Mitochondrial dysfunction and oxidative damage cooperatively fuel axonal degeneration in X-linked adrenoleukodystrophy.

[adrenomyeloneuropathy]

X-linked adrenoleukodystrophy (X-ALD ) is the most frequent inherited monogenic demyelinating disease (minimal incidence 1 :17 ,000 ). It is often lethal and currently lacks a satisfactory therapy . The disease is caused by loss of function of the ABCD 1 gene , a peroxisomal ATP-binding cassette transporter , resulting in the accumulation of VLCFA (very long -chain fatty acids ) in organs and plasma . Understanding of the aetiopathogenesis is a prerequisite for the development of novel therapeutic strategies . Functional genomics analysis of an ABCD 1 null mouse , a mouse model for adrenomyeloneuropathy , has revealed presymptomatic alterations in several metabolic pathways converging on redox and bioenergetic homeostasis , with failure of mitochondrial OXPHOS disruption and mitochondrial depletion . These defects could be major contributors to the neurodegenerative cascade , as has been reported in several neurodegenerative disorders . Drugs targeting the redox imbalance /mitochondria dysfunction interplay have shown efficacy at halting axonal degeneration and associated disability in the mouse , and thus offer therapeutic hope .

Diseases
Validation

Diseases presenting "loss of function" symptom

adrenomyeloneuropathy

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

congenital adrenal hyperplasia

cystinuria

familial hypocalciuric hypercalcemia

gm1 gangliosidosis

harlequin ichthyosis

hirschsprung disease

holt-oram syndrome

kabuki syndrome

kallmann syndrome

krabbe disease

lamellar ichthyosis

papillon-lefèvre syndrome

pendred syndrome

triple a syndrome

trochlear dysplasia

x-linked adrenoleukodystrophy

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