基因治療AADC基因突變引發的芳香族-胺基酸類脫羧基酶缺乏症

09-24

來自專欄罕見遺傳病的基因檢測和藥物治療10 人贊了文章

寫這文章的時候我在想，中國是否有人知道這個病，如果全中國都沒有人知道這個病，我這文章到底寫給誰看呢？不過反正我不指望靠知乎掙錢，不用求點贊，不用圈粉，不用蹭熱點，妖怪本來就是來知乎玩耍的，自己開心就好。

今天說的常染色體隱性遺傳病芳香族L-胺基酸類脫羧基酶缺乏症，是一種非常罕見的代謝遺傳病，全世界醫學文獻報道的案例大約100例，其中約20例在台灣。根據中國巨大的人口基數和大陸和台灣的群體遺傳學關係，我個人推斷中國大陸這個病的病人數目大約應該在100位左右，只不過因為絕大多數中國醫生不知道這個病的存在和基因檢測不夠普及的原因，所以未見報道。

首先了解一下Aromatic l-amino acid decarboxylase(AADC)這個芳香族L-胺基酸類脫羧基酶是幹嘛的，見下圖：

右下的melatonin就是大家熟知的腦白金，中間的Dopamine就是非常重要的神經遞質多巴胺，看到這裡，你就能理解AADC這個酶的重要性了。

AADC酶缺陷會造成自律神經失調，引發很多問題，包括低血壓，低血糖，肌無力，出汗，不容易控制體溫，眼瞼下垂，瞳孔移動困難等等。單憑這些臨床癥狀，如果不知道這個病，沒有做基因檢測，根本就無法確診進行治療。

確診之後，可以開展相關藥物治療：

(1)多巴胺激動劑如溴隱亭(bromocriptine)或Pergolide。

(2)單胺氧化酵素抑製劑(MAO inhibitors)如Parnate(tranylcypromine)為主。

其他藥物還有(3)抗膽礆類Trihexyphenidyl (即Artane)或是採用(4)維生素B6（Pyridoxine)(5)L-DOPA等。

跟大多數遺傳病一樣，這些藥物是治標不治本，所以這病最高發的台灣開展了腺病毒基因治療的1/2期臨床試驗研究，具體單位是位於台北的台灣大學附屬醫院。文獻附在下面，希望給病人家屬留點希望。

Lancet Child Adolesc Health. 2017 Dec;1(4):265-273. doi: 10.1016/S2352-4642(17)30125-6. Epub 2017 Oct 23.

Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial.

Chien YH1, Lee NC1, Tseng SH2, Tai CH3, Muramatsu SI4, Byrne BJ5, Hwu WL6.

Author information

Abstract

BACKGROUND:

Aromatic l-amino acid decarboxylase (AADC) deficiency is an inherited disease that causes depletion of neurotransmitters and severe motor dysfunction in infants and children. We previously reported compassionate use of an adeno-associated virus (AAV) vector containing the human AADC gene (AAV2-hAADC) in four children with AADC deficiency (aged 4-6 years). In this study, we aimed to establish the efficacy and safety of this treatment.

METHODS:

We did an open-label, phase 1/2 trial at the National Taiwan University Hospital (Taipei, Taiwan). We included patients who had a definitive diagnosis and clinical symptoms of AADC deficiency (hypotonia, dystonia, and oculogyric crisis), who were older than 24 months or had skull bones suitable for stereotactic surgery, and who had an anti-AAV2 antibody titre lower than 1·0 optical density. All patients received bilateral intraputaminal injections of AAV2-hAADC (1·81?×?1011 vg in total) through stereotactic brain surgery. Primary efficacy outcomes were an increase in the Peabody Developmental Motor Scales (second edition; PDMS-2) score of greater than 10 points and an increase in homovanillic acid (HVA) or 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the cerebrospinal fluid 12 months after gene therapy. We assessed patients at baseline and at 3, 6, 9, and 12 months after gene therapy, and every 6 months thereafter for one further year; all patients who received the treatment were included in the analysis. We assessed for surgical complications (cerebrospinal fluid leakage and intracerebral haemorrhage) at days 3-7 after AAV2 gene therapy, and we assessed adverse events during the follow-up evaluations for 12 months. This study is registered with ClinicalTrials.gov, number NCT01395641.