Asfotase alfa improved skeletal mineralization and fracture healing in a child with MCAHS.
Asfotase alfa improved skeletal mineralization and fracture healing in a child with MCAHS.
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DOI：
10.1016/j.bone.2023.116778
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发表时间：
2023-04
期刊：
影响因子：
4.1
通讯作者：
M. Kang;Malinda Wu;Janet L. Crane
中科院分区：
文献类型：
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作者：
M. Kang;Malinda Wu;Janet L. Crane
组织非特异性碱性磷酸酶（TNSALP）是一种通过糖基磷脂酰肌醇（GPI）连接到细胞膜并将无机焦磷酸盐转化为无机磷酸盐的酶。无机磷酸盐与钙结合形成羟基磷灰石，这是骨骼中的主要矿物质。当TNSALP有缺陷时，无机焦磷酸盐向无机磷酸盐的转化受损，骨骼处于矿化不足的风险中。N类磷脂酰肌醇聚糖锚生物合成基因（PIGN）是GPI生物合成家族中20多个基因之一。在多发性先天性异常-肌张力减退-癫痫发作综合征（OMIM 614080）中已鉴定出PIGN的致病性变体，但尚未报告代谢性骨病或骨骼脆性表型。我们描述了一个女孩与多先天性异常-肌张力减退-癫痫综合征由于一个复合杂合致病变异PIGN谁持续低创伤股骨远端骨折在7.4岁。我们假设GPI合成缺陷可能导致TNSALP在骨中锚定不足导致代谢性骨病，并启动了阿司弗泰斯阿尔法（一种人骨靶向重组TNSALP-Fc-十-天冬氨酸肽），因为它可以绕过可能导致骨骼脆弱的PIGN遗传缺陷。阿司弗泰斯阿尔法开始在8.5岁。基线X线检查显示腕关节和膝关节轻度佝偻病，治疗5个月后消退。治疗16个月后，双能X线骨密度仪（DXA）评估的骨密度（BMD）显示脊柱、髋关节和全身（不包括头部）轻度改善，而桡骨下降。在治疗后11个月和15个月，她的右胫骨和左肱骨颈发生了额外的低创伤骨折，并迅速愈合。在18个月的治疗中，钙、磷和甲状旁腺激素水平保持在正常范围内。对于不良反应，她在治疗第一周出现皮疹和不适，使用布洛芬和苯海拉明后消退。她还出现了皮下脂肪萎缩。总的来说，在这个患有PIGN复合致病性变异的孩子中，阿司弗泰斯阿尔法的标签外使用通常耐受良好，副作用最小，佝偻病消退，但她仍然很脆弱。
Tissue non-specific alkaline phosphatase (TNSALP) is an enzyme that is tethered to the cell membrane by glycosylphosphatidylinositol (GPI) and converts inorganic pyrophosphate to inorganic phosphate. Inorganic phosphate combines with calcium to form hydroxyapatite, the main mineral in the skeleton. When TNSALP is defective, conversion of inorganic pyrophosphate to inorganic phosphate is impaired and the skeleton is at risk of under-mineralization. Phosphatidylinositol glycan anchor biosynthesis class N (PIGN) is one of more than 20 genes in the GPI-biosynthesis family. Pathogenic variants in PIGN have been identified in multiple congenital anomalies-hypotonia-seizures syndrome (OMIM 614080), although a metabolic bone disease or skeletal fragility phenotype has not been reported. We describe a female child with multiple congenital anomalies-hypotonia-seizures syndrome due to a compound heterozygous pathogenic variant in PIGN who sustained a low-trauma distal femur fracture at age 7.4 years. We hypothesized that the GPI synthesis defect may result in metabolic bone disease from inadequate anchoring of TNSALP in bone and initiated asfotase alfa, a human bone-targeted recombinant TNSALP-Fc-deca-aspartate peptide, as it could bypass the PIGN genetic defect that possibly caused her skeletal fragility. Asfotase alfa was begun at 8.5 years. Baseline X-rays revealed mild rachitic findings of wrists and knees, which resolved by 5 months of treatment. Bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA) showed mild improvement in spine, hip and total body less head after 16 months of treatment, while radius declined. She sustained additional low trauma fractures at right tibia and left humeral neck at 11 and 15 months into treatment, which healed quickly. Calcium, phosphorus, and parathyroid hormone levels have remained within the normal range over the 18 months of treatment. For adverse effect, she experienced a rash and discomfort in the first week of treatment which resolved with ibuprofen and diphenhydramine. She also developed subcutaneous fat atrophy. Overall, in this child with a compound pathogenic variant in PIGN, off-label use of asfotase alfa has been generally well tolerated with minimal side effects and resolution of rickets, but she continues to remain skeletally fragile.