Neutral lipid storage disease with myopathy (ORPHA:98908)
A form of neutral lipid storage disease characterized by adult onset of slowly progressive muscular weakness of the limbs and axial muscles, and accumulation of lipid droplets in the muscles and leukocytes.
Epidemiology
Prevalence and incidence of Neutral Lipid Storage Disease with Myopathy (NLSD-M) are unknown. About 100 cases have been described in the literature, with about 30 different gene mutations. The disease is diffuse worldwide, with more reported cases in Italy, China and Japan. It is thought that the disease, due to lack of knowledge, may be underdiagnosed.
Clinical description
The expression of phenotype is highly variable, from very mild to severe disease. Generally, the disease starts in young-adult age with an asymmetrical weakness and atrophy of proximal muscle of a limb which frequently involves cervical and lumbar muscles, and finally, the distal muscles of limbs. Generally, bulbar and respiratory muscles are spared. Some patients are wheelchair confined. Cardiomyopathy is developed by a little less than 50% of patients in the later disease course. Additional, less frequent, variable manifestations include triglycerides infiltration of liver, thyroid, pancreas and kidney. Serum creatine kinase is always elevated.
Etiology
The pathophysiology of the disease is largely unclear and phenotype-genotype correlations remain incomplete. The disease is associated with mutations of the PNPLA2 gene. PNPLA2 gene encode for ATGL, a lipase that is a lipid droplet-associated protein and catalyzes the first step in the hydrolysis of triacylglycerols. The mutations in both alleles of the PNPLA2 gene cause the production of a defective protein. The detachment of fatty acids from triglycerides is compromised, therefore triglycerides accumulate in lipid droplets within the cytoplasm of cells. There is evidence of altered mitochondrial metabolism, likely a consequence of the low availability of fatty acids. However, many unresolved issues remain, such as muscle fiber damage resulting in muscle atrophy.
Diagnostic methods
The diagnosis is suspected when a patient presents hyperckemia and limb weakness. Peripheral blood smear reveals triacylglycerol-containing lipid droplets in leukocytes (Jordan's anomaly), a very sensitive diagnostic marker present in 100% of patients. Muscle biopsy reveals a massive accumulation of lipid droplets. The diagnosis is then confirmed by genetic testing.
Differential diagnosis
Based on the clinical phenotype, many hereditary and acquired myopathies can be differentially diagnosed with NLSD-M. Furthermore, from a histological point of view, all myopathies with lipid accumulation, such as multiple acyl-CoA dehydrogenase deficiency or primary carnitine deficiency, can constitute a diagnostic alternative.
Antenatal diagnosis
The disease is very rare and the mode of transmission is recessive, so prenatal screening is not required except in the cases of consanguinity of parents with a family history of NLSD-M.
Genetic counseling
Genetic counseling could be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. There is no genotype-phenotype correlation; therefore, it is impossible to predict the expression of the genetic mutation in a child of a carrier couple.
Management and treatment
There is no specific therapy. Supportive therapies can improve cardiomyopathy and generally the consequences of damage to internal organs. Some cases required implantation of cardiac devices. Strength training or aerobic exercise programs, or both, might optimize muscle and cardiorespiratory function and prevent additional disuse atrophy and deconditioning.
Prognosis
Quality of life is mainly influenced by motor disability. There are no studies on the life expectancy of people affected by this disease.

                            Last update: 
                            January 2024


                            - Expert reviewer(s): 
                            Pr Enrico BERTINI | EURO-NMD* - Dr Elena PENNISI 


                                * European Reference Network