Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history.
X-Linked adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder with a highly complex clinical presentation. ALD is caused by mutations in the ABCD1 gene, which leads to the accumulation of very long-chain fatty acids in plasma and tissues. Virtually all men with ALD develop adrenal insufficiency and myelopathy. Approximately 60% of men develop progressive cerebral white matter lesions (known as cerebral ALD). However, one cannot identify these individuals until the early changes are seen using brain imaging. Women with ALD also develop myelopathy, but generally at a later age than men and adrenal insufficiency or cerebral ALD are very rare. Owing to the multisystem symptomatology of the disease, patients can be assessed by the paediatrician, general practitioner, endocrinologist or a neurologist. This Review describes current knowledge on the clinical presentation, diagnosis and treatment of ALD, and highlights gaps in our knowledge of the natural history of the disease owing to an absence of large-scale prospective cohort studies. Such studies are necessary for the identification of new prognostic biomarkers to improve care for patients with ALD, which is particularly relevant now that newborn screening for ALD is being introduced.
Department of Pediatrics, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.|Genetic Metabolic Diseases, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Stephan
S
Kemp
Department of Pediatrics, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.|Pediatric Neurology, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Irene C
IC
Huffnagel
Endocrinology and Metabolism, Academisch Medisch Centrum, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Gabor E
GE
Linthorst
Department of Pediatrics, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.|Genetic Metabolic Diseases, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Ronald J
RJ
Wanders
Department of Pediatrics, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.|Pediatric Neurology, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Marc
M
Engelen
D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000309:Adrenal Insufficiency / Q000378:metabolism; D000326:Adrenoleukodystrophy / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging; D018450:Disease Progression; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D020249:Hormone Replacement Therapy; D006801:Humans; D056784:Leukoencephalopathies / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D010523:Peripheral Nervous System Diseases / Q000378:metabolism; D013118:Spinal Cord Diseases / Q000378:metabolism
C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D005227:Fatty Acids; D005938:Glucocorticoids