Adrenoleukodystrophy and white matter at a glimpse

What is at stake?

Adrenoleukodystrophy (ALD) is a severe, progressive genetic disease affecting the adrenal glands, spinal cord and white matter of the nervous system. X-linked adrenoleukodystrophy (X-ALD), caused by mutations in the ABCD1 gene, is the most common peroxisomal disease. It is also the most common leukodystrophy in males.

This rare condition is probably poorly diagnosed, making it difficult to determine its true frequency in the general population.

Currently, the estimated incidence is around

             1/15,000 births

It is probably much more prevalent than we currently estimate. This difficulty underscores the need to develop simple, reliable diagnostic tools, and to develop effective treatments.

 

Why does white matter matter?

ALD is the most common peroxisomal disease characterized by the alteration of peroxisomal β-oxidation. This leads to the accumulation of VLCFA in plasma and tissues, such as white matter in the brain, spinal cord, adrenal glands and testicular Leydig cells. Several studies suggest or demonstrate that AGTLC has direct toxic effects on the different cell types of tissues that are altered in patients, such as oligodendrocytes that are responsible for the production of myelin in the brain.

In X-ALD, a significant reduction in microglia density would appear to precede complete degeneration of oligodendrocytes and myelin. There are no links between genotype and phenotype and plasma VLCFA levels do not predict disease progression.

 

How measuring the brain can become a game changer in treatment and drug development?

Better monitoring disease progression by analyzing and measuring the evolution of lesions in the patient’s white matter is essential for:

    • Adjusting Patient Tracking Frequency
    • Providing the right treatment at the right time to the right patient

Fanny MOCHEL, Coordinator of the Paris Rare disease center for Leukodystropies, comments: “Adrenoleukodystrophy is an orphan disease that faces many challenges, particularly in terms of diagnosis and patient management. While some significant efforts are being made by the biotech industry to develop new disease-modifying drugs, there is a strong need for relevant biomarkers and monitoring of disease evolution to enable efficient patient care“.

 

Need for biomarkers capable of early

diagnostics and monitoring brain inflammation

 

 

Need for myelin alterations follow up for disease evolution

or drug efficacy monitoring with relevant biomarkers

 

 

 

Ressources :

– https://www.crmr-leucodystrophie-paris.fr/

– https://www.youtube.com/watch?v=wsrCAIk0mqw&feature=youtu.be

– https://elainternational.eu/colloque-familles-chercheurs/

 

References:

– Aubourg P, Mosser J, Douar A.M, Sarde C.O, Lopez J, Mandel J.L. Adrenoleukodystrophy gene: unexpected homology to a protein involved in peroxisome biogenesis. Biochimie. 1993; 75 (3-4), 293-302.

– Engelen M, Kemp S, de Visser M, van Geel B, JA Wanders R, Aubourg P, Poll-The BT. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet Journal of Rare Diseases. 2012; 7:51.

– Engelen M, van Ballegoij WJC, Mallack EJ, et al. International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach. Neurology. 2022; 99(21):940-951.

– Kemp S and Wanders R. Biochemical Aspects of X-linked Adrenoleukodystrophy. Brain Pathol. 2010; 20(4): 831-837.

– Kemp S, Berger J, Aubourg P. “X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects”. Biochimica et biophysica Acta. 1822 (2012) 1465-1474.

– Manor J, Chung H, Bhagwat PK, Wangler MF. ABCD1 and X-linked adrenoleukodystrophy: A disease with a markedly variable phenotype showing conserved neurobiology in animal models. J Neurosci Res. 2021; 99(12):3170-3181.

– Moser AB, O. Jones R, C. Hubbard W, Tortorelli S, J. Orsini J, Caggana M, H. Vogel B, V. Raymond G. Newborn Screening for X-Linked Adrenoleukodystrophy. Int J Neonatal Screen. 2016; 2(4).

 

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Last update : 09/07/2024