Tronstad Rune Rose, Berland Siren, Tjora Erling, El Jellas Khadija, Aukrust Ingvild, Kristensen Kurt, Tveitnes Dag, Molven Anders, Marschall Hanns-Ulrich, Rao Anuradha, Dawson Paul A
Department of Pediatrics and Adolescent Medicine, Haukeland University Hospital, Bergen, Norway.
Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
JPGN Rep. 2022 Aug;3(3):e229. doi: 10.1097/pg9.0000000000000229. Epub 2022 Jul 25.
A bile acid homeostasis disorder was suspected in 2 siblings and their second cousin who presented in infancy with fat malabsorption, severe fat-soluble vitamin deficiency, rickets, and mild liver involvement. Our aims were to identify the genetic cause, describe the disease, and evaluate the response to ursodeoxycholic acid (UDCA) treatment.
Whole exome sequencing, immunohistochemistry of duodenal biopsies and candidate variant testing in a cell-based model was performed. Fecal fat excretion, serum bile acids, 7α-hydroxy-4-cholesten-3-one (C4), and fibroblast growth factor 19 (FGF19) were quantified in both siblings on and off UDCA treatment.
A novel homozygous variant of , which encodes the bile acid carrier organic solute transporter (OST)-α, was identified in all affected children. OSTα protein expression was readily detected by immunohistochemistry in duodenum of pediatric control subjects but not in the affected siblings. The siblings had low serum levels of bile acids and C4 and high serum levels of FGF19 consistent with repression of hepatic bile acid synthesis. On treatment with UDCA, fecal fat excretion was reduced and serum levels of C4, FGF19, and liver enzymes normalized.
We report an apparent deficiency of OSTα associated with early onset fat malabsorption and mild liver involvement. The clinical presentation partially overlaps previous reports for 3 patients with OSTα or OSTβ deficiency and extends the clinical spectrum associated with loss of expression. Our data suggest that repression of hepatic bile acid synthesis contributes to fat malabsorption in OSTα-OSTβ deficiency but can be partly reversed with UDCA treatment.
在2名兄弟姐妹及其二级表亲中怀疑存在胆汁酸稳态紊乱，他们在婴儿期出现脂肪吸收不良、严重脂溶性维生素缺乏、佝偻病和轻度肝脏受累。我们的目的是确定遗传原因、描述该疾病并评估对熊去氧胆酸（UDCA）治疗的反应。
进行了全外显子组测序、十二指肠活检的免疫组织化学检测以及基于细胞模型的候选变异体检测。对两名接受UDCA治疗和未接受UDCA治疗的兄弟姐妹的粪便脂肪排泄、血清胆汁酸、7α-羟基-4-胆甾烯-3-酮（C4）和成纤维细胞生长因子19（FGF19）进行了定量分析。
在所有患病儿童中均鉴定出一种新的纯合变异体，该变异体编码胆汁酸载体有机溶质转运体（OST）-α。通过免疫组织化学在儿科对照受试者的十二指肠中很容易检测到OSTα蛋白表达，但在患病的兄弟姐妹中未检测到。这些兄弟姐妹的血清胆汁酸和C4水平较低，FGF19血清水平较高，这与肝脏胆汁酸合成受抑制一致。用UDCA治疗后，粪便脂肪排泄减少，C4、FGF19血清水平和肝酶恢复正常。
我们报告了一种明显的OSTα缺乏症，与早发性脂肪吸收不良和轻度肝脏受累有关。临床表现部分与先前报道的3例OSTα或OSTβ缺乏症患者重叠，并扩展了与 表达缺失相关的临床谱。我们的数据表明，肝脏胆汁酸合成受抑制导致了OSTα-OSTβ缺乏症中的脂肪吸收不良，但可用UDCA治疗部分逆转。
