ATP7B variant spectrum in a French pediatric Wilson disease cohort.

BACKGROUND/AIM: The spectrum of ATP7B variants varies significantly according to geographic distribution, and there is insufficient data on the variants observed in the French population. METHODS: Clinical data of 113 children included in the French WD national registry were gathered from March 01, 1995 to July 01, 2020. Data included epidemiological, clinical, laboratory, genetics. RESULTS: Diagnosis was made at a mean age of 11.0 ± 4.1 years (range 1-18 years). At diagnosis, 91 patients (79.8 %) had hepatic manifestations, 18 (15.8 %) presented neurological manifestations, and 4 patients (3.5 %) were asymptomatic. Only 29 patients (25 %) were homozygous for a variant. We have found a total of 102 different variants including 14 novel variants. Recurrent variant p.His1069Gln was the most prevalent, n = 31 alleles (14,2%), with only seven homozygous; in contrast 55% of variants are identified in only one family. 45% were truncating variants. In respect of mutated exon, the three most prevalent were exon 14 (16.5%), exon 8 (13.8%), and exon 3 (11.5%). When considering patients with two Nonsense / Frameshift variants as a group and those with two Missense variants, we found significantly lower ceruloplasmin for the former: 2.8 ± 0.7 mg/dl vs 8.4 ± 5mg/dl (p<0.05). CONCLUSION: p.His1069Gln is the most frequent variant (14,2%) and exons 14, 8, and 2 of the ATP7B gene account for 41.7% of total variants. However, there is significant heterogeneity in the French population concerning the other ATP7B variants. Nonsense / Frameshift variants were associated with lower ceruloplasmin levels.

mTOR inhibitors in pediatric liver transplant recipients.

BACKGROUND: During the past decade, mTOR inhibitors (mTORi), everolimus and sirolimus, have been increasingly used after adult liver transplantation (LT). The aim of the present study was to describe the use of mTORi in pediatric LT recipients. METHODS: All pediatric LT recipients who received mTORi before December 2017 from 4 European pediatric LT centers were included and analyzed. RESULTS: The present retrospective study included 30 patients; 21 were male (70%), median age was 9.3 years (range: 1.2-17.1 years) at mTORi introduction. Main indications for mTORi introduction were pre-existing liver malignancy (43.3%), calcineurin inhibitor (CNI) nephrotoxicity (26.7%), or rejection (23.4%). At last follow-up, mTORi CNIs were withdrawn in 10 patients (10/29, 34.5%). The median dose of mTORi was 1.8 mg/day (range: 0.3-5.0) or 0.058 mg/kg/day (range: 0.01-0.26), and the median trough level was 5.1 µg/L (range: 1.0-15.5). After a median follow-up of 2.8 years (range: 0.2-10.0), 50.0% of the patients presented with at least one adverse event. The main adverse events included hyperlipidemia, proteinuria, dermatitis, and mucitis. Overall mTORi discontinuation rate was 23.3% (10.0% because of adverse event). Introduction of mTORi had no significant impact on renal function. CONCLUSION: Our results suggest that mTORi can be used in pediatric LT recipients in different clinical situations, both to reinforce immunosuppressive therapy, and to reduce CNI and related toxicity.