However, some patients present atypical CDS features, with myopathy and cardiomyopathy but without ichthyosis and mutation in ABHD5. This phenotype was called NLSDM and further facilitated the discovery of new causative gene, patatin-like phospholipase domain containing 2 (PNPLA2), encoding ATGL (37). So far, the AMD3100 ic50 mutations in ABHD5 Inhibitors,research,lifescience,medical have been reported to cause protein truncations but not absence, suggesting that the mutant protein is not completely deficient but functionally impaired (33). In NLSDM, almost all mutations in PNPLA2 are located on C-terminal region, preserving the proposed

active site of the enzyme. These truncated enzyme Inhibitors,research,lifescience,medical variants have later been shown impaired in their ability to bind to cellular lipid droplets in vitro (38). NLSD is characterized by systemic TG deposition in multiple tissues, including skin, muscle, liver, central nervous

system, and blood leukocytes. Clinically, it is often present with ichthyosis, mild myopathy, hepatomegaly and, variably, ophthalmologic symptoms, neurosensory hearing loss, mental retardation and short stature (39-41). In NLSDI, the ichthyosis represents nonbullous congenital ichthyosiform erythroderma and the weakness is usually mild and predominant proximal. However, in NLSDM, no ichthyosis is observed and the slowly progressive muscle involvement Inhibitors,research,lifescience,medical could be in both proximal and distal limbs, with a predominant distal weakness in some patients. Importantly, the cardiomyopathy is exclusively seen in almost half of the patients with NLSDM (41), but not NLSDI while neurosensory defects and mental retardation are commonly seen in NLSDI but not NLSDM. Inhibitors,research,lifescience,medical CK level is usually mildly to moderately elevated. The detection Inhibitors,research,lifescience,medical of lipid accumulation in leukocytes, muscle fibers and fibroblasts is critical for the diagnosis of NLSD as the clinical manifestations of NLSD are inconstant and the biochemical investigations

for lipid dysmetabolism usually do not show any abnormality. The intracytoplasmic lipid storage in leukocytes is visible on peripheral blood smear, which is called Jordan’s anomaly. In skeletal muscles, increased lipid droplets could be observed even in presymptomatic period. Noteworthily, rimmed vacuoles in the muscles were reported in some NLSDM patients (Fig. 2D) (42, 43), suggesting a different pathomechanism from other LSMs, either which might be associated with membrane phospholipid abnormalities caused by decreased DG availability. So far, there is still no effective treatment in NLSD. The functions of ATGL and CGI-58 are still largely unknown. However, the production of the mice lacking ATGL has provided an opportunity to prompt the understanding of NSLDM (44), though unfortunately, the phenotype of CGI-58-deficient mice has not been reported yet.