Phenotypic heterogeneity of an adult form of adrenoleukodystrophy in monozygotic twins
Abstract
We describe genetically proven monozygotic twins with the adult form of adrenoleukodystrophy with significant phenotypic heterogeneity. Myeloneuropathy was common to both patients, but cognitive impairment and affective symptoms with extensive demyelination in the brain were prominent in the older twin, while adrenal insufficiency was predominant in the younger twin. The younger twin, however, exhibited affective symptoms similar to those displayed by his elder twin 10 years later. These findings suggest that nongenetic factors are important in determining the phenotypic variation of adrenoleukodystrophy gene.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The few studied monozygotic twins with X-ALD showed less discordant phenotypes.
“Devastating childhood cALD and late adulthood AMN may co-exist within the same family [103,104,105,106], whereas the few studied monozygotic twins showed less discordant phenotypes [107,108,109,110].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [108]
Reports of varying phenotypes in identical twins suggest that environmental factors may be involved in X-ALD phenotypic variation.
“However, reports of varying phenotypes in identical twins suggest that environmental factors may be involved [Sobue et al., 1994;Korenke et al., 1996].”
From ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations (2001) · cites this paper as Sobue et al., 1994
Cites
Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters
Mosser, J., Douar, A.-M., Sarde, C.-O., Kioschis, P., Feil, R., Moser, H., Poustka, A.-M., Mandel, J.-L., & Aubourg, P. (1993) · Nature · doi:10.1038/361726a0 · Cited by 1,202 · see citing works
Aubourg, P., Blanche, S., Jambaqué, I., Rocchiccioli, F., Kalifa, G., Naud-Saudreau, C., Rolland, M.-O., Debré, M., Chaussain, J.-L., Griscelli, C., et al. (1990) · New England Journal of Medicine · doi:10.1056/nejm199006283222607 · Cited by 366 · see citing works
Adrenoleukodystrophy: Survey of 303 cases: Biochemistry, diagnosis, and therapy
Moser, H. W., Moser, A. E., Singh, I., & OʼNeill, P. (1984) · Annals of Neurology · doi:10.1002/ana.410160603 · Cited by 259 · see citing works
Adrenoleukodystrophy: Phenotypic variability and implications for therapy
Moser, H. W., Moser, A. B., Smith, K. D., Bergin, A., Borel, J., Shankroff, J., Stine, O. C., Merette, C., Ott, J., Krivit, W., et al. (1992) · Journal of Inherited Metabolic Disease · doi:10.1007/bf01799621 · Cited by 239 · see citing works
The adrenoleukomyeloneuropathy complex
O’Neill, B. P., Mannion, L. C., & Feringa, E. R. (1981) · Neurology · doi:10.1212/wnl.31.2.151 · Cited by 92 · see citing works
Adrenoleukodystrophy: Frequency of presentation as a psychiatric disorder
Kitchin, W., Cohen-Cole, S. A., & Mickel, S. F. (1987) · Biological Psychiatry · doi:10.1016/0006-3223(87)90072-2 · Cited by 43 · see citing works
Clinical improvement of adrenoleukodystrophy following intravenous gammaglobulin therapy
Miike, T., Taku, K., Tamura, T., Ohta, J., Ozaki, M., Yamamoto, C., Sakai, T., Antoku, Y., & Yadomi, C. (1989) · Brain and Development · doi:10.1016/s0387-7604(89)80083-x · Cited by 38 · see citing works
Very‐late‐onset adrenoleukodystrophy: Possible precipitation of demyelination by cerebral contusion
Weller, M., Liedtke, W., Petersen, D., Opitz, H., & Poremba, M. (1992) · Neurology · doi:10.1212/wnl.42.2.367 · Cited by 33 · see citing works
Adrenoleukodystrophy in a mother and son.
Simpson, R. H. W., Rodda, J., & Reinecke, C. J. (1987) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.50.9.1165 · Cited by 17 · see citing works
Adrenoleukodystrophy: heterogeneity in two brothers.
Elrington, G., Bateman, D. E., Jeffrey, M. J., & Lawton, N. (1989) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.52.3.310 · Cited by 17 · see citing works
Saha, N., Undevia, J. V., Juneja, R., Gahne, B., & Tay, J. S. H. (1992) · Human Heredity · doi:10.1159/000154099 · Cited by 12 · see citing works
Affective Symptoms and Adrenoleukodystrophy
Menza, M. A., Blake, J., & Goldberg, L. (1988) · Psychosomatics · doi:10.1016/s0033-3182(88)72350-6 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Kemp, S., Pujol, A., Waterham, H. R., van Geel, B. M., Boehm, C. D., Raymond, G. V., Cutting, G. R., Wanders, R. J. A., & Moser, H. W. (2001) · Human Mutation · doi:10.1002/humu.1227 · Cited by 332 · see citing works
Adrenoleukodystrophy—Neuroendocrine pathogenesis and redefinition of natural history
Kemp, S., Huffnagel, I. C., Linthorst, G. E., Wanders, R. J., & Engelen, M. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.90 · Cited by 275 · see citing works
Peroxisomal Disorders: Genotype, Phenotype, Major Neuropathologic Lesions, and Pathogenesis
Powers, J. M., & Moser, H. W. (1998) · Brain Pathology · doi:10.1111/j.1750-3639.1998.tb00139.x · Cited by 208 · see citing works
Identical but not the same: The value of discordant monozygotic twins in genetic research
Zwijnenburg, P. J. G., Meijers-Heijboer, H. E. J., & Boomsma, D. I. (2010) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31091 · Cited by 142 · see citing works
X linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy
van Geel, B. M., Assies, J., Wanders, R. J. A., & Barth, P. G. (1997) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.63.1.4 · Cited by 162 · see citing works
Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype
Korenke, G. C., Wilichowski, E., Hunneman, D. H., Hanefeld, F., Fuchs, S., Krasemann, E., & Doerr, H. G. (1996) · Annals of Neurology · doi:10.1002/ana.410400221 · Cited by 117 · see citing works
Kumar, N. (2007) · Neurologic Clinics · doi:10.1016/j.ncl.2006.11.001 · Cited by 98 · see citing works
The neuropsychiatry of adult-onset adrenoleukodystrophy
Rosebush, P. I., Garside, S., Levinson, A. J., & Mazurek, M. F. (1999) · The Journal of Neuropsychiatry and Clinical Neurosciences · doi:10.1176/jnp.11.3.315 · Cited by 72 · see citing works
Depreter, M., Espeel, M., & Roels, F. (2003) · Microscopy Research and Technique · doi:10.1002/jemt.10330 · Cited by 63 · see citing works
Lee, C. A. A., Seo, H. S., Armien, A. G., Bates, F. S., Tolar, J., & Azarin, S. M. (2018) · Fluids and Barriers of the CNS · doi:10.1186/s12987-018-0094-5 · Cited by 52 · see citing works
Mutations in the adrenoleukodystrophy gene
Dodd, A. W., Rowland, S. A., Hawkes, S. L. J., Kennedy, M. A., & Love, D. R. (1997) · Human Mutation · doi:10.1002/(sici)1098-1004(1997)9:6 · Cited by 47 · see citing works
Monozygotic twins with X-linked adrenoleukodystrophy and different phenotypes
Di Rocco, M., Doria‐Lamba, L., & Caruso, U. (2001) · Annals of Neurology · doi:10.1002/ana.1220 · Cited by 45 · see citing works
Epigenomic signature of adrenoleukodystrophy predicts compromised oligodendrocyte differentiation
Schlüter, A., Sandoval, J., Fourcade, S., Díaz‐Lagares, Á., Ruíz, M., Casaccia, P., Esteller, M., & Pujol, A. (2018) · Brain Pathology · doi:10.1111/bpa.12595 · Cited by 35 · see citing works
ALDP expression in fibroblasts of patients with X-linked adrenoleukodystrophy
Kemp, S., Mooyer, P. A. W., Bolhuis, P. A., van Geel, B. M., Mandel, J. L., Barth, P. G., Aubourg, P., & Wanders, R. J. A. (1996) · Journal of Inherited Metabolic Disease · doi:10.1007/bf01799844 · Cited by 37 · see citing works
AUBOURG, P., & MANDEL, J. (1996) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1996.tb18637.x · Cited by 58 · see citing works
Korenke, G., Roth, C., Krasemann, E., Hufner, M., Hunneman, D., & Hanefeld, F. (1997) · European Journal of Endocrinology · doi:10.1530/eje.0.1370040 · Cited by 38 · see citing works
Kumar, N., Taneja, K. K., Kalra, V., Behari, M., Aneja, S., & Bansal, S. K. (2011) · PLoS ONE · doi:10.1371/journal.pone.0025094 · Cited by 25 · see citing works
ABCD1 translation–initiator mutation demonstrates genotype–phenotype correlation for AMN
O’Neill, G. N., Aoki, M., & Brown, R. H. (2001) · Neurology · doi:10.1212/wnl.57.11.1956 · Cited by 28 · see citing works
Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy
Palakuzhiyil, S. V., Christopher, R., & Chandra, S. R. (2020) · World Journal of Biological Chemistry · doi:10.4331/wjbc.v11.i3.99 · Cited by 24 · see citing works
(2006) · Springer eBooks · doi:10.1007/3-540-29623-9_9160 · Cited by 21 · see citing works
Clinical and Genetic Aspects in Twelve Korean Patients with Adrenomyeloneuropathy
Park, H. J., Shin, H. Y., Kang, H., Choi, B., Suh, B. C., Kim, H. J., Choi, Y., Lee, P. H., & Kim, S. M. (2014) · Yonsei Medical Journal · doi:10.3349/ymj.2014.55.3.676 · Cited by 20 · see citing works
Trompier, D., & Savary, S. (2013) · Colloquium Series on The Genetic Basis of Human Disease · doi:10.4199/c00075ed1v01y201303gbd004 · Cited by 16 · see citing works
ABCD1 mutations and phenotype distribution in Chinese patients with X-linked adrenoleukodystrophy
Niu, Y., Wang, N., & Wu, Z. (2013) · Gene · doi:10.1016/j.gene.2013.03.067 · Cited by 13 · see citing works
New views on the complex interplay between degeneration and autoimmunity in multiple sclerosis
Stys, P. K., Tsutsui, S., Gafson, A., Hart, B. A. ‘., Belachew, S. M., & Geurts, J. J. G. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1426231 · Cited by 12 · see citing works
Mehrpour, M., & Gohari, F. (2016) · Journal of Molecular and Genetic Medicine · doi:10.4172/1747-0862.1000222 · Cited by 12 · see citing works
On the Front of X-Linked Adrenoleukodystrophy
Aubourg, P. R. (1999) · Neurochemical Research · doi:10.1023/a:1022583813171 · Cited by 12 · see citing works
Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
Bougnères, P., & Le Stunff, C. (2025) · Genes · doi:10.3390/genes16050590 · Cited by 11 · see citing works
Pierpont, E. I., Isaia, A., McCoy, E., Brown, S. J., Gupta, A. O., & Eisengart, J. B. (2022) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12581 · Cited by 11 · see citing works
Alteration of the serotoninergic system in fatal familial insomnia
Cortelli, P., Polinsky, R. J., Montagna, P., & Lugaresi, E. (2001) · Annals of Neurology · doi:10.1002/ana.1145 · Cited by 10 · see citing works
(2005) · Springer eBooks · doi:10.1007/3-540-27660-2_21 · Cited by 9 · see citing works
Kano, S., Watanabe, M., Kanai, M., Koike, R., Onodera, O., Tsuji, S., Okamoto, K., & Shoji, M. (1998) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(98)00120-8 · Cited by 8 · see citing works
Kallabi, F., Ellouz, E., Tabebi, M., Salah, G. B., Kaabechi, N., Keskes, L., Triki, C., & Kamoun, H. (2015) · Clinica Chimica Acta · doi:10.1016/j.cca.2015.12.014 · Cited by 7 · see citing works
Dohr, K. A., Tokic, S., Gastager-Ehgartner, M., Stojaković, T., Dumić, M., Plecko, B., & Dumic, K. K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065957 · Cited by 6 · see citing works
Psychosis associated with leukodystrophies
Rosebush, P. I., Anglin, R., & Mazurek, M. F. (2010) · Cambridge University Press eBooks · doi:10.1017/cbo9780511789977.019 · Cited by 5 · see citing works
S149R, a novel mutation in theABCD1gene causing X-linked adrenoleukodystrophy
Yan, F., Wang, W., Ying, H., Li, H., Chen, J., & Xu, C. (2017) · Oncotarget · doi:10.18632/oncotarget.20974 · Cited by 4 · see citing works
Özgür Günes, Y., Le Stunff, C., & Bougnères, P. (2025) · Human Gene Therapy · doi:10.1089/hum.2024.175 · Cited by 2 · see citing works
Intracranial hypertension as an unusual presentation of adrenoleukodystrophy
Smadja, D., Cabre, P., Kujas, M., Vernant, J. C., & Rivierez, M. (1997) · European Journal of Neurology · doi:10.1111/j.1468-1331.1997.tb00371.x · Cited by 2 · see citing works
Adrenoleukodystrophy: two case reports
Kundu, G. K., Rahman, M., Amin, M. R., Habib, M. A., Ahmed, S., Kabir, M. S., & Laila, K. (2016) · Bangladesh Medical Journal · doi:10.3329/bmj.v44i3.27379 · Cited by 2 · see citing works
Adrenoleukodystrophy: Two Case Reports and a Review of the Literature
Okan, B., & Gedik, O. (2000) · Cited by 1 · see citing works
X-linked adrenoleukodystrophy; Recent Advances in Classification, Diagnosis and Management
정을식, 강훈철, & 고아라 (2016) · Annals of Child Neurology · doi:10.26815/jkcns.2016.24.3.71 · Cited by 1 · see citing works
Increased activity of surviving locus ceruleus neurons in Alzheimer's disease
Moser (1999) · Pure Amsterdam UMC · doi:10.1002/1531-8249(199901)45:1
Why Study Regulation of Genes in Inherited Disorders?
Roels, F. (2003) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-9072-3_1
Phänotypen der x-Adrenoleukodystrophie
Binder, C. T. (2008) · Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver · doi:10.17169/refubium-17659
Logan, H. E., Byers, D. M., Ridgway, N. D., & Cook, H. W. (1998) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(98)00021-0
Genotype–Phenotype Correlations
Bird, T. D., & Davis, M. Y. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-410529-4.00002-4
Variable Clinical Presentations in a Korean Family with an Adrenoleukodystrophy
윤민정, 장윤경, 박기덕, 최지현, 최영철, 박형준, & Hyeon Jin, K. (2014) · Jouranl of Korean Association of EMG Electrodiagnostic Medicine · doi:10.18214/jkaem.2014.16.2.95
X-linked Adrenoleukodystrophy in Three Filipino Families
Chiong, M. A. D., Tan, M. A., Cruz-Rama, K. I. D., Demata, M. A., Salonga, A. M., & Lee, J. Y. (2009) · Acta Medica Philippina · doi:10.47895/amp.v43i1.2455
A Case of Adrenoleucodystrophy: Newer Challenge to Rehabilitation
Newaz, F., Jashimuddin, J., Nuery, N., & Uddin, T. (2019) · Bangladesh Medical Journal · doi:10.3329/bmj.v48i2.51294
Leon, T. A., Nelson, S. M., Gilman, A. C., Kluesner, J. K., & Williams, J. P. (2025) · Cureus · doi:10.7759/cureus.86485
James, J., Mukunda, A., Jacob, R., & George, A. M. (2025) · BMJ Case Reports · doi:10.1136/bcr-2025-265277
Preclinical gene therapy using recombinant AAV vectors in mouse models of two human diseases
Günes, Y. Ö. (2022) · theses.fr (ABES) · doi:10.70675/52c9a808z1652z42c4zae82zc812b95f1723
Molina-Blas, S., Pujalte, S. P., Álvarez, A. M., Álvarez‐Ríos, A. I., Cabello, B. M., Moreno, C. N., Gómez-Gila, A. L., Fuentes, E., Venegas-Moreno, E. M., & Delgado‐Pecellín, C. (2026) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.70269
(1996) · PubMed Central · Cited by 99 · see citing works
Incidence of X-linked adrenoleukodystrophy and the relative frequency of its phenotypes
Bezman, L., & Moser, H. W. (1998) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19980413)76:5
- Authors
- Sobue, G., Ueno‐Natsukari, I., Okamoto, H., Connell, T. A., Aizawa, I., Mizoguchi, K., Honma, M., Ishikawa, G., Mitsuma, T., & Natsukari, N.
- Affiliations
- Aichi Medical University (JP)
- Hamamatsu University (JP)
- National Institute of Health Sciences (JP)
- Corresponding author
- Natsukari, Naoki
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 1994-12
- Volume
- 36
- Issue
- 6
- Pages
- 912-915
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2066171458
- Cited by
- 56
- References
- 12
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 2 · 2020: 1 · 2019: 1 · 2018: 3 · 2017: 1 · 2016: 4 · 2015: 1 · 2014: 3 · 2013: 2
- FWCI
- 1.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- adrenoleukodystrophy, monozygotic twins, phenotypic heterogeneity, myeloneuropathy, cognitive impairment, affective symptoms, demyelination, adrenal insufficiency, non-genetic factors, genotype-phenotype correlation
- MeSH terms
- Adrenoleukodystrophy, Adult, Brain, Diseases in Twins, Humans, Magnetic Resonance Imaging, Male, Pedigree, Phenotype, Twins, Monozygotic, Genetic Heterogeneity
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
