Biochemical defect

Stephan Kemp, Ph.D.

The biochemical defect in ALD

By the early 1970’s, twelve fully documented clinical reports were available describing boys with adrenocortical atrophy and diffuse cerebral sclerosis in combination with strong evidence of an X-linked recessive mode of inheritance. Biochemical analysis of the brain at autopsy revealed the first clue pointing towards an underlying metabolic cause.

In 1973, Powers and Schaumburg demonstrated unusual striations in the inner adrenocortical cells, which were shown to consist of intracytoplasmic lamellae and lamellar lipid inclusions by electron microscopy (Figure). These lipid inclusions were also found in cells of the central nervous system (brain and spinal cord) and testicular cells from patients with ALD.

Subsequent, biochemical analysis of these lipid inclusion bodies 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 the VLCFA is the key factor in the pathogenesis of ALD.

A few years later, this hypothesis was confirmed with the demonstration that the oxidation of VLCFA is reduced in fibroblasts from ALD patients Singh et al 1981, whereas oxidation of radiolabeled long-chain fatty acids was fully normal in ALD cells. While long-chain fatty acids are metabolized in mitochondria, the beta-oxidation of VLCFA takes place exclusively in peroxisomes and not in mitochondria (Kemp 2004).

The discovery that VLCFA (in particular C26:0) are also elevated in readily accessible materials like blood cells and plasma of ALD patients has been of crucial importance for the diagnosis of ALD (Moser 1981). This finding allowed unequivocal identification of male patients. Today, plasma VLCFA analysis is still the best initial biomarker for the diagnosis of ALD (but only in males!).

In women with ALD plasma VLCFA levels often are increased. However, it should be stressed that studies in women with ALD have shown false negative results in approximately 20% of cases. Thus, a normal plasma VLCFA level does not exclude the diagnosis ALD.

In 2005, it was demonstrated that brain VLCFA levels in normal appearing white matter (unaffected brain tissue) correlate with the clinical phenotype (Asheuer 2005). In comparison with age-matched controls, C26:0 levels were increased 3-fold in cerebral ALD patients, and 1.9-fold in AMN patients.

Toxicity of VLCFA

VLCFA are extremely hydrophobic and they 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).

The inclusion of C26:0 in a model membrane disrupts membrane structure. Too much VLCFA affects the normal function of the membrane and cause toxicity to adrenocortical cells, oligodendrocytes, astrocytes and neurons (Whitcomb et al 1988, Hein et al 2008). For example, VLCFA induce depolarization of mitochondria and deregulation of the intracellular calcium homeostasis (Hein et al 2008). VLCFA cause oxidative damage to proteins (Fourcade et al 2008). And in brain, excess amounts of VLCFA can cause activation and apoptosis of microglia (Eichler et al 2008). This indicates that cell death of microglia caused by toxic levels of VLCFA may constitute an early pathogenic change in cerebral ALD.

Last modified | 2019-04-01