. 2022 Nov 22;99(21):940-951.

doi: 10.1212/WNL.0000000000201374. Epub 2022 Sep 29.

International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach

Marc Engelen¹, Wouter J C van Ballegoij², Eric James Mallack², Keith P Van Haren², Wolfgang Köhler², Ettore Salsano², A S P van Trotsenburg², Fanny Mochel², Caroline Sevin², Molly O Regelmann², Nicholas A Tritos², Alyssa Halper², Robin H Lachmann², James Davison², Gerald V Raymond², Troy C Lund², Paul J Orchard², Joern-Sven Kuehl², Caroline A Lindemans², Paul Caruso², Bela Rui Turk², Ann B Moser², Frédéric M Vaz², Sacha Ferdinandusse², Stephan Kemp², Ali Fatemi², Florian S Eichler², Irene C Huffnagel²

Affiliations

¹ From the Department of Pediatric Neurology/Emma Children's Hospital (M.E., W.J.C.B., I.C.H.), Amsterdam UMC, Amsterdam Leukodystrophy Center, University of Amsterdam, the Netherlands; Division of Child Neurology (E.J.M.), Department of Pediatrics, Weill Cornell Medicine/NewYork-Presbyterian Hospital, NY; Department of Neurology & Pediatrics/Lucile Packard Children's Hospital (K.P.V.H.), Stanford University School of Medicine, Palo Alto, CA 4. Department of Neurology, Leukodystrophy Clinic, University of Leipzig Medical Center, Germany; Unit of Rare Neurodegenerative and Neurometabolic Diseases (E.S.), Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy; Department of Pediatric Endocrinology/Emma Children's Hospital (A.S.P.T.), Amsterdam UMC, University of Amsterdam, the Netherlands; AP-HP (F.M.), Department of Medical Genetics, Reference Center for Adult Neurometabolic Diseases and Leukodystrophies, and INSERM U 1127, CNRS UMR 7225, Paris Brain Institute, La Pitié-Salpêtrière University Hospital, Paris, France; Department of Pediatric Neurology/Hôpital Bicêtre Paris Sud (C.S.), France, Reference Center for Children Leukodystrophies Inserm U1127, ICM-Hôpital Pitié Salpêtrière, Paris, France; Division of Pediatric Endocrinology and Diabetes (M.O.R.), Children's Hospital at Montefiore, Albert Einstein College of Medicine of Medicine, Bronx, NY; Neuroendocrine Unit (N.A.T.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (N.A.T.), Boston, MA; Division of Pediatric Endocrinology (A.H.), Department of Pediatrics, Massachusetts General Hospital, Boston, MA, and Harvard Medical School (A.H.), Boston, MA; Charles Dent Metabolic Unit (R.H.L.), National Hospital for Neurology and Neurosurgery, London, United Kingdom; Metabolic Medicine (J.D.), Great Ormond Street Hospital for Children, London United Kingdom; Department of Genetic Medicine (G.V.R.), Johns Hopkins, Baltimore, MD; Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy (T.L., P.J.O.), University of Minnesota, Minneapolis; Pediatric Oncology (J.-S.K.), Hematology, Hemostaseology, University Hospital Leipzig, Germany; Pediatric Blood and Bone Marrow Transplantation (C.A.L.), Princess Maxima Center Utrecht, the Netherlands; Department of Pediatrics (C.A.L.), Wilhemina Children's Hospital, UMC Utrecht, Utrecht University, the Netherlands; Director of Pediatric Neuroimaging (P.C.), Lenox Hill Radiology and Medical Imaging Associates, New York, NY; Moser Center for Leukodystrophies (B.R.T., A.F.), Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltimore, MD; Department of Neurogenetics (A.B.M.), Kennedy Krieger Institute, Baltimore, MD; Laboratory Genetic Metabolic Diseases (F.M.V., S.F., S.K.), Department of Clinical Chemistry and Pediatrics, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, the Netherlands; and Department of Neurology (F.S.E.), Massachusetts General Hospital, Boston, MA. Dr. van Ballegoij is currently at the Department of Neurology, Zaans Medisch Centrum, Zaandam. m.engelen@amsterdamumc.nl.
² From the Department of Pediatric Neurology/Emma Children's Hospital (M.E., W.J.C.B., I.C.H.), Amsterdam UMC, Amsterdam Leukodystrophy Center, University of Amsterdam, the Netherlands; Division of Child Neurology (E.J.M.), Department of Pediatrics, Weill Cornell Medicine/NewYork-Presbyterian Hospital, NY; Department of Neurology & Pediatrics/Lucile Packard Children's Hospital (K.P.V.H.), Stanford University School of Medicine, Palo Alto, CA 4. Department of Neurology, Leukodystrophy Clinic, University of Leipzig Medical Center, Germany; Unit of Rare Neurodegenerative and Neurometabolic Diseases (E.S.), Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy; Department of Pediatric Endocrinology/Emma Children's Hospital (A.S.P.T.), Amsterdam UMC, University of Amsterdam, the Netherlands; AP-HP (F.M.), Department of Medical Genetics, Reference Center for Adult Neurometabolic Diseases and Leukodystrophies, and INSERM U 1127, CNRS UMR 7225, Paris Brain Institute, La Pitié-Salpêtrière University Hospital, Paris, France; Department of Pediatric Neurology/Hôpital Bicêtre Paris Sud (C.S.), France, Reference Center for Children Leukodystrophies Inserm U1127, ICM-Hôpital Pitié Salpêtrière, Paris, France; Division of Pediatric Endocrinology and Diabetes (M.O.R.), Children's Hospital at Montefiore, Albert Einstein College of Medicine of Medicine, Bronx, NY; Neuroendocrine Unit (N.A.T.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (N.A.T.), Boston, MA; Division of Pediatric Endocrinology (A.H.), Department of Pediatrics, Massachusetts General Hospital, Boston, MA, and Harvard Medical School (A.H.), Boston, MA; Charles Dent Metabolic Unit (R.H.L.), National Hospital for Neurology and Neurosurgery, London, United Kingdom; Metabolic Medicine (J.D.), Great Ormond Street Hospital for Children, London United Kingdom; Department of Genetic Medicine (G.V.R.), Johns Hopkins, Baltimore, MD; Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy (T.L., P.J.O.), University of Minnesota, Minneapolis; Pediatric Oncology (J.-S.K.), Hematology, Hemostaseology, University Hospital Leipzig, Germany; Pediatric Blood and Bone Marrow Transplantation (C.A.L.), Princess Maxima Center Utrecht, the Netherlands; Department of Pediatrics (C.A.L.), Wilhemina Children's Hospital, UMC Utrecht, Utrecht University, the Netherlands; Director of Pediatric Neuroimaging (P.C.), Lenox Hill Radiology and Medical Imaging Associates, New York, NY; Moser Center for Leukodystrophies (B.R.T., A.F.), Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltimore, MD; Department of Neurogenetics (A.B.M.), Kennedy Krieger Institute, Baltimore, MD; Laboratory Genetic Metabolic Diseases (F.M.V., S.F., S.K.), Department of Clinical Chemistry and Pediatrics, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, the Netherlands; and Department of Neurology (F.S.E.), Massachusetts General Hospital, Boston, MA. Dr. van Ballegoij is currently at the Department of Neurology, Zaans Medisch Centrum, Zaandam.

PMID: 36175155
PMCID: PMC9687408
DOI: 10.1212/WNL.0000000000201374

International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach

Marc Engelen et al. Neurology. 2022.

. 2022 Nov 22;99(21):940-951.

doi: 10.1212/WNL.0000000000201374. Epub 2022 Sep 29.

Authors

Affiliations

¹ From the Department of Pediatric Neurology/Emma Children's Hospital (M.E., W.J.C.B., I.C.H.), Amsterdam UMC, Amsterdam Leukodystrophy Center, University of Amsterdam, the Netherlands; Division of Child Neurology (E.J.M.), Department of Pediatrics, Weill Cornell Medicine/NewYork-Presbyterian Hospital, NY; Department of Neurology & Pediatrics/Lucile Packard Children's Hospital (K.P.V.H.), Stanford University School of Medicine, Palo Alto, CA 4. Department of Neurology, Leukodystrophy Clinic, University of Leipzig Medical Center, Germany; Unit of Rare Neurodegenerative and Neurometabolic Diseases (E.S.), Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy; Department of Pediatric Endocrinology/Emma Children's Hospital (A.S.P.T.), Amsterdam UMC, University of Amsterdam, the Netherlands; AP-HP (F.M.), Department of Medical Genetics, Reference Center for Adult Neurometabolic Diseases and Leukodystrophies, and INSERM U 1127, CNRS UMR 7225, Paris Brain Institute, La Pitié-Salpêtrière University Hospital, Paris, France; Department of Pediatric Neurology/Hôpital Bicêtre Paris Sud (C.S.), France, Reference Center for Children Leukodystrophies Inserm U1127, ICM-Hôpital Pitié Salpêtrière, Paris, France; Division of Pediatric Endocrinology and Diabetes (M.O.R.), Children's Hospital at Montefiore, Albert Einstein College of Medicine of Medicine, Bronx, NY; Neuroendocrine Unit (N.A.T.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (N.A.T.), Boston, MA; Division of Pediatric Endocrinology (A.H.), Department of Pediatrics, Massachusetts General Hospital, Boston, MA, and Harvard Medical School (A.H.), Boston, MA; Charles Dent Metabolic Unit (R.H.L.), National Hospital for Neurology and Neurosurgery, London, United Kingdom; Metabolic Medicine (J.D.), Great Ormond Street Hospital for Children, London United Kingdom; Department of Genetic Medicine (G.V.R.), Johns Hopkins, Baltimore, MD; Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy (T.L., P.J.O.), University of Minnesota, Minneapolis; Pediatric Oncology (J.-S.K.), Hematology, Hemostaseology, University Hospital Leipzig, Germany; Pediatric Blood and Bone Marrow Transplantation (C.A.L.), Princess Maxima Center Utrecht, the Netherlands; Department of Pediatrics (C.A.L.), Wilhemina Children's Hospital, UMC Utrecht, Utrecht University, the Netherlands; Director of Pediatric Neuroimaging (P.C.), Lenox Hill Radiology and Medical Imaging Associates, New York, NY; Moser Center for Leukodystrophies (B.R.T., A.F.), Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltimore, MD; Department of Neurogenetics (A.B.M.), Kennedy Krieger Institute, Baltimore, MD; Laboratory Genetic Metabolic Diseases (F.M.V., S.F., S.K.), Department of Clinical Chemistry and Pediatrics, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, the Netherlands; and Department of Neurology (F.S.E.), Massachusetts General Hospital, Boston, MA. Dr. van Ballegoij is currently at the Department of Neurology, Zaans Medisch Centrum, Zaandam. m.engelen@amsterdamumc.nl.
² From the Department of Pediatric Neurology/Emma Children's Hospital (M.E., W.J.C.B., I.C.H.), Amsterdam UMC, Amsterdam Leukodystrophy Center, University of Amsterdam, the Netherlands; Division of Child Neurology (E.J.M.), Department of Pediatrics, Weill Cornell Medicine/NewYork-Presbyterian Hospital, NY; Department of Neurology & Pediatrics/Lucile Packard Children's Hospital (K.P.V.H.), Stanford University School of Medicine, Palo Alto, CA 4. Department of Neurology, Leukodystrophy Clinic, University of Leipzig Medical Center, Germany; Unit of Rare Neurodegenerative and Neurometabolic Diseases (E.S.), Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy; Department of Pediatric Endocrinology/Emma Children's Hospital (A.S.P.T.), Amsterdam UMC, University of Amsterdam, the Netherlands; AP-HP (F.M.), Department of Medical Genetics, Reference Center for Adult Neurometabolic Diseases and Leukodystrophies, and INSERM U 1127, CNRS UMR 7225, Paris Brain Institute, La Pitié-Salpêtrière University Hospital, Paris, France; Department of Pediatric Neurology/Hôpital Bicêtre Paris Sud (C.S.), France, Reference Center for Children Leukodystrophies Inserm U1127, ICM-Hôpital Pitié Salpêtrière, Paris, France; Division of Pediatric Endocrinology and Diabetes (M.O.R.), Children's Hospital at Montefiore, Albert Einstein College of Medicine of Medicine, Bronx, NY; Neuroendocrine Unit (N.A.T.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (N.A.T.), Boston, MA; Division of Pediatric Endocrinology (A.H.), Department of Pediatrics, Massachusetts General Hospital, Boston, MA, and Harvard Medical School (A.H.), Boston, MA; Charles Dent Metabolic Unit (R.H.L.), National Hospital for Neurology and Neurosurgery, London, United Kingdom; Metabolic Medicine (J.D.), Great Ormond Street Hospital for Children, London United Kingdom; Department of Genetic Medicine (G.V.R.), Johns Hopkins, Baltimore, MD; Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy (T.L., P.J.O.), University of Minnesota, Minneapolis; Pediatric Oncology (J.-S.K.), Hematology, Hemostaseology, University Hospital Leipzig, Germany; Pediatric Blood and Bone Marrow Transplantation (C.A.L.), Princess Maxima Center Utrecht, the Netherlands; Department of Pediatrics (C.A.L.), Wilhemina Children's Hospital, UMC Utrecht, Utrecht University, the Netherlands; Director of Pediatric Neuroimaging (P.C.), Lenox Hill Radiology and Medical Imaging Associates, New York, NY; Moser Center for Leukodystrophies (B.R.T., A.F.), Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltimore, MD; Department of Neurogenetics (A.B.M.), Kennedy Krieger Institute, Baltimore, MD; Laboratory Genetic Metabolic Diseases (F.M.V., S.F., S.K.), Department of Clinical Chemistry and Pediatrics, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, the Netherlands; and Department of Neurology (F.S.E.), Massachusetts General Hospital, Boston, MA. Dr. van Ballegoij is currently at the Department of Neurology, Zaans Medisch Centrum, Zaandam.

PMID: 36175155
PMCID: PMC9687408
DOI: 10.1212/WNL.0000000000201374

Abstract

Pathogenic variants in the ABCD1 gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary. We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoietic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses and presymptomatic individuals is increasing because of newborn screening and greater availability of next-generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.

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Figures

**Figure 1. Literature Review Flowchart—Selection of Records**

**Figure 2. Scale Used to Define Consensus**

**Figure 3. Diagnostic Algorithm**
Ideally, biochemical and genetic testing are combined to establish diagnosis. *Male patients are stratified by clinical status. The clinical status of ALD is positive if any symptom or sign relatable to ALD is present. This can include cerebral ALD with symptoms, cerebral ALD based on MRI abnormalities only, myeloneuropathy, or adrenal insufficiency. If no symptoms or signs relatable to ALD are present, the clinical status is negative. **Sensitivity of C26:0-lysoPC is >99%, whereas it is 85% for VLCFA. Analyze C26:0-lysoPC in case of normal plasma VLCFA. ALD = adrenoleukodystrophy; VLCFA = very-long-chain fatty acid

**Figure 4. Overview of the Management of Patients With ALD**
ALD = adrenoleukodystrophy

See this image and copyright information in PMC

Comment in

Can We Generalize Key Principles in the Care of Rare Diseases? The Case for Adrenoleukodystrophy.
Carlson MD, Kang PB. Carlson MD, et al. Neurology. 2022 Nov 22;99(21):929-930. doi: 10.1212/WNL.0000000000201400. Epub 2022 Sep 29. Neurology. 2022. PMID: 36175146 No abstract available.

References

1. Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016;12(10):606-615. - PubMed
1. Mosser J, Douar AM, Sarde CO, et al. . Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature. 1993;361(6414):726-730. - PubMed
1. Singh I, Moser AE, Moser HW, Kishimoto Y. Adrenoleukodystrophy: impaired oxidation of very long chain fatty acids in white blood cells, cultured skin fibroblasts, and amniocytes. Pediatr Res. 1984;18(3):286-290. - PubMed
1. Wanders RJ, van Roermund CW, van Wijland MJ, et al. . Peroxisomal very long-chain fatty acid beta-oxidation in human skin fibroblasts: activity in Zellweger syndrome and other peroxisomal disorders. Clin Chim Acta. 1987;166(2-3):255-263. - PubMed
1. Moser HW, Moser AB, Frayer KK, et al. . Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids. Neurology. 1981;31(10):1241-1249. - PubMed

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International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach

Affiliations

International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach

Authors

Affiliations

Abstract

Figures

Comment in

References

Publication types

MeSH terms

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Full Text Sources

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Medical

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