Wolman disease
Wolman disease is a rare autosomal recessive disorder caused by a deficiency of the enzyme lysosomal acid lipase (LAL). This deficiency leads to the accumulation of cholesteryl esters and triglycerides in various organs, resulting in severe multisystem organ damage and typically early death, often within the first year of life if untreated. The condition is linked to mutations in the LIPA gene, located on chromosome 10, which is essential for the proper breakdown of these lipids. Symptoms usually appear in infancy and may include excessive vomiting, diarrhea, hepatosplenomegaly (enlarged liver and spleen), anemia, and adrenal calcifications observable via imaging.
While Wolman disease progresses rapidly, a related and milder condition known as cholesteryl ester storage disease (CESD) exhibits a more variable presentation and can allow affected individuals to live into adulthood. Diagnosis of Wolman disease can involve assays of LAL enzyme activity from various tissue samples, including blood, with genetic testing confirming mutations in the LIPA gene. Treatment options include hematopoietic stem cell transplantation (HSCT), which can restore normal enzyme function, as well as enzyme replacement therapies like sebelipase alfa. Without intervention, the prognosis for Wolman disease is poor, whereas individuals with CESD may have a normal life span with appropriate management. Genetic counseling is recommended for families with a history of the disorder.
Wolman disease
ALSO KNOWN AS: Lysosomal acid lipase deficiency; acid lipase deficiency; cholesteryl ester storage disease; familial xanthomatosis; LAL deficiency; LIPA deficiency
DEFINITION Wolman disease is a rare, autosomal recessive disorder caused by deficiency of the enzyme lysosomal acid lipase (LAL). Insufficiency of this enzyme causes accumulation of cholesteryl esters and triglycerides throughout the body, resulting in multisystem organ damage and death.
Risk Factors
Individuals with mutations in both copies of the LIPA gene are at risk for either Wolman disease or a milder condition known as cholesteryl ester storage disease (CESD). Full siblings of affected individuals have a 25 percent risk of inheriting the disorder. Males and females are affected with equal frequency. Cases have been reported in a variety of different ethnic groups; given the rarity of the condition, it is difficult to ascertain whether a higher prevalence truly exists among any particular group.
Etiology and Genetics
Located on chromosome 10q23.2q23.3, the LIPA gene produces the LAL enzyme, which is involved in the breakdown of cholesteryl esters and triglycerides within the lysosomes of the cell. This process is part of a tightly regulated system allowing the body to use these and other lipids (fats) appropriately, then recycle or dispose of them as needed.
Deficient LAL activity prevents the breakdown of cholesteryl esters and triglycerides; the effects of their subsequent accumulation within the lysosomes disrupt lipid processing throughout the body. The lysosomes become engorged, ultimately destroying the cell and eventually impairing the function of involved organs, such as the liver.
Mutations in the LIPA gene and subsequent deficiency of LAL can also result in the comparatively milder CESD phenotype. Whereas the Wolman is characterized by the tissue storage of both cholesteryl esters and triglycerides, CESD is characterized by cholesteryl ester storage. While Wolman disease is typically diagnosed in infancy and characterized by rapid progression and death, CESD (while quite variable) can remain undiagnosed into adulthood and be compatible with a normal life span.
The factors determining the expression of the Wolman disease phenotype versus the CESD phenotype have not been completely elucidated. Studies of LIPA gene mutations indicate the presence of one common mutation involved with CESD not typically seen in individuals with Wolman disease. This mutation (called Δ254-277) affects how the LIPA gene is put together (spliced) and read by the body and is believed to result in the production of both normal and unstable LAL enzyme. The production of at least some normal LAL enzyme is thought to play a role in the milder phenotype of CESD.
Mutation type may not be the only factor that determines the clinical expression of this condition, as evidenced by the clinical variability among individuals with the common mutation. It is postulated that environmental risk factors and genetic background may also play a role, though the specific factors remain to be determined.
Symptoms
Wolman disease initially manifests in infancy with excessive vomiting and diarrhea. Affected infants typically have markedly distended abdomens due to enlargement of the liver and spleen (hepatosplenomegaly), in addition to progressive anemia and developmental regression. Calcification of the adrenal glands, a characteristic feature, can be observed on certain imaging studies, such as computed tomography (CT) scan. In contrast, hepatosplenomegaly is often the only physical sign of CESD, though affected individuals are at increased risk for premature atherosclerosis. Adrenal calcifications are rarely noted.
Screening and Diagnosis
Aside from looking for adrenal calcifications on abdominal imaging, there is no screening test that suggests a diagnosis of Wolman disease. Though tissue lipid levels are remarkably high, plasma lipids are typically within normal range in Wolman disease. If suspected based on clinical presentation, both Wolman disease and CESD can be diagnosed by assaying LAL enzyme activity in white blood cells, liver biopsy, or fibroblasts. LAL activity can be measured using dried blood spots and Lalistat 2, an inhibitor of LAL. Further confirmation of the diagnosis can be achieved by sequencing of the LIPA gene.
Treatment and Therapy
Infants diagnosed with Wolman disease have been treated using hematopoietic stem cell transplantation (HSCT). Donor stem cells with normal LAL activity are transplanted into an affected individual; if successful, the LAL expressed by the donor cells is enough to constitute normal activity within the host. Among those that survive the HSCT process and for whom the procedure is successful (complete donor cell engraftment), the features of Wolman syndrome are largely ameliorated. Widely used for standard hypercholesterolemia therapy, cholesterol-lowering drugs have been used in the treatment of CESD, as have liver transplants. Sebelipase alfa has been successful in treating both adults and infants/children with Wolman disease.
Prevention and Outcomes
Without treatment with HSCT, affected infants typically die within the first year of life. The life span after successful HSCT treatment is unknown, though ongoing survival into early adolescence has been documented. Though widely variable, individuals with CESD can have a normal life span with symptomatic treatment. Prenatal diagnostic options and genetic counseling should be made available to those individuals with a family history of these conditions.
Bibliography
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