Neutral lipid storage disease
Neutral lipid storage disease is a congenital autosomal recessive disorder characterized by accumulation of triglycerides in the cytoplasm of leukocytes, muscle, liver, fibroblasts, and other tissues. It commonly occurs as one of two subtypes, cardiomyopathic neutral lipid storage disease, or ichthyotic neutral lipid storage disease, which are characterized primarily by myopathy and ichthyosis, respectively. Normally, the ichthyosis that is present is typically non-bullous congenital ichthyosiform erythroderma which appears as white scaling.
It has been associated genetically with mutations in the CGI-58 gene or the ATGL/''PNPLA2'' gene.
Cause
Neutral lipid storage disease is caused by the abnormal and excessive accumulation of lipids in certain bodily tissues, including the liver, the heart, and muscle. Normally, these lipids are stored as lipid droplets and are normally used for metabolism, cell signaling and trafficking of vesicles. Neutral lipid storage disease is a disease that is diagnosed with the simultaneous occurrence of myopathy and/or ichthyosis. Myopathy is defined as a disease of the muscle tissue. Ichthyosis is a skin related disease in which the skin becomes very scaly, thick, and dry.Genetics
Neutral lipid storage disease occurs in one of two genetic and clinical subtypes. Both subtypes are autosomal recessive disorders, meaning that a mutant allele must be inherited from both parents in order to cause disease.Subtype I: Neutral Lipid Storage Disease with Myopathy, is caused by a mutation in the PNPLA2 gene, which reduces the normal expression or function of the ATGL protein. PNPLA2 is located on chromosome 11. ATGL is an enzyme involved in catabolism of triglycerides into fatty acids within the body In the absence of fully functional ATGL, triglycerides accumulate in the bloodstream and bodily tissues. Interestingly, individuals with NLSD are not typically obese. It has been proposed that the assimilation, rather than degradation of triglycerides is the main factor in fat accumulation in adipose cells. In the absence of functional ATGL, triglycerides accumulate in the bloodstream and bodily tissues. Patients with NLSD-M display progressive skeletal myopathy and severe cardiomyopathy in ~40% of cases. The pathophysiology and mechanistic basis of myopathy arising from deficits in lipid metabolism is not yet known.
Subtype II: Neutral Lipid Storage Disease with Ichthyosis, or Chanarin-Dorfman syndrome, is caused by a mutation in the CGI-58 protein. CGI-58 is a coactivator of ATGL, and together these proteins sustain blood lipid levels between meals. Disruption of CGI-58 gives rise to the symptoms of ichthyosis, a dermatological condition in which skin becomes very scaly, thick and dry.
Ichthyosis is an inherited disorder, like NLSD, and has been found to be genetically linked in some situations with the PNPLA2 gene. Therefore, sometimes when there is a mutation in the PNPLA2 gene, the linked allele of CG-58 is mutated as well. This specific gene, however, does not produce ichthyosis on its own. Ichthyosis can be diagnosed individually in a patient and the genetic cause for unlinked ichthyosis is different from the gene linked with PNPLA2. Keep in mind these disorders may occur individually within a patient as well.
Pathophysiology
The functional changes that occur with this disease are mostly metabolic. Accumulation of triglycerides in the body without an efficient mode for catabolism is thought to lead to the eventual symptoms of this disease. Upon digestion and absorption of fat by the small intestine, triglycerides are combined with vitamins and cholesterol to form chylomicrons. Chylomicrons travel from the intestine into the lymph system before entering the bloodstream. Enzymatic catalysis of chylomicrons by lipases in the bloodstream enables the uptake of lipids and fatty acids by cells. In individuals with NLSD, their triglycerides are not catabolized in the blood, and cells accumulate partially processed lipid droplets over time, which may lead to dysfunction in absorbing tissues. In affected individuals, muscle cells, fibroblasts, and leukocytes appear to be prone to the excessive accumulation of triglycerides as lipid droplets. Excessive accumulation of lipids in tissues not designed for long-term storage may underlie the clinical manifestations of weakened skeletal and cardiac muscle, fatty liver, pancreatitis, hypothyroidism, and type 2 diabetes.Diagnosis
Main physical signs include a fatty liver, a weakened and enlarged heart, inflammation of the pancreas, reduced thyroid activity, type 2 diabetes, abnormal levels of creatine kinase in blood, and increased weakness of proximal muscles due to fatty replacement of skeletal muscle fibers. Accurate diagnosis is complicated by symptomatic overlap with other disorders. One of the earliest symptoms to manifest clinically is peripheral limb weakness, which becomes progressively more severe over time. Specifically, asymmetric right shoulder weakness is an idiosyncratic hallmark of NLSD enabling it to be distinguished from myopathies arising from alternative muscular disorders.NLSD is often diagnosed by the presence of lipid inclusions within leukocytes, which can be detected using histology and electron microscopy.
Classically, NLSD is associated with myopathy and can, in some cases, be linked with ichthyosis. Therefore, with these symptoms or diagnosis, it is likely that the patient could and would be diagnosed with NLSD.
Although lipid accumulation is most prominent in myocytes, hepatocytes, and granulocytes, other tissues displayed elevated deposits as well. For the purpose of diagnosis, MRIs have been used to identify large fat deposits within muscle tissue.
People can live with NLSD, but there can be complications due to the effects this disease has on other major parts of the body like the liver, the heart, and skeletal muscle, although myopathy won't necessarily show up until a patient is in the third decade of their life, a child born with ichthyosis, is immediately evaluated for NLSD, in which it is detected very early on. Also, the earlier that NLSD can be detected and symptoms treated, the better quality of life the patient can have.