Biochemical defect
The biochemical defect in ALD
By the early 1970s, there were twelve fully documented clinical reports describing boys with adrenocortical atrophy and diffuse cerebral sclerosis combined with strong evidence of X-linked inheritance. Biochemical analysis of the brain at autopsy provided the first clue to an underlying metabolic cause.
In 1973, Powers and Schaumburg demonstrated unusual striations in the inner adrenocortical cells, which were shown by electron microscopy to consist of intracytoplasmic lamellae and lamellar lipid inclusions (Figure). These lipid inclusions were also found in cells of the central nervous system (brain and spinal cord) and in testicular cells from patients with ALD.
Subsequent biochemical analysis of these lipid inclusions revealed that they contained cholesterol, phospholipids, and gangliosides esterified with saturated very long-chain fatty acids (VLCFA) (Igarashi 1976). These findings defined ALD as a lipid storage disease and led to the hypothesis that aberrant metabolism of VLCFA is the key factor in the pathogenesis of ALD.
A few years later, this hypothesis was confirmed with the demonstration that oxidation of VLCFA is reduced in fibroblasts from ALD patients Singh et al 1981, whereas oxidation of radiolabeled long-chain fatty acids was completely normal in ALD cells. While long-chain fatty acids are metabolized in mitochondria, beta-oxidation of VLCFA occurs exclusively in peroxisomes and not in mitochondria (Kemp 2004).
The discovery that VLCFA (especially C26:0) are also elevated in readily accessible materials such as blood cells and plasma from ALD patients has been crucial to the diagnosis of ALD (Moser 1981). This finding allowed the unambiguous identification of male patients. Today, plasma VLCFA analysis is still the best initial biomarker for the diagnosis of ALD (but only in males!).
Females with ALD often have elevated plasma VLCFA levels. However, it should be emphasized that studies in women with ALD have shown false negative results in about 10 to 15% of cases. Thus, a normal plasma VLCFA level does not exclude the diagnosis of ALD.
In 2005, it was shown that brain VLCFA levels in normal-appearing white matter (unaffected brain tissue) correlate with the clinical phenotype (Asheuer 2005). Compared to age-matched controls, C26:0 levels were elevated 3-fold in patients with cerebral ALD, and 1.9-fold in patients with spinal cord disease (AMN).
Toxicity of VLCFA
VLCFA are extremely hydrophobic and have different physiological properties than long-chain fatty acids. The rate of desorption from biological membranes decreases exponentially with increasing chain length. The desorption of C26:0 from a lipid membrane is 10,000 times slower than that of C16:0 and C18:0 fatty acids (Ho et al 1995).
Incorporation of C26:0 into a model membrane disrupts the membrane structure. Too much VLCFA disrupts the normal function of the membrane and causes toxicity to adrenocortical cells, oligodendrocytes, astrocytes and neurons (Whitcomb et al 1988, Hein et al 2008). For example, VLCFA induce mitochondrial depolarization and deregulation of intracellular calcium homeostasis (Hein et al 2008). VLCFA cause oxidative damage to proteins (Fourcade et al 2008). And in the brain, excessive amounts of VLCFA can cause activation and apoptosis of microglia (Eichler et al 2008). This suggests that microglial cell death caused by toxic levels of VLCFA may be an early pathogenic change in cerebral ALD.
Last modified | 2024-06-25