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cerebral adrenoleukodystrophy

Young boy sitting on a bench through playground equipmentCerebral adrenoleukodystrophy (CALD) is the most severe manifestation of adrenoleukodystrophy (ALD), a rare, X-linked, metabolic disorder. Approximately 35-40% of boys diagnosed with ALD will progress to CALD, typically between the ages of 3 and 12 years. CALD is characterized by a rapidly progressive neurologic decline leading to severe loss of neurologic function and death, in most untreated patients.

What are the symptoms?

Symptoms of CALD usually occur in early childhood. Initial symptoms include learning disabilities and behavioral problems, often misdiagnosed as attention-deficit/hyperactivity disorder (ADHD). For many boys, adrenal insufficiency is the first detected symptom, preceding the onset of neurologic symptoms by years or even decades.1 As the disease progresses, boys develop loss of vision and blindness, deafness, seizures, and loss of brain and muscle tissue.2 If left untreated, CALD can progress rapidly, leading to severe loss of neurologic function, and eventual death, in most patients.3 The early stages of CALD can be detected by brain MRI in boys with known ALD, even when they don’t have any noticeable symptoms.4

What causes it?

ALD is caused by mutations in the ABCD1 gene that affect the production of adrenoleukodystrophy protein (ALDP) and subsequently cause toxic accumulation of very long-chain fatty acids (VLCFAs) in the adrenal cortex and white matter of the brain and spinal cord. In CALD, accumulation of these fatty acids leads to the progressive destruction of myelin, the protective sheath of the nerve cells in the brain that are responsible for thinking and muscle control.5 6

How is it diagnosed?

In boys, ALD may be suspected due to any of the following: family history, newborn screening results, adrenal insufficiency of unknown cause, or unexplained progressive cognitive decline or behavioral problems. If ALD is suspected, the diagnosis can be made by measuring blood plasma levels of VLCFA, and confirmed by molecular testing of the ABCD1 gene. Molecular testing can also be used to provide  genetic counseling to family members and for prenatal diagnosis. 
 
ALD was added to the Recommended Uniform Screening Panel (RUSP) in the United States in February 2016.7 8 While newborn screening for ALD is implemented in a limited number of states, more states are set to become activated in the future, and there are ongoing pilot newborn screening programs elsewhere in the world.9 
 
Currently, there is no way to predict which boys with ALD will develop CALD. Therefore, in order to detect early signs of brain involvement, it is recommended that all boys diagnosed with ALD have annual MRI monitoring until the age of 3, every 6 months between the ages of 3 and 12, and annually thereafter.10 Since newborn screening detects ALD at birth, it allows boys at risk for CALD to be monitored and identified prior to the onset of symptoms.

What is the individual impact?

CALD is a devastating condition for affected boys and their families, with a profound symptom burden and rapid decline in neurologic function without treatment. CALD is associated with six major functional disabilities which severely compromise a patient’s ability to function independently: loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, and complete loss of voluntary movement.11 12

How common is ALD and CALD?

The worldwide incidence of ALD is approximately 1 in 17,000 newborns (both male and female), and approximately 1 in 21,000 newborn males.13

 

CALD develops in approximately 35-40% of affected boys and in a smaller number of adult men.14

 

Find out more

You can find more information about ALD by visiting patient resources.

1Laureti S, Casucci G, Santeusanio F, Angeletti G, Aubourg P, Brunetti P. X-linked adrenoleukodystrophy is a frequent cause of idiopathic Addison's disease in young adult male patients. J Clin Endocrinol Metab. 1996;81(2):470-474. https://www.ncbi.nlm.nih.gov/pubmed/8636252. Accessed March 2019. 2Engelen M, Kemp S, de Visser M, et al. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012;7:51. https://www.ncbi.nlm.nih.gov/pubmed/22889154. Accessed March 2019. 3bluebird bio. bluebird bio Presents Updated Data from Phase 2/3 Starbeam Study of Investigational Lenti-D™ Gene Therapy for CALD and Initial Data from Observational Study ALD-103 of Allogeneic Hematopoietic Stem Cell Transplant in CALD at 2018 SSIEM. http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-presents-updated-data-phase-23-starbeam-study. Published September 5, 2018. Accessed March 2019. 4Engelen M, Kemp S, de Visser M, et al. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012;7:51. https://www.ncbi.nlm.nih.gov/pubmed/22889154. Accessed March 2019. 5Powers JM, Liu Y, Moser AB, Moser HW. The inflammatory myelinopathy of adreno-leukodystrophy: cells, effector molecules, and pathogenetic implications. J Neuropathol Exp Neurol. 1992;51(6):630-643. https://www.ncbi.nlm.nih.gov/pubmed/1362438. Accessed March 2019. 6Mahmood A, Raymond GV, Dubey P, Peters C, Moser HW. Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol. 2007;6(8):687-692. https://www.ncbi.nlm.nih.gov/pubmed/17618834. Accessed March 2019. 7Kemp S, Huffnagel IC, Linthorst GE, et al. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016;12(10):606-615. https://www.ncbi.nlm.nih.gov/pubmed/27312864. Accessed March 2019. 8Kemper AR, et al. Newborn screening for X-linked adrenoleukodystrophy: evidence summary and advisory committee recommendation. Genet Med. 2016;19(1):121-126. https://www.ncbi.nlm.nih.gov/pubmed/27337030. Accessed March 2019. 9Kemp S, Huffnagel IC, Linthorst GE, et al. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016;12(10):606-615. https://www.ncbi.nlm.nih.gov/pubmed/27312864. Accessed March 2019. 10Engelen M, Kemp S, de Visser M, et al. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012;7:51. https://www.ncbi.nlm.nih.gov/pubmed/22889154. Accessed March 2019. 11Engelen M, Kemp S, de Visser M, et al. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012;7:51. https://www.ncbi.nlm.nih.gov/pubmed/22889154. Accessed March 2019. 12Miller W. Stem cell-transplantation therapy for adrenoleukodystrophy: current perspectives. Journal of Neurorestoratology. 2017;5:5-19. https://www.dovepress.com/stem-cell-transplantation-therapy-for-adrenoleukodystrophy-current-per-peer-reviewed-article-JN. Accessed March 2019. 13Bezman L, et al. Adrenoleukodystrophy: Incidence, new mutation rate, and results of extended family screening. Ann Neurol. 2001;49:512–517. https://www.researchgate.net/publication/227799607. Accessed March 2019. 14Moser HW, et al. X-linked adrenoleukodystrophy. Nat Clin Pract Neurol. 2007;3(3):140-51. https://www.ncbi.nlm.nih.gov/pubmed/17342190. Accessed March 2019.