Medical Genetics, Baystate Medical Center, Springfield, MA 01199, USA.
Mol Genet Metab. 2011 Dec;104(4):583-6. doi: 10.1016/j.ymgme.2011.08.003. Epub 2011 Aug 11.
We report the clinical course of a patient with severe infantile onset Pompe disease [cross-reactive immunologic material (CRIM) negative, R854X/R854X] who was diagnosed prenatally and received standard dosing of alglucosidase alfa (Myozyme®) enzyme replacement therapy (ERT) from day 10 of life until she passed away at the age of 3 years 9 months. In the immediate neonatal period there was cardiomegaly on chest X-ray, cardiac hypertrophy by echocardiogram, and development of a wide complex tachycardia. CRIM negative (CN) status was suspected based on her family history, and the available data at the time indicated that CN patients had limited survival even with ERT. However, given the opportunity for very early treatment, the treating provider and family elected to initiate treatment with ERT, without immune modulation. By 9 months of age echocardiogram was normal. Early motor development was within normal limits but by 2 years of age her developmental progress had slowed. She seroconverted by the 4th month of ERT, and anti-rhGAA antibody titers peaked at 25,600 in the 27th month. Immunomodulatory therapy was considered but declined by family. She acquired Influenza A at 2 years 6 months, which led to a prolonged hospitalization with invasive respiratory support, and placement of tracheostomy and gastrostomy tube. Her developmental progress ceased, and she died suddenly at home from a presumed cardiac event at age 3 years 9 months. The poor outcomes observed in CN patients have been attributed to the development of high sustained antibody titers. Although this CN patient's anti-rhGAA response was elevated and sustained, it is unlike any of the 3 patterns that have been previously described: high titer CN, high titer CRIM positive (HTCP), and low titer CP (LTCP) patients. This patient's clinical course, with achievement of 24 months of motor gains, 30 months of ventilator-free survival and 45 month survival, is like that of only a fraction of ERT treated CN patients, yet it is identical to other reported CN patients in its relentless progression and early fatality. The immunologic response (moderate sustained antibody titers) described here has not been previously reported and may have played a role in the overall pattern of developmental decline. In light of proposed universal newborn screening for Pompe disease, there is an urgent need for improved understanding of the interplay between immunologic responses to the only available treatment, ERT, and the relentless nature of this disease in CN patients.
我们报告了一例严重婴儿期起病庞贝病（交叉反应免疫物质 [CRIM] 阴性，R854X/R854X）患者的临床病程。该患者产前诊断，出生后第 10 天开始接受常规剂量的艾葡糖苷酶α（Myozyme®）酶替代疗法（ERT），直至 3 岁零 9 个月去世。新生儿期胸片显示心脏扩大，超声心动图显示心肌肥厚，并出现宽复合性心动过速。根据家族史怀疑为 CRIM 阴性（CN）状态，当时的可用数据表明，即使接受 ERT，CN 患者的生存机会也有限。然而，鉴于有机会进行早期治疗，治疗医生和家属选择在没有免疫调节的情况下开始 ERT 治疗。9 个月大时，超声心动图正常。早期运动发育正常，但 2 岁时发育进展缓慢。她在 ERT 的第 4 个月时发生血清学转换，第 27 个月时抗 rhGAA 抗体滴度达到峰值 25600。曾考虑过免疫调节治疗，但被家属拒绝。她在 2 岁零 6 个月时感染了甲型流感，导致长时间住院，需要有创呼吸支持，并进行气管造口和胃造口管置管。她的发育进展停止，3 岁零 9 个月时在家中突然死于疑似心脏事件。CN 患者的不良预后归因于持续高滴度抗体的产生。尽管该 CN 患者的抗 rhGAA 反应升高且持续，但与以前描述的 3 种模式均不相同：高滴度 CN（high titer CN，HTCP）、高滴度 CRIM 阳性（high titer CRIM positive，HTCP）和低滴度 CP（low titer CP，LTCP）患者。该患者的临床病程达到了 24 个月的运动获益、30 个月的无呼吸机生存和 45 个月的生存，与接受 ERT 治疗的 CN 患者中的一小部分患者相似，但与其他报道的 CN 患者一样，病情进展迅速且预后不良。这里描述的免疫反应（中度持续抗体滴度）以前没有报道过，可能在整体发育下降模式中发挥了作用。鉴于提议对庞贝病进行普遍的新生儿筛查，迫切需要更好地了解对唯一可用治疗方法 ERT 的免疫反应与 CN 患者疾病的无情性质之间的相互作用。
