• Abetalipoproteinemia
• Familial hypobetalipoproteinemia
• Lean nonalcoholic fatty liver disease
• Palatine-like phospholipase domain-containing-3
• Transmembrane 6 superfamily member 2

• Fatty acids
• Microvescles
• NAFLD
• SPMs
• Therapy
• Triacylglycerols

• Humans
• Non-alcoholic Fatty Liver Disease/therapy
• Non-alcoholic Fatty Liver Disease/metabolism
• Lipidomics
• Liver/metabolism
• Liver Cirrhosis/complications
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Fibrosis
• Inflammation/metabolism
• Lipids
• Disease Progression

Lysosomal storage disorders (LSD) are a rare group of genetic disorders. The major LSDs that cause liver dysfunction are disorders of sphingolipid lipid storage [Gaucher disease (GD) and Niemann-Pick disease] and lysosomal acid lipase deficiency [cholesteryl ester storage disease and Wolman disease (WD)]. These diseases can cause significant liver problems ranging from asymptomatic hepatomegaly to cirrhosis and portal hypertension. Abnormal storage cells initiate hepatic fibrosis in sphingolipid disorders. Dyslipidemia causes micronodular cirrhosis in lipid storage disorders. These disorders must be keenly differentiated from other chronic liver diseases and non-alcoholic steatohepatitis that affect children and young adults. GD, Niemann-Pick type C, and WD also cause neonatal cholestasis and infantile liver failure. Genotype and liver phenotype correlation is variable in these conditions. Patients with LSD may survive up to 4-5 decades except for those with neonatal onset disease. The diagnosis of all LSD is based on enzymatic activity, tissue histology, and genetic testing. Enzyme replacement is possible in GD and Niemann-Pick types A and B though there are major limitations in the outcome. Those that progress invariably require liver transplantation with variable outcomes. The prognosis of Niemann-Pick type C and WD is universally poor. Enzyme replacement therapy has a promising role in cholesteryl ester storage disease. This review attempts to outline the natural history of these disorders from a hepatologist’s perspective to increase awareness and facilitate better management of these rare disorders.

• Lysosomal
• Gaucher
• Niemann-Pick
• Wolman
• Cholesteryl ester
• Children

• Cholesteryl ester storage disease
• Lysosomal acid lipase deficiency
• Pediatrics
• Wolman disease

• Adolescent
• Adult
• Child
• Cholesterol Ester Storage Disease/diagnosis
• Cholesterol Ester Storage Disease/drug therapy
• Cholesterol Ester Storage Disease/genetics
• Hepatomegaly
• Humans
• Infant
• Sterol Esterase/genetics
• Sterol Esterase/therapeutic use
• Wolman Disease/diagnosis
• Wolman Disease/genetics

• Acid lipase deficiency
• CESD
• Cholesterol ester storage disease
• DBS
• Dried blood spot
• LAL
• Screening
• Wolman

Independent disease registries for pre-and post-approval of novel treatments for rare diseases are increasingly important for healthcare professionals, patients, regulators and the pharmaceutical industry. Current registries for rare diseases to evaluate orphan drugs are mainly set up and owned by the pharmaceutical industry which leads to unacceptable conflicts of interest. To ensure independence from commercial interests, disease registries should be set up and maintained by healthcare professionals and patients. Public funding should be directed towards an early establishment of international registries for orphan diseases, ideally well before novel treatments are introduced. Regulatory bodies should insist on the use of data from independent disease registries rather than company driven, drug-oriented registries.

• Disease registries
• Orphan drugs
• Real world data
• Registries

Cholesteryl ester storage disease (CESD) is a rare genetic disease. Its symptoms and severity are highly variable. CESD is a systemic disease that can lead to the accumulation of fat and inflammation in the liver, as well as gastrointestinal and cardiovascular disease. The majority of patients require liver transplantation due to decompensated cirrhosis. Enzyme replacement therapy has been approved based on a randomized trial. Our study aims to clinically and genetically evaluate two siblings with CESD who underwent liver transplantation, as well as their first-degree family members.

The siblings were compound heterozygous for the missense variant in LIPA exon 8, c.894G>A, (p.Gln298Gln) and a single base pair deletion, c.482del (p.Asn161Ilefs*19). Analyses of single nucleotide polymorphisms showed variants with an increased risk of fatty liver disease and fibrosis for both patients. Clinically, both patients show signs of recurrence of CESD in the liver after transplantation and additional gastrointestinal and cardiovascular signs of CESD. Three family members who were LIPA heterozygous had a lysosomal acid lipase activity below the reference value. One of these carriers, a seven-year-old boy, was found to have severe dyslipidemia and was subsequently treated with statins.

Our study underlines that CESD is a multi-organ disease, the progression of which may occur post-liver transplantation. Our findings underline the need for monitoring of complications and assessment of possible further treatment.

• Lysosomal acid lipase deficiency
• Lysosomal storage disease
• Non-alcoholic fatty liver disease
• Liver transplantation
• Sebelipase alfa
• Case report

• Alanine Transaminase
• Humans
• Liver
• Male
• Siblings
• Wolman Disease/drug therapy
• Wolman Disease

• Acid sphingomyelinase deficiency
• Cholesteryl ester storage disease
• Enzyme replacement therapy
• Gaucher disease
• Liver fibrosis
• Lysosomal acid lipase deficiency
• Niemann–Pick disease
• Substrate reduction therapy

• Adult
• Enzyme Replacement Therapy
• Gaucher Disease
• Humans
• Italy
• Lysosomal Storage Diseases/diagnosis
• Lysosomal Storage Diseases/drug therapy
• Lysosomal Storage Diseases/genetics
• Lysosomal Storage Diseases/metabolism
• Lysosomes/enzymology
• Niemann-Pick Diseases
• Societies, Medical
• Sphingomyelin Phosphodiesterase/deficiency
• Wolman Disease

• Adult
• Child
• Disease Progression
• Humans
• Liver
• Liver Diseases
• Wolman Disease
• Wolman Disease