龐貝氏症:新生兒篩檢發現個案之突變分析及治療成果

Abstract

背景: 龐貝氏症是一種因為溶小體缺乏酸性醣苷酶無法分解肝醣所引起之疾病。最近針對龐貝氏症，已有酵素補充療法可以使用。嬰兒型龐貝氏症患者經由酵素補充療法，可有效延長性命，恢復心臟正常大小，但是大部分患者的運動及呼吸功能無法恢復正常；晚發型龐貝氏症治療後，其症狀之可逆性也很有限。本研究的目的在探求新生兒篩檢可以早期診斷龐貝氏症，給予患者早期治療的機會。 方法: 我們首先分析台灣龐貝氏症患者之表現型、基因型、以及個案之分佈，以及是否有導致治療失敗之因子。我們接著開發龐貝氏症新生兒篩檢之方法，並且進行前導篩檢作業。篩檢結果之分析，包括篩檢個案之表現型及基因型分析，以及嬰兒型龐貝氏症早期治療之成果。經由比較臨床個案及篩檢結果，試圖去預測台灣族群龐貝氏症之分佈，以及台灣未來關於龐貝氏症之診斷與治療之策略。 結果: 臨床個案分析顯示嬰兒型龐貝氏症患者接受酵素治療後，其肌肉對治療之反應不一，但是並沒有證據顯示患者之腦部會有不可逆之變化。經由新生兒篩檢檢出之嬰兒型患者，因為治療開始時間較早，其預後明顯比臨床個案要好。這些患者的基因型與臨床發現個案相類似，主要為p.D645E突變。新生兒篩檢同時檢出部分患者酵素活性缺乏，懷疑為晚發型龐貝氏症患者。這些患者的基因型與臨床發現的晚發型龐貝氏症患者部分類似，但是其發生率以及突變位置未確定的比例均較臨床個案為高。經由族群篩檢我們發現了高比例之龐貝氏症基因變異型。這些變異型會使得酸性醣苷酶活性偏低，我們目前不能排除這些基因變異型是否參與龐貝氏症臨床表現之決定。 結論與展望: 新生兒篩檢可以達到早期診斷龐貝氏症之目的，並改善嬰兒型龐貝氏症之預後。台灣族群中帶有相當高比例之龐貝氏症基因變異型，可能引起龐貝氏症診斷之困難或混淆。新生兒篩檢疑似晚發型龐貝氏症之發生率尚待進一步證實，但結果也暗示臨床上可能有部分晚發型龐貝氏症患者沒有被診斷出來。

Background: Pompe disease is due to a deficiency of lysosomal acid alpha glucosidase (GAA), and currently an enzyme replacement therapy has been developed. In infantile-onset Pompe disease, enzyme replacement therapy can prolong survival and reverse cardiomegaly, however, some patients cannot regain motor or respiratory function. In late-onset Pompe disease, most of the symptoms cannot be reversed by treatment. In this study, we hypothesis that newborn screening for Pompe disease can offer an opportunity for early treatment of Pompe disease. Methods: We first analyzed phenotype and genotypes of Pompe disease in Taiwan, and explored factors which may affect the outcome. We then developed a method of newborn screening for Pompe disease, and started a pilot screening program. We analyzed the genotypes, aiming at predicting phenotypes and comparing outcomes between early treatment and late treatment. Results: Patients diagnosed clinical during infancy have poor responses to the treatment in view of skeletal muscle function. However, there was no irreversible changes in their brains. Patients with infantile-onset pompe disease identified by newborn screen could have an earlier onset of treatment and better outcomes in comparism to those identified by clinical symptoms. GAA gene mutations were similar between the two groups, and p.D645E is the most common one. We also identified babies with GAA deficiency but may have late-onset Pompe disease. They had GAA gene mutations previously seen in patients with late-onset Pompe disease, but the babies tended to have a higher incidence of mutations with unknown significance. Through newborn screening, we also identified prominent GAA gene variations in our population, including the “pseudodeficiency” allele and alleles which may modify the clinical manifestations of Pompe disease.

Conclusion: Results from this study highlight the benefits of early diagnosis, which can be achieved only by newborn screening. of the intense gene variations in the population can confuse the diagnosis. The high incidence of late-onset Pompe disease from the screening program needs further confirmation, but our results do suggest the possibility of under diagnosis of Pompe disease in current clinical practice.