Pathophysiology of X-linked adrenoleukodystrophy.

[adrenomyeloneuropathy]

Currently the molecular basis for the clinical heterogeneity of X-linked adrenoleukodystrophy (X-ALD ) is poorly understood . The genetic bases for all different phenotypic variants of X-ALD are mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC ) transporter , ABCD 1 (formerly adrenoleukodystrophy protein , ALDP ). ABCD 1 transports CoA-activated very long -chain fatty acids from the cytosol into the peroxisome for degradation . The phenotypic variability is remarkable ranging from cerebral inflammatory demyelination of childhood onset , leading to death within a few years , to adults remaining pre-symptomatic through more than five decades . There is no general genotype-phenotype correlation in X-ALD . The default manifestation of mutations in ABCD 1 is adrenomyeloneuropathy , a slowly progressive dying-back axonopathy affecting both ascending and descending spinal cord tracts as well as in some cases , a peripheral neuropathy . In about 60 % of male X-ALD patients , either in childhood (35 -40 %) or in adulthood (20 %), an initial , clinically silent , myelin destabilization results in conversion to a devastating , rapidly progressive form of cerebral inflammatory demyelination . Here , ABCD 1 remains a susceptibility gene , necessary but not sufficient for inflammatory demyelination to occur . Although the accumulation of very long -chain fatty acids appears to be essential for the pathomechanism of all phenotypes , the molecular mechanisms underlying these phenotypes are fundamentally different . Cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axon-glial interactions seem pertinent to the dying-back axonopathy . Various dynamic mechanisms may underlie the initiation of inflammation , the altered immune reactivity , the propagation of inflammation , as well as the mechanisms leading to the arrest of inflammation after hematopoietic stem cell transplantation . An improved understanding of the molecular mechanisms involved in these events is required for the development of urgently needed therapeutics .

Diseases
Validation

Diseases presenting "necessary but not sufficient for inflammatory demyelination to occur" symptom

adrenomyeloneuropathy

x-linked adrenoleukodystrophy

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