Esterified cholesterol and triglycerides are degraded by lysosomal acid lipase in lysosomes. The resulting non- esterified cholesterol can be used as a substrate for steroidogenesis. Lysosomal acid lipase (LAL) deficiency caused by biallelic genetic alterations in the gene LIPA leads to the accumulation of esterified cholesterol and triglycerides in the lysosomes. The deficiency of intracellular cholesterol can lead to impaired steroidogenesis affecting glucocorticoid and mineralocorticoid production. A wide range of phenotypes are seen in LAL deficiency. The infantile onset form known as Wolman disease is characterized by malabsorption, hepatomegaly, and ad renal insufficiency. The later onset forms collectively known as cholesteryl ester storage disease (CESD) may present in childhood in a similar manner to Wolman disease or in later life with lipid abnormalities, hepatosplenomegaly, and elevated liver enzymes. Adrenal insufficiency can occasionally be seen in CESD.
Peroxisomes are found in virtually all eukaryotic cells. Their principal function is the β- oxidation of very long chain fatty acids (VLCFAs), amino acids, and uric acid. They are also important in producing cholesterol and plasmalogens, a distinct class of glycerophospholipids. Disruption of peroxisome function results in adrenal insufficiency, ostensibly as a result of the accumulation of VLCFAs initiating apoptotic mechanisms and resulting in the generation of reactive oxidative species.
X- linked adrenoleukodystrophy (ALD), caused by alterations in the gene ABCD1 which mediates transport of VLCFA across the peroxisome membrane, manifests as a spectrum of different phenotypes affecting the adrenal gland and the nervous system. There are three main patterns of involvement seen in affected males. In the childhood cerebral form, inflammatory cerebral demyelination often presents with mild learning disability or behavioural problems that are progressive. In the adrenomyeloneuropathy form loss of axons and demyelination in the gracile and corticospinal tracts leads to progressive spasticity and leg weakness presenting in adult hood. In both of these forms of X- linked ALD, affected individuals generally have adrenocortical dysfunction by the time their neuro logical problems are apparent. The third common presentation of X- linked ALD is isolated adrenal insufficiency, which can present in childhood or adulthood. A significant proportion of heterozygote females manifest adrenomyeloneuropathy symptoms, but adrenal function appears to be preserved. There is no correlation between the molecular insult in the ABCD1 gene and the age of onset or severity of the resulting phenotype. The most common disease- causing alteration in ABCD1 is c.1415_ 1416delAG, which leads to a frameshift and premature truncation of the resultant protein.
Zellweger spectrum disorder (ZSD) caused by mutations in the PEX genes leads to a range of phenotypes. The PEX genes encode peroxin proteins required for the assembly and maintenance of peroxisome membranes and the import of peroxisome matrix proteins. In severe disease infants are born with congenital mal formations, make poor developmental progress, and typically die in the first year of life. In milder disease progressive peroxisome dysfunction leads to retinal dystrophy, sensorineural hearing loss, neurological deficits, liver dysfunction, and renal oxalate stones. There is a high prevalence of adrenal insufficiency in ZSD. The majority of cases of ZSD are related to alterations in PEX1. Two common variants in PEX1 have been identified p.Ile700TyrfsTer42 and p.Gly843Asp. These variants are found within specific haplotypes implying that they have arisen as a result of the dissemination of specific founder mutations.
