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.

Pompe disease: dramatic improvement in gastrointestinal function following enzyme replacement therapy. A report of three later-onset patients.

Pompe disease is a lysosomal storage disease due to deficient acid α-glucosidase (GAA) activity. Infants with the classic infantile-onset subtype present with severe hypotonia and cardiomegaly, and most expire in the first year of life, whereas the severity of the muscle-based manifestations in patients with the late infantile/juvenile and adult-onset subtypes depends on the level of GAA residual enzymatic activity. The clinical features of later-onset Pompe disease are still emerging, and even the natural history and progression of muscle weakness and respiratory failure, hallmarks of the later-onset subtypes, are not well documented. For example, we report here three later-onset patients who had chronic diarrhea, postprandial bloating and abdominal pain, previously unrecognized manifestations of later-onset Pompe disease. Two patients had intestinal incontinence and one reported synchronous vomiting and diarrhea on a daily basis. These symptoms significantly interfered with their quality of life, often limiting their ability to leave home. All gastrointestinal symptoms resolved within the first six months of enzyme replacement therapy (ERT) with recombinant human alglucosidase alpha (rhGAA). All three patients gained weight and remain symptom free, two for over four years. Thus, gastrointestinal symptoms occur in later-onset patients with Pompe disease and are resolved with ERT.