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      Lysosomal Acid Lipase Deficiency — A New Therapy for a Genetic Lipid Disease

      New England Journal of Medicine

      New England Journal of Medicine (NEJM/MMS)

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          Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease.

          Cholesteryl ester storage disease (CESD) is caused by deficient lysosomal acid lipase (LAL) activity, predominantly resulting in cholesteryl ester (CE) accumulation, particularly in the liver, spleen, and macrophages throughout the body. The disease is characterized by microvesicular steatosis leading to liver failure, accelerated atherosclerosis and premature demise. Although CESD is rare, it is likely that many patients are unrecognized or misdiagnosed. Here, the findings in 135 CESD patients described in the literature are reviewed. Diagnoses were based on liver biopsies, LAL deficiency and/or LAL gene (LIPA) mutations. Hepatomegaly was present in 99.3% of patients; 74% also had splenomegaly. When reported, most patients had elevated serum total cholesterol, LDL-cholesterol, triglycerides, and transaminases (AST, ALT, or both), while HDL-cholesterol was decreased. All 112 liver biopsied patients had the characteristic pathology, which is progressive, and includes microvesicular steatosis, which leads to fibrosis, micronodular cirrhosis, and ultimately to liver failure. Pathognomonic birefringent CE crystals or their remnant clefts were observed in hepatic cells. Extrahepatic manifestations included portal hypertension, esophageal varices, and accelerated atherosclerosis. Liver failure in 17 reported patients resulted in liver transplantation and/or death. Genotyping identified 31 LIPA mutations in 55 patients; 61% of mutations were the common exon 8 splice-junction mutation (E8SJM(-1G>A)), for which 18 patients were homozygous. Genotype/phenotype correlations were limited; however, E8SJM(-1G>A) homozygotes typically had early-onset, slowly progressive disease. Supportive treatment included cholestyramine, statins, and, ultimately, liver transplantation. Recombinant LAL replacement was shown to be effective in animal models, and recently, a phase I/II clinical trial demonstrated its safety and indicated its potential metabolic efficacy. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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            Enzyme replacement therapy for lysosomal diseases: lessons from 20 years of experience and remaining challenges.

            In 1964, Christian de Duve first suggested that enzyme replacement might prove therapeutic for lysosomal storage diseases (LSDs). Early efforts identified the major obstacles, including the inability to produce large quantities of the normal enzymes, the lack of animal models for proof-of-concept studies, and the potentially harmful immune responses to the "foreign" normal enzymes. Subsequently, the identification of receptor-mediated targeting of lysosomal enzymes, the cloning and overexpression of human lysosomal genes, and the generation of murine models markedly facilitated the development of enzyme replacement therapy (ERT). However, ERT did not become a reality until the early 1990s, when its safety and effectiveness were demonstrated for the treatment of type 1 Gaucher disease. Today, ERT is approved for six LSDs, and clinical trials with recombinant human enzymes are ongoing in several others. Here, we review the lessons learned from 20 years of experience, with an emphasis on the general principles for effective ERT and the remaining challenges.
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              Lysosomal acid lipase deficiency--an under-recognized cause of dyslipidaemia and liver dysfunction.

              Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. The age at onset and rate of progression vary greatly and this may relate to the nature of the underlying mutations. Patients presenting in infancy have the most rapidly progressive disease, developing signs and symptoms in the first weeks of life and rarely surviving beyond 6 months of age. Children and adults typically present with some combination of dyslipidaemia, hepatomegaly, elevated transaminases, and microvesicular hepatosteatosis on biopsy. Liver damage with progression to fibrosis, cirrhosis and liver failure occurs in a large proportion of patients. Elevated low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels are common features, and cardiovascular disease may manifest as early as childhood. Given that these clinical manifestations are shared with other cardiovascular, liver and metabolic diseases, it is not surprising that LAL-D is under-recognized in clinical practice. This article provides practical guidance to lipidologists, endocrinologists, cardiologists and hepatologists on how to recognize individuals with this life-limiting disease. A diagnostic algorithm is proposed with a view to achieving definitive diagnosis using a recently developed blood test for lysosomal acid lipase. Finally, current management options are reviewed in light of the ongoing development of enzyme replacement therapy with sebelipase alfa (Synageva BioPharma Corp., Lexington, MA, USA), a recombinant human lysosomal acid lipase enzyme.
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                Author and article information

                Journal
                New England Journal of Medicine
                N Engl J Med
                New England Journal of Medicine (NEJM/MMS)
                0028-4793
                1533-4406
                September 10 2015
                September 10 2015
                : 373
                : 11
                : 1071-1073
                10.1056/NEJMe1509055
                © 2015
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