukodystrophy (ALD) is a serious progressive, genetic disorder that affects the adrenal glands, the spinal cord, and the white matter (myelin) of the nervous system. It was first recognized in 1923 and has also been known as Schilder’s disease and sudanophilic leukodystrophy. In the 1970s, the name adrenoleukodystrophy was introduced as a means of better describing the disease manifestations. ‘Adreno’ refers to the adrenal glands; ‘leuko’ refers to the white matter of the brain, and ‘dystrophy’ means abnormal growth or development. This disorder has no relation to “neonatal adrenoleukodystrophy” which belongs to the peroxisomal biogenesis disorders of the Zellweger spectrum.

Biochemistry

Adrenoleukodystrophy is an inherited metabolic storage disease whereby a defect in a specific enzyme results in the accumulation of very long-chain fatty acids (VLCFA) in all tissues of the body. These VLCFA are harmful to some cells and organs. For reasons that remain to be resolved, brain, spinal cord, testis and the adrenal glands are primarily affected. In the central nervous system, the build-up of VLCFA eventually destroys the myelin sheath that surrounds the nerves leading to neurologic problems. VLCFA are toxic to adrenal gland cells, and their malfunction causes Addison’s disease (adrenal insufficiency).

VLCFA homeostasis in an ALD cell. A defect in ALDP blocks peroxisomal VLCFA degradation and results in a storage of VLCFA
Figure 1: VLCFA that accumulate in adrenoleukodystrophy are mainly a result of long-chain fatty acid elongation. To maintain the tight balance in VLCFA homeostasis, excess amounts of VLCFA have to be degraded. VLCFA can only be degraded in peroxisomes. All cells of the body, except red blood cells, have peroxisomes. Adrenoleukodystrophy is caused by pathogenic variants in the ABCD1 gene that produces the adrenoleukodystrophy protein (ALDP). ALDP functions as a transporter of VLCFA from the cytosol into the peroxisome. A deficiency in ALDP blocks this transport, which results in impaired degradation of VLCFA and a subsequent build-up of VLCFA in cells, tissues and organs. The enzymes that are required for the breakdown of VLCFA are present within the peroxisomes, but the VLCFA cannot reach them.

Epidemiology

Adrenoleukodystrophy occurs all over the world and is observed across all ethnicities and geographies. The overall prevalence of adrenoleukodystrophy is approximately 1 in 15.000 newborns.

Genetics

Adrenoleukodystrophy is an X-linked disorder, which means that the adrenoleukodystrophy gene (its official name is ABCD1) is located on the X-chromosome. Men have one X-chromosome and one Y-chromosome (XY; Figure 2). When the father is carrying the defective adrenoleukodystrophy gene, there is no other X-chromosome for protection; therefore, he will experience adrenoleukodystrophy symptoms. Females have two X-chromosomes (XX; Figure 2). Females who carry the defective gene used to be referred to as “carriers” because it was thought that only a small percentage of these females would develop clinical symptoms. However, it is now clear that this is not the case. See below and the page (Females with ALD). The clinical symptoms in females are somewhat milder than in men, however, 80% of females with ALD do eventually develop symptoms. Therefore, the terminology “adrenoleukodystrophy carriers” is misleading, and should no longer be used. The most likely explanation for females developing a milder form of the disease is the presence of a normal copy of the ABCD1 gene on their other X-chromosome. It is thought that the presence of cells that express the healthy copy of the ABCD1 gene protects females with ALD from developing the brain variant (cerebral ALD).

Possible outcomes with each newborn are different when either the mother or the father carries the deficient gene
Figure 2: (Left) If a female is a carrier for the defective adrenoleukodystrophy gene she has the following possible outcomes with each newborn: when the child is a daughter, there is a 50% chance that the daughter receives the defective adrenoleukodystrophy gene and a 50% chance that the daughter is unaffected. In case the child is a boy, there is a 50% chance that the son has adrenoleukodystrophy and a 50% chance that he will be unaffected. (Right) For an X-linked disorder, such as adrenoleukodystrophy, if an affected man has children, then all of his sons will be free of the disease, since the father always passes his Y-chromosome on to his sons. However, all of his daughters will inherit the defective adrenoleukodystrophy gene (he always passes his only (affected) X-chromosome on to his daughter).

Clinical course

Patients with adrenoleukodystrophy do not display any symptoms at birth. In males, the first manifestation of adrenoleukodystrophy is usually adrenal insufficiency, which can occur in young babies. In adulthood, males develop myelopathy (spinal cord disease). Males with adrenoleukodystrophy can develop progressive cerebral demyelination (cerebral ALD), both in childhood and adulthood. Cerebral ALD can either be the first manifestation of adrenoleukodystrophy or in addition to adrenal insufficiency and/or myelopathy (Figure 3). Females with ALD are also affected and not merely carriers of the adrenoleukodystrophy gene deficiency, as greater than 80% of these individuals develop the signs and symptoms associated with myelopathy by the age of 60 years. Females with ALD rarely develop adrenal insufficiency or cerebral demyelination.

The clinical spectrum of ALD in menFigure 3: The clinical spectrum of adrenoleukodystrophy in men. Patients with adrenoleukodystrophy do not display any symptoms at birth. The colored bars indicate the age‐range of onset for adrenal insufficiency (blue bar), myelopathy (mauve bar) and cerebral ALD (green bar). Onset of adrenal insufficiency can be as early as 5 months of age. In adulthood, men invariably develop a chronic progressive myelopathy. Cerebral ALD can occur at any age, with the youngest reported patient at 3 years of age. The primary defect in the adrenoleukodystrophy gene and the storage of VLCFA in tissues results in adrenal insufficiency and myelopathy (together referred to as adrenomyeloneuropathy). Initiation of cerebral ALD is most likely defined by the interplay of the primary adrenoleukodystrophy gene defect and a combination of, as of yet unknown environmental triggers and/or genetic factors. It is important to recognize that patients with adrenal insufficiency and/or myelopathy remain at risk of developing cerebral ALD.

Adrenal insufficiency (or even a life threatening Addisonian crisis) can be the presenting symptom of adrenoleukodystrophy in boys and men, years or even decades before the onset of neurological symptoms. A study on neurologically pre-symptomatic boys with adrenoleukodystrophy showed that 80% of these boys already had impaired adrenal function at the time of diagnosis of adrenoleukodystrophy. The most common signs of adrenal insufficiency are chronic, or long lasting, fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain and unexplained vomiting. Other symptoms may include nausea, diarrhea, low blood pressure (that drops further when a person stands up, causing dizziness or fainting), irritability and depression, craving salty foods, low blood sugar, headache, or sweating. Individuals may or may not have increased skin pigmentation resulting from excessive adrenocorticotropin hormone (ACTH) secretion.
Myelopathy: Virtually all male patients with adrenoleukodystrophy who reach adulthood develop a myelopathy, typically between the 20-40 years of age. Symptoms are limited to the spinal cord and the peripheral nerves. Initially, the neurologic disability is slowly progressive. The diagnosis of adrenoleukodystrophy is rarely made during the first 3–5 years of clinical symptoms, unless other cases of adrenoleukodystrophy have been identified in the same family. Patients develop a slowly progressive gait disorder due to stiffness and weakness of the legs. Individuals can also develop bladder dysfunction with urinary urgency, which can progress to full incontinence. All symptoms are progressive over years or decades, with most patients losing unassisted ambulation by the 5th – 6th decade of life.
Adrenomyeloneuropathy (AMN): The term adrenomyeloneuropathy refers to male patients with both impaired adrenal function and a myelopathy.
Cerebral ALD: Boys and men with adrenoleukodystrophy are at risk of developing demyelinating lesions in the cerebral white matter (cerebral ALD). The onset of cerebral ALD has never been reported before the age of 3 years. In the past, cerebral ALD was considered to be rare in adolescence (4‐7%) and adulthood (2‐5%). However, now that we systematically follow a large group of men with adrenoleukodystrophy with yearly MRI scans it appears that these numbers are higher. Currently, we cannot predict if or when a patient will develop cerebral ALD. A possible environmental trigger is head trauma, but other – as of yet – unknown genetic and environmental factors are likely required for the development of cerebral ALD. Symptoms of cerebral ALD are in general rapidly progressive. A newborn male patient has a 35–40% risk to develop cerebral ALD between the ages of 3 and 18 years. In elementary school-aged boys, the first symptoms are usually behavioral problems and learning deficits manifesting as a decline in school performance. These early clinical symptoms are often initially attributed to other disorders such as attention deficit/hyperactivity disorder, which can delay the diagnosis of adrenoleukodystrophy. In adult patients the first symptoms are often psychiatric as well and can resemble depression or psychosis. In these patients, the diagnosis of adrenoleukodystrophy is often delayed; especially when no family history of adrenoleukodystrophy is present and when clinical symptoms of adrenal insufficiency are absent. As the disease progresses, overt neurologic deficits become apparent, which include hearing and visual impairment, weakness of the arms and legs, problems with coordination and seizures. At this stage progression is extremely rapid and wholly devastating. Affected patients can lose the ability to understand language and walk within a few months. Eventually, patients are bedridden, blind, unable to speak or respond, requiring full-time nursing care and feeding by nasogastric tube or gastrostomy. Death generally occurs 2 to 4 years after onset of the initial symptoms, or – if well cared for – patients may remain in this apparent vegetative state for years.
Females with ALD: As in many X-linked diseases, it was originally assumed that females carrying the deficient adrenoleukodystrophy gene remain asymptomatic. However, it is now established that this notion is incorrect. In fact, more than 80% of females with ALD develop symptoms by the age of 60 years. The full text of the research paper describing the sign and symptoms in females with ALD can be viewed and downloaded (as a pdf). In general, their onset of neurologic symptoms occurs at a later age than in males with myelopathy; typically, between 40 to 50 years of age. Disease progression is generally slower than in males. Interestingly, and in contrast to males, fecal incontinence is a frequent complaint in females with ALD. It is important to note that the myelopathy in females with ALD is often misdiagnosed as multiple sclerosis. Both adrenal failure and cerebral ALD are very rare, less than 1%, respectively. For more details see (Females with ALD).

Testing

Adrenoleukodystrophy is diagnosed by a simple blood test, which measures the very long-chain fatty acids levels. This test is accurate in males, and is widely accepted as a highly accurate means of diagnosing males of all ages. However, in about 15% of females with ALD the VLCFA test shows normal levels and thus provides the individual with a “false negative” result. One way to accurately identify “false negative” patients is via a DNA test. This laboratory test permits accurate identification of females with ALD by genetic testing, and normal results can assure a female that she is not a carrier of the defective adrenoleukodystrophy gene. In 2020, it was shown that the VLCFA containing C26:0-lysoPC is elevated in all ALD men and women: even women with ALD with plasma VLCFA levels in the normal range had elevated levels of C26:0-lysoPC in dried blood spots and plasma [Jaspers et al 2020]. Thus, C26:0-lysoPC outperforms VLCFA analysis as an ALD diagnostic biomarker.

Newborn screening

Early diagnosis of adrenoleukodystrophy is the key to saving lives, because newborn screening allows prospective monitoring for adrenal function and the onset of cerebral ALD. A newborn screening test has been developed. It detects elevated VLCFA levels (as C26:0-lysoPC) in bloodspots. On December 30, 2013, the state of New York initiated screening for adrenoleukodystrophy in newborns. In February 2016, adrenoleukodystrophy was added to the United States Recommended Uniform Screening Panel (RUSP). Since then other states and countries have started newborn screening programs, or have initiated processes intended to add adrenoleukodystrophy to their existing newborn screening program. Detailed and up-to-date information on adrenoleukodystrophy newborn screening can be found at the page “Newborn screening”.

Research

Extensive research on adrenoleukodystrophy is being done around the world. In 1993, the gene for adrenoleukodystrophy was identified through the combined efforts of Drs. Patrick Aubourg and Jean-Louis Mandel in France and Dr. Hugo Moser in the U.S. This has opened new doors for further study. Research activities are focused on many aspects, to answer fundamental questions, such as: “How do the VLCFA eventually result in the loss of myelin?”; “Why does one patient develop cerebral ALD while another (which can even be the patient’s brother) develops a myelopathy at a later age?”.

Treatment

Today there is no curative treatment for adrenoleukodystrophy.
Adrenal steroid replacement therapy: Most male adrenoleukodystrophy patients develop adrenal insufficiency. Adrenal insufficiency of often the first manifestation of adrenoleukodystrophy: One insightful study revealed that 80% of neurologically pre-symptomatic boys with adrenoleukodystrophy who were identified through extended family screening already had impaired adrenal function at the age of 4 years. For these patients, adrenal steroid replacement therapy is mandatory, and may be lifesaving, however, successfully managing adrenal dysfunction has no effect on neurological symptoms.
For the myelopathy, that affects 85% of all adrenoleukodystrophy patients (males and females combined), no curative therapy is available.
Dietary restriction: Because VLCFA are toxic to myelin, the adrenals and testis, several attempts were made to lower the plasma concentrations of VLCFA. Dietary restriction of VLCFA intake alone has no effect on plasma VLCFA levels.
Lorenzo’s oil: VLCFA are primarily synthesized via chain-elongation of shorter fatty acids. In the laboratory, the addition of mono-unsaturated fatty acids to the cell culture medium of adrenoleukodystrophy fibroblasts reduces the VLCFA concentrations to normal levels. This can be explained because the enzymes that are required for the synthesis of VLCFA are the same for mono-unsaturated fatty acids and for saturated fatty acids. But their affinity for the monounsaturated fatty acids is higher. This finding formed the basis of a dietary approach. Oral administration of oleic acid in triglyceride form (GTO), and erucic acid in triglyceride form (GTE) normalized the plasma VLCFA levels within 1 month in most patients with adrenoleukodystrophy. The combination of GTO and GTE in a 4:1 ratio became known as “Lorenzo’s oil”, a tribute to Lorenzo Odone, the first patient treated with the mixture. Lorenzo’s oil was thought to hold great promise. However, several open-label trials have shown that the oil failed to improve neurological or endocrine function or that it could arrest the progression of the disease. More details at the page (Lorenzo’s oil).
Lovastatin was demonstrated to have an effect on VLCFA. This finding, however, could not be reproduced by others. In fact, later experiments showed that statins had no effect on brain and adrenal VLCFA levels in adrenoleukodystrophy mice, and even caused accumulation of VLCFA in these tissues. Because of these conflicting results, a randomized double-blind placebo-controlled clinical trial to test the effect of lovastatin as a VLCFA lowering therapy for adrenoleukodystrophy has been performed at the Academic Medical Center in Amsterdam. The results and conclusions demonstrate that lovastatin treatment results in a small decrease in plasma VLCFA, but it does not affect VLCFA at the cellular level, since C26:0 levels in red and white blood cells were unchanged. More details at the page (Lovastatin).
Bezafibrate: In the search for compounds that may reduce VLCFA levels, bezafibrate, a drug used for the treatment of hyperlipidaemia, was identified as a VLCFA-lowering agent. Experiments in fibroblasts showed that bezafibrate reduced VLCFA levels by directly inhibiting the activity of the VLCFA-specific elongase ELOVL1. An open-label pilot study was performed to evaluate the effect of bezafibrate on VLCFA accumulation in blood cells of adrenoleukodystrophy patients. Unfortunately, bezafibrate failed to lower VLCFA levels in blood cells of adrenoleukodystrophy patients. Most likely this was attributable to its inability to reach adequate drug levels in patients.
Bone-marrow transplant: In boys and adolescents with early-stage cerebral ALD, allogeneic hematopoietic stem cell transplantation (HSCT) can arrest the progression of cerebral demyelination in adrenoleukodystrophy provided the procedure is performed at a very early stage of the disease. The efficacy of HSCT is based on the renewal of ALDP-deficient brain microglial cells by normal microglial cells that originate from the donor bone-marrow stem cells. More details at the page (Hematopoietic stem cell transplantation).
Gene therapy: It is anticipated that in the not too distant future transplantation of autologous (the patient’s own bone marrow cells) hematopoietic stem cells that have been genetically corrected ex vivo (outside of the patient’s body) with a lentiviral vector prior to re-infusion might become an additional therapeutic option. This optimism is based on the highly encouraging results reported in 2009 in the first two treated ALD patients, and on the recent data from the Starbeam Study published in October 2017. More details at the page  (Gene Therapy for ALD).

A 10 minute overview of adrenoleukodystrophy


Produced by Youreka Science in collaboration with ALD Connect, Inc.
Please see the ALD Connect Educational Videos & Webinars page for more videos

Newborn screening

Authors: Rachel Salzman, DVM (CSO, The Stop ALD Foundation) and Stephan Kemp, Ph.D (listen to a podcast on ALD newborn screening).

Introduction

Babies born with adrenoleukodystrophy (ALD) are neurologically normal at birth. However, early diagnosis of boys with ALD can lead to life-saving interventions. These include initiating timely adrenal steroid replacement therapy following detection of adrenal insufficiency, and for providing allogeneic hematopoietic stem cell transplantation (HSCT) as a means of treating cerebral ALD. HSCT can arrest the often fatal progression of cerebral demyelination provided that the procedure is performed at a very early stage of the disease. Unfortunately, this can only be effective during a narrow therapeutic window, which is often missed. Newborn screening provides access to this “window of opportunity” and allows for timely initiation of these established therapies.

In February 2016, ALD was added to the Recommended Uniform Screening Panel (RUSP) in the USA. This is the federal list of all genetic diseases recommended for state newborn screening programs. The state of New York initiated screening for ALD in newborns on December 30, 2013. Since then other states began ALD newborn screening (Fig 1). In the US, several additional states have legislative approval. It is expected that ALD newborn screening will commence in these states as soon as budgetary resources, testing procedures and follow-up protocols are in place.

Outside the US, Taiwan initiated ALD newborn screening in November 2016 (Chen et al. 2022) and a pilots are ongoing in Japan (Shimozawa et al. 2021) and Italy (Bonaventura et al. 2023). In the Netherlands, the Dutch Health Council recommended to only screen male newborns for ALD. The novelty of sex-specific newborn screening and the lack of an example for a boys-only screening algorithm required a pilot study before ALD can be included in the nationwide screening program. A one-year pilot was carried out in 2021 (see below).

Newborn Screening Map showing US states that have included ALD in their newborn screening programFigure 1: Map showing the states in the US that have initiated ALD newborn screening.

Criteria for inclusion in the screening program

There is broad international consensus on the criteria for inclusion of a disease in a newborn screening program.

History

In 2004, at the National Advisory Committee for Newborn Screening meeting, Dr. Hugo Moser suggested adding ALD to the United States’ RUSP. The only problem was that a valid test for newborn screening was not available. To overcome this, he raised funds and recruited a team of researchers at the Kennedy Krieger Institute (Baltimore, MD) to identify a suitable biomarker and develop a test using tandem mass spectrometry (MS/MS). In 2006, the team reported the identification of C26:0-lysophosphatidylcholine (C26:0-LPC) in postnatal venous dried blood spots (DBS) from ALD males (Hubbard et al. 2006). Over the ensuing years scientists continued to improve the analysis (Hubbard et al. 2009; Theda et al. 2014). Together with investigators at the Mayo Clinic (Rochester, Minnesota), a high-throughput method for the analysis of C26:0-LPC was then developed (Haynes and De Jesús 2012; Turgeon et al. 2015). In 2013, this method was validated using a 100,000 anonymous dried blood spots.

Aidan’s Law

In April 2012, following the death of their son, Aidan, who had cerebral ALD, but was diagnosed too late, the Seeger family drafted and supported the passage of Aidan’s Law in the State of New York. The bill was approved in February 2013 and became law in March 2013. On 30 December 2013, New York State’s newborn screening laboratory began testing babies for ALD.

New York State

During the first three years, New York State has screened over 700,000 newborns and identified 45 babies with ALD: 22 boys and 23 girls (Moser et al. 2016). Based on these numbers, the birth-incidence of ALD is 1 in 15,000. When a newborn with ALD is identified, the family’s primary physician is notified and a referral is made to a clinical geneticist for confirmation of the diagnosis, along with genetic counseling for support services and screening of other family members at risk of ALD (extended family screening).

For males, it is imperative to initiate serial monitoring by brain MRI to detect the earliest evidence of onset of cerebral ALD; and to initiate adrenal function testing to detect adrenal insufficiency. Comprehensive evaluation of neurologic, neuropsychological, neuroradiology, and adrenal function is necessary because there is no test to predict the clinical outcome of an individual baby born with an ALD pathogenic variant.

The newborn screening test

The details of the C26:0-LPC test may differ slightly across laboratories. In general, the ALD diagnosis is accomplished using a three-tier algorithm (Fig 2). The first tier is a high-throughput standard MS/MS analysis of C26:0-LPC. Samples that have an elevated C26:0-LPC concentration are then screened in the second tier, using HPLC–MS/MS. This test is more sensitive, but it is also somewhat more time-consuming. In those samples that still show elevated C26:0-LPC, the third-tier sequencing of the ABCD1 gene is performed.

Figure 2: The principles of ALD 3-tier screening.

Challenges

In different countries there are significant challenges and ongoing ethical discussions with respect to the implementation of ALD newborn screening.

The Netherlands

In 2015, the Dutch Ministry of Health adopted the advice of the Health Council of the Netherlands (‘Neonatal screening: new recommendations’) to add ALD to the neonatal screening panel. The Dutch Health Council adheres to the Wilson and Jungner criteria, and recommended to only screen male newborns for ALD, because boys are at high risk of developing adrenal insufficiency and/or cerebral ALD and therefore will have direct benefit from newborn screening. This required the addition of a sex-determination step to the screening process. Boys with ALD can be identified by the combination of: 1) elevated C26:0-lysoPC, 2) sex-determination and 3) an ABCD1 pathogenetic variant.

The SCAN study

World-wide there was no example of a newborn screening program that screens either only boys or only girls. Therefore, ALD newborn screening started with a pilot study (performed in 2021). This pilot was referred to as the SCAN study (Screening for ALD in the Netherlands). The aim of the SCAN study was to enable an optimal implementation of newborn screening for ALD by examining the test characteristics and practical implications of the C26:0-lysoPC, the sex-determination and the final diagnosis of ALD. This concerns logistical implications (both ICT and analytical), information dissemination e.g. brochures and a website for parents and health professionals (https://scanstudie.nl/) etc., clinical care pathway and secondary findings, psychosocial aspects and a concise analysis of healthcare costs. The publication covering the Dutch NBS process, the boys-only ALD screening algorithm as well as the multidisciplinary, centralized follow up protocol and a flowchart to confirm the diagnosis is freely accessible at: (Barendsen et al. 2020).

In the pilot, 71,208 newborns were screened for ALD. This has resulted in the identification of four boys with ALD who, following referral to the pediatric neurologist and confirmation of the diagnosis, enrolled in a long-term follow up program at the Amsterdam Leukodystrophy Center of the Amsterdam UMC. The results of the pilot show the feasibility of employing a boys-only screening algorithm that identifies males with ALD. The results have been published and are freely accessible at (Albersen et al. 2022).

Starting October 1, 2023, newborn boys in the Netherlands will be screened for ALD.

Guidelines for management

Authors: Marc Engelen, M.D., Ph.D. and Stephan Kemp, Ph.D.

Introduction

The clinical spectrum in males with adrenoleukodystrophy ranges from isolated adrenal insufficiency and slowly progressive myelopathy to devastating cerebral demyelination (cerebral ALD). The majority of affected females will develop symptoms by the age of 60 years. In the absence of a genotype–phenotype correlation, it is not possible to predict disease course; not even within individual families. This article provides guidelines for the management of patients with adrenoleukodystrophy and provides a guideline for clinicians that encounter patients with this highly complex disorder.

The flowchart below summarizes the recommendations for follow-up of boys and men with adrenoleukodystrophy.

Boys with adrenoleukodystrophy

Follow-up in boys with adrenoleukodystrophy is important for two reasons: 1) early detection of adrenal insufficiency and 2) early detection of cerebral ALD to propose allogeneic hematopoietic stem cell transplantation (HSCT) if a HLA-matched donor or cord blood is available. Despite significant mortality risk, allogeneic HSCT remains the only therapeutic intervention that can arrest the progression of cerebral demyelination in adrenoleukodystrophy, provided the procedure is performed very early, i.e., when affected boys have no or minor symptoms due to cerebral demyelinating disease.

In the future, transplantation of autologous hematopoietic stem cells that have been genetically corrected with a lentiviral vector before re-infusion might become an alternative to allogeneic HSCT, once the very encouraging results obtained in the first two treated patients will have been extended to a larger number of patients with cerebral ALD.

If boys do not have Addison’s disease it is recommended that an endocrinologist evaluates them yearly for adrenal dysfunction by measuring the plasma ACTH levels and performing an ACTH test. Steroid replacement therapy can then be initiated if necessary.

Boys without neurological deficits should be monitored closely for radiological signs of cerebral ALD. Cerebral ALD has not been reported before the age of 2.5 years. We recommend an MRI of the brain every 6 months in boys aged 3 to 12 years old to screen for early signs of cerebral ALD. If symptoms suggestive of cerebral ALD (for instance declining school performance) occur the MRI should be performed at the earliest available opportunity. But it is our experience that the detection of brain MRI abnormalities precedes any detectable cognitive dysfunction by at least 6 months to 1 year. After the age of 12 years, the incidence of cerebral ALD decreases, but an MRI scan must be performed yearly or earlier if new symptoms occur.

It is important to detect cerebral ALD as early as possible, preferably in the asymptomatic stage with only moderate radiological abnormalities to discuss the possibility to perform allogeneic HSCT. Accordingly, if a brain MRI shows abnormalities, even very limited such as an increased signal intensity on T2 or FLAIR sequences in the splenium or genu of the corpus callosum, brain MRI must be repeated within 3 months to evaluate disease progression and in particular to identify the presence of gadolinium rim enhancement of lesions. Because the disease can be very rapidly progressive, it is strongly advised to discuss the possibility of allogeneic HSCT as soon as brain MRI abnormalities typical of cerebral ALD are detected. After a successful transplant, the lesions on MRI stabilize and even regress. Treatment results are better the earlier treatment is started.

Adult men with adrenoleukodystrophy

Follow-up in men with adrenoleukodystrophy is important for the early detection of adrenal insufficiency. If men do not have Addison’s disease it is recommended that an endocrinologist evaluates them yearly for adrenocortical dysfunction by measuring the plasma ACTH levels and performing an ACTH test. Steroid replacement therapy can then be initiated if necessary.

For adult men with or without signs of myelopathy, we advise evaluation by a neurologist yearly or bi-annually to screen for symptoms of myelopathy and to administer symptomatic treatment if necessary (for instance, medication against spasticity). Referral to a rehabilitation physician and urologist will often become necessary.

Adult men can develop cerebral ALD and in our centers, we offer an MRI of the brain every single year. There is no proven treatment for cerebral ALD in adults. It seems likely that allogeneic HSCT is also effective in adults with early stage cerebral ALD, but there are no published studies or cases describing this treatment. We tend to consider allogeneic HSCT in an adult patient with early stage cerebral ALD, after carefully counseling the patient about the lack of evidence for the treatment and the risk of the procedure which is significantly higher than in boys.

For the spinal cord disease there is no effective disease modifying therapy available yet. Although Lorenzo’s oil had great promise, several open-label trials have shown that the disease progresses even when plasma VLCFA are normalized by Lorenzo’s oil treatment. A large randomized placebo-controlled clinical trial was designed to provide a definitive answer, but was unfortunately aborted before completion by the safety monitoring board because of presumed side effects of the placebo treatment. There is also a retrospective study suggesting that if pre-symptomatic boys are started on Lorenzo’s oil, it may delay the onset of neurological symptoms. We consider the scientific evidence to support the efficacy of Lorenzo’s oil weak, and do not offer this treatment to our patients. Regular follow-up of patients with myelopathy remains important, however, mainly to provide symptomatic treatment.

Females with adrenoleukodystrophy

Females with ALD should be evaluated for the development of neurologic symptoms. Since females with ALD very rarely develop adrenal insufficiency or cerebral involvement, periodic evaluation of adrenal function and brain MRI is not mandatory. Greater awareness among physicians that females can develop neurologic symptoms is important for counseling but also to prevent unnecessary diagnostic tests and erroneous diagnosis. We know of cases of females with ALD who underwent cervical laminectomy for presumed cervical spondylogenic myelopathy. For symptomatic females with ALD, we advise (as for adult men with adrenoleukodystrophy) a yearly evaluation by a neurologist to discuss the indication of rehabilitation, the referral to an urologist and treatment of spasticity and neuropathic pain.

The text on this page is a summary of the paper: “X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management”. The full paper was published as Open Access in Orphanet Journal of Rare Diseases (for readability, the references have been removed). The full text can be viewed and downloaded (as a pdf).

Variants in ABCD1

The ABCD1 Variant Database reports all variants in accordance with the nomenclature recommended by the Human Genome Variation Society. All variants, including those that have been published in the past, are annotated using Alamut software. The transcript NM_000033.3 on GRCh37 (hg19) is used as the reference sequence. The ABCD1 Variant Database is a community-driven project. Its strength lies in its collaborative nature, with diagnostic laboratories, researchers, and physicians able to contribute new variants and updates regarding pathogenicity. If you use the ABCD1 Variant Database as a reference guide, then please share ABCD1 variants and/or updates regarding pathogenicity with the ABCD1 Variant Database. This will help us to continuously make improvements (your contribution will be acknowledged).
Because ABCD1 pathogenic variants have no predictive value with respect to the clinical outcome of an individual patient, no phenotypic information is provided. Instead, we report cases. An ALD case is defined as an individual who has been diagnosed with clinical signs and symptoms related to ALD (adrenal disease, myeloneuropathy and/or cerebral ALD), and a biochemical or genetic confirmation. Where available in the scientific literature, experimental data were extracted supporting the pathogenicity of a particular variant.
Go to The ABCD1 Variant Database