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Neutral lipid storage disease



Neutral lipid storage disease (NLSD) is a group of autosomal recessive disorders characterized by the excessive accumulation of neutral lipids in multiple tissues. Recently, two genes, adipose triglyceride lipase (ATGL/PNPLA2) and CGI-58/ABHD5, have been shown to cause NLSD.

ATGL specifically hydrolyzes the first fatty acid from triacylglycerols (TG) and CGI-58/ABHD5 stimulates ATGL activity by a currently unknown mechanism. Mutations in both the ATGL and the CGI-58 gene are associated with systemic TG accumulation. Yet, the resulting clinical manifestations are not identical. Patients with defective ATGL function suffer from more severe myopathy (NLSDM) than patients with defective CGI-58 function. On the other hand, CGI-58 mutations are always associated with ichthyosis (NLSDI), which was not observed in patients with defective ATGL function. These observations indicate an ATGL-independent function of CGI-58. This review summarizes recent findings with the goal of relating structural variants of ATGL and CGI-58 to functional consequences in lipid metabolism.

Neutral lipid storage disease with ichthyosis

Neutral lipid storage disease (NLSD) is a rare non-lysosomal, autosomal recessive lipid storage disorder characterized by systemic triacylglycerol (TG) deposition in multiple tissues including skin, muscle, liver, central nervous system, and blood leukocytes. One of the diagnostic characteristics of NLSD, the lipid containing vacuoles in leukocytes, was originally observed by Jordans  in two brothers suffering from muscular dystrophy and subsequently the condition was named Jordans’ anomaly. In 1966, Rozenszajn described two sisters exhibiting the clinical manifestation of neutral lipid containing vacuoles in leukocytes combined with severe ichthyosis. In the 1970s, Dorfman and Chanarin et  reported additional cases of NLSD with ichthyosis and lipid accumulation in leukocytes,gastrointestinal epithelium, bone marrow, cultured fibroblasts, liver, and striated muscle.

More variable clinical features included liver steatosis, hepatosplenomegaly, skeletal- and cardiomyopathy, double-sided cataracts, growth retardation, ataxia, bilateral sensorineural hearing loss, horizontal nystagmus, and/or mental retardation (7;12;45). In recognition of these early works, NLSD with ichthyosis was subsequently named Chanarin-Dorfman-Syndrome (CDS).

The specific form of ichthyosis associated with CDS represents non-bullous congenital ichthyosiform erythroderma and is characterized by a pronounced defect in the permeability barrier function of the skin . The condition is thought to result from the excessive incorporation of non-polar lipids into the lamellar membrane. As a consequence, lipid microinclusions form a non-lamellar phase within the stratum corneum interstices, impairing the barrier function (10;13).

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