A Novel Variant in the LIPA Gene Associated with Distinct Phenotype.

Deficiency of lysosomal acid lipase (LAL-D) is caused by biallelic pathogenic variants in the LIPA gene. Spectrum of LAL-D ranges from early onset of hepatosplenomegaly and psychomotor regression (Wolman disease) to a more chronic course (cholesteryl ester storage disease - CESD). The diagnosis is based on lipid and biomarker profiles, specific liver histopathology, enzyme deficiency, and identification of causative genetic variants. Biomarker findings are a useful for diagnostics of LAL-D, including high plasma concentration of chitotriosidase as well as elevated oxysterols. Current treatment options include enzyme replacement therapy (sebelipase-alpha), statins, liver transplantation, and stem cell transplantation. We present two pairs of siblings from Serbia with a distinctive phenotype resembling LAL-D with a novel variant of unknown significance (VUS) detected in the LIPA gene and residual LAL activity. All patients presented with hepatosplenomegaly at early childhood. In siblings from family 1, compound heterozygosity for a pathogenic c.419G>A (p.Trp140Ter) variant and a novel VUS c.851C>T (p.Ser284Phe) was detected. Patients from family 2 were homozygous for c.851C>T VUS and both have typical histopathologic findings for LAL-D in the liver. Enzyme activity of LAL was tested in three patients and reported as sufficient, and therefore enzyme replacement therapy could not be approved. When confronted with a challenge of diagnosing an inherited metabolic disorder, several aspects are taken into consideration: clinical manifestations, specific biomarkers, enzyme assay results, and molecular genetic findings. This report brings cases to light which have a considerable discrepancy between those aspects, namely the preserved LAL enzyme activity in presence of clinical manifestations and rare variants in the LIPA gene.

[Pathohistologic diagnosis of cholesterol ester storage disease]. / Patohistoloska dijagnostika bolesti nagomilavanja estra holesterola.

Cholesteryl ester storage disease (CESD) is rare and characterised by accumulation of cholesteryl esters and triglycerides in many tissues due to the deficiency of lysosomal acid lipase. We report on a 2 1/2-year old child with CESD. The diagnosis was made by liver biopsy and finding of heat-sensitive birefrigent crystals seen in frozen liver tissue under polarized light. In world literature the number of cases previously described is small (in paediatric age group does not exceed 40), and this was the reason for the presentation of our patient.

[Autoimmune hepatitis in children]. / Autoimunski hepatitis kod dece.

UNLABELLED: Autoimmune hepatitis is a rare chronic disease of unknown aetiology with female predominance, circulating autoantibodies, hypergammaglobulinaemia, typical major human leukocyte antigen types (HLA A1/B8/DR3) and a good response to immunosuppressive therapy. It seems that the main features in autoimmune hepatitis are a primary or secondary defective suppressor-T-cell function. Recently, we are realizing the recommendations of the International Autoimmune Hepatitis Study Group, using a combination of clinical, biochemical and serological features. METHODS: Two hundred and twenty one patients with chronic liver disease were studied. In this study, 221 consecutive percutaneous liver biopsies were performed, with a Menghini needle, during a 5-year period. All children were under 18 years. RESULTS: We found 17 patients with autoimmune hepatitis (7.7%) among children with chronic liver disease. In summary, final diagnosis was established in 16 patients (94%). Using minimum required (main) parameters final diagnosis was established in 10 patients (59%). We found no significant differences between histologic parameters and response to therapy. Our patients with autoimmune hepatitis were predominantly females (3.25:1) with antibodies to smooth muscle (59%). The main histologic findings were bridging necrosis, rosetting of the liver cells and plasma cell infiltration (83%). In two cases we found granulomas and in one case centrilobular necrosis. DISCUSSION AND CONCLUSION: Over a period of 5 years, the diagnosis of autoimmune hepatitis was established in 17 children. This is similar to the findings published in other paediatric studies [7, 8]. Patients were predominantly females as in the most recent studies [10, 11, 13-15]. Our results regarding the validation of the scoring system showed that we found no significant differences between histologic parameters and response to therapy [16-18]. Histologic findings were not pathognomonic but suggestive of autoimmune hepatitis diagnosis [1, 4, 8, 15-18]. The remission rate induced by the initial therapy was 88%, but in 53% of cases the disease was reactivated [3, 4, 11, 14, 15].