The packet lists no certified causative-gene claim for lysosomal acid lipase deficiency, and no gene is named here. The packet's inheritance field is empty. GeneReviews describes the condition as inherited in an autosomal recessive manner, and states that family history is typically consistent with that pattern, although the absence of a known family history does not preclude the diagnosis.

GeneReviews describes the condition in terms of deficient lysosomal acid lipase enzyme activity. It reports that, in general, pathogenic null variants with no residual enzyme function result in infantile-onset disease, while pathogenic variants that allow residual enzyme activity result in childhood/adult-onset disease.

GeneReviews notes that consensus diagnostic and treatment guidelines for LAL-D are available and that biochemical and genetic testing are available. It states that newborn screening is possible but has not yet been implemented in the United States. The packet does not certify a state newborn screening status.

For infantile-onset LAL-D, GeneReviews describes suspicion arising from faltering growth, persistent vomiting, refractory diarrhea and malabsorption, abdominal distention with hepatosplenomegaly, and acute liver failure with jaundice. Supportive laboratory findings it lists include hemophagocytic lymphohistiocytosis, anemia and pancytopenia, evidence of liver dysfunction, elevated markers of inflammation and macrophage activation (ferritin, lactate dehydrogenase, C-reactive protein), low fat-soluble vitamin concentrations, and elevated LDL, low HDL, and high triglycerides. Imaging may show adrenal calcification, hepatomegaly or a steatotic liver, and splenomegaly. GeneReviews calls attention to the fact that normal serum lipid levels do not exclude the diagnosis.

For childhood/adult-onset LAL-D, GeneReviews lists hepatomegaly, splenomegaly, jaundice, chronic diarrhea, steatorrhea, malabsorption symptoms, and coronary artery disease, aneurysm, or stroke as clinical findings; elevated transaminases, high LDL, low HDL, elevated triglycerides, and anemia as laboratory findings; and liver fibrosis or cirrhosis on imaging. Liver biopsy may show microvesicular or mixed steatosis with bridging fibrosis or cirrhosis, and intestinal biopsy may show lipid accumulation in macrophages.

According to GeneReviews, the diagnosis is established by molecular genetic testing identifying biallelic pathogenic or likely pathogenic variants and/or by deficient lysosomal acid lipase enzyme activity in peripheral blood leukocytes or dried blood spots. The differential diagnosis it lists includes primary mitochondrial disorders, congenital disorders of glycosylation, cholestatic liver diseases, glycogen storage diseases, tyrosinemia type I, galactosemia, and neuropathic Gaucher and Niemann-Pick disease.

GeneReviews states there is no cure for infantile-onset LAL-D and describes enzyme replacement therapy combined with reduction of long-chain dietary fat as the current standard of care. It describes dietary substrate reduction as involving restriction of long-chain fat with supplementation of fat-soluble vitamins, essential fatty acids, protein, and carbohydrates, and notes that parenteral nutrition is likely to be required at diagnosis in symptomatic persons. GeneReviews describes departures from dietary fat restriction as associated with complications such as mesenteric lymphadenopathy, recurrence of gastrointestinal symptoms, and deterioration in liver function.

The packet lists one active verified FDA record: Kanuma (sebelipase alfa), approved by the FDA as a biologic license application product in December 2015 and currently marketed. It is the current FDA-approved option in the packet. GeneReviews describes sebelipase alfa as an intravenously administered enzyme replacement therapy and reports that enzyme replacement therapy does not appear to be as effective in reducing gastrointestinal lipid deposition and gastrointestinal symptoms, and that long-term benefits, outcomes, and complications are still emerging.

GeneReviews reports that hematopoietic stem cell transplantation has been performed successfully in some children already treated with enzyme replacement therapy for specific indications, including hemophagocytic lymphohistiocytosis, poor response associated with anti-drug antibodies, and progressive gastrointestinal lipid accumulation. It states that further long-term evidence is required before the procedure can be considered a definitive treatment.

GeneReviews describes surveillance for infantile-onset LAL-D at set intervals covering growth, gastrointestinal status, liver enzymes, essential fatty acids and fat-soluble vitamin levels, anti-drug antibodies in those receiving enzyme replacement therapy, blood counts, and abdominal imaging of the liver, spleen, and mesenteric lymph nodes, with assessment of family support needs. The packet does not certify patient assistance program information.

The packet does not certify a structured natural history record. GeneReviews describes untreated infantile-onset LAL-D as an early-onset, rapidly progressive storage disorder, and states that liver failure is the most frequent cause of death in untreated individuals. It describes the childhood/adult-onset forms as a clinical spectrum. The packet does not certify survival or life-expectancy data.

The packet lists active clinical studies relevant to this condition, including a recruiting registry for the condition and an expanded newborn screening study that is active but not recruiting. The packet's trial summary indicates no gene therapy trials among them. GeneReviews describes a trial studying in utero enzyme replacement in lysosomal storage diseases, including LAL-D, and describes preclinical gene therapy work as promising. Active clinical trials for this condition are listed on ClinicalTrials.gov.