妥瑞症病童血中Nociceptin/Orphanin FQ濃度之研究

A Study of the Plasma Nociceptin/Orphanin FQ Levels in Children with Tourette Syndrome.

杜戎玨(Jung-Chieh Du)

指導教授 ： 邱麗珠

國立臺灣大學/醫學院/臨床醫學研究所/碩士(2009年)

https://doi.org/10.6342/NTU.2009.00656

摘要

妥瑞症(Gilles de Tourette syndrome)是兒童常見的慢性神經精神疾病之一，在疾病分類上屬於抽動症(tic disorder)的一種，此類疾病最顯著的症狀即是在兒童或是青少年時期斷斷續續地出現多種短暫且重複的不自主動作及/或聲音,稱作所謂的抽動(tic)。抽動又可分為『動作型』與『聲語型』兩大類，如果在21歲以前即同時出現三種以上的『動作型抽動』與一種以上的『聲語型抽動』，且症狀持續超過一年以上，臨床診斷即為妥瑞症。妥瑞症是一種多基因遺傳的疾病，而且表現率(penetrance)有性別上的差異。妥瑞症的病人也常同時罹患其他神經精神方面的合併症，包括注意力不足過動症、強迫症、自我傷害行為、攻擊行為及睡眠異常等等。過去對於妥瑞症病理機轉的了解大多來自於觀察病人對藥物的治療反應、臨床神經影像檢查及腦部病理解剖研究的結果，基底核(basal ganglia)結構異常、大腦皮質-紋狀體-視丘之神經迴路(cortico-striato-thalamo-cortical circuits)功能失常、多巴胺(dopamine)系統和其他神經傳導物質協調異常以及下視丘-腦下垂體-腎上腺系統(hypothalamic-pituitary-adrenal axis, HPA axis)對壓力的過激反應都是可能的病理機轉。
Nociceptin/orphanin FQ(N/OFQ)是一種具有17個胺基酸的胜肽(peptide)，具有調控疼痛、抗憂鬱、增加進食量、抑制活動力、抗癲癇、降低心跳血壓等功用，與學習、記憶、與情緒也有關係。N/OFQ peptide receptor (NOP)則也廣泛分布於神經、心血管、腸胃、泌尿及免疫系統上。大部分的多巴胺神經元都會表現NOP receptors，且許多動物研究皆顯示內生性的N/OFQ具有抑制多巴胺系統活性的功能，且N/OFQ也具有調節HPA axis對壓力反應的作用，所以我們推測妥瑞症患者的血中N/OFQ濃度與正常兒童不同，與抽搐症狀嚴重度可能也有關聯。所以本研究在兒童病人身上探討N/OFQ與臨床症狀及其合併症的相關性，希望對妥瑞症病理機轉有更多的了解。
從2007年10月至2008年10月，總共有30位妥瑞症病童、9位短暫性抽動症病童及10位健康對照組納入本研究中。所有參與本研究之兒童皆接受血中N/OFQ濃度之測量(本研究以放射免疫分析法RIA的方式測量N/OFQ濃度) ，所有病童之抽動症狀嚴重度皆以『耶魯抽動嚴重度量表』(Yale Global Tic Severity Scale，YGTSS)來評估及量化，並探討其與N/OFQ濃度之相關性。本研究顯示妥瑞症患者的血中N/OFQ濃度(137.9±23.6pg/ml)遠高於對照組(25.6±4.9pg/ml )及短暫性抽動症患者(19.1±4.2pg/ml )，達到統計上顯著之差異(p=0.001)，且N/OFQ濃度與其動作型YGTSS分數有顯著之負相關性(r=-0.54, p=0.002)，尤其與動作數目(numbers)的負相關性最為明顯(r=-0.51, p=0.004)。30位妥瑞症病童中有13位被診斷同時患有注意力不足過動症(ADHD)，據此可將妥瑞症病童分成單純妥瑞症組與共病妥瑞症組，比較兩組血中N/OFQ濃度可發現單純妥瑞症組之N/OFQ濃度比共病妥瑞症組有略高的趨勢，但未達統計上顯著之差異(164.7±36.8pg/ml v.s. 102.7±23.5pg/ml, p=0.33) 。 其中單純妥瑞症組之N/OFQ濃度與動作型YGTSS分數中的動作數目(numbers)有顯著之負相關性(r=-0.50, p=0.04)，而共病妥瑞症組之N/OFQ濃度則與動作型YGTSS分數有顯著之負相關性(r=-0.57, p=0.04) ，但與聲語型YGTSS分數中的聲語複雜度(complexity)卻有顯著之正相關(r=0.57, p=0.04)。
本研究顯示妥瑞症兒童比正常的兒童有較高的血中N/OFQ濃度，因為N/OFQ與多巴胺在中樞神經系統中呈現相互拮抗的作用，據此推測妥瑞症病童血中N/OFQ濃度升高可能是一種代償作用的結果。而且N/OFQ濃度與其臨床上動作型抽動症狀的嚴重度有顯著的負相關性，尤其是病患的動作型抽動症狀的數目。因為妥瑞症患者的抽動症狀嚴重度與突發性多巴胺釋放(phasic dopamine release)的數量有關，當N/OFQ的濃度越高時，可能突發性多巴胺釋放被抑制的程度就越高，所以動作型抽動的症狀也就越輕微。另一方面，單純妥瑞症病童之血中N/OFQ濃度與共病妥瑞症病童相比有略高之趨勢，且兩組之N/OFQ濃度與其動作型抽動症狀嚴重度皆有負相關性，特別的是共病妥瑞症病童之N/OFQ濃度與其聲語型症狀中的複雜度竟有正相關性，因此推測N/OFQ與ADHD的症狀可能也有關，但仍需進一步的研究來釐清。
這是第一個探討血中N/OFQ濃度與兒童妥瑞症臨床抽動症狀嚴重度相關性的研究，同時也是第一個得到正常兒童血中N/OFQ濃度範圍的研究，將來如果有好的妥瑞症動物模式被建立出來，也許可以進一步研究N/OFQ對於妥瑞症或抽動症狀的生理及藥理作用，之後或許還能逐步發展出新的抗抽動藥物。

關鍵字

妥瑞症 ； 抽動症 ； 注意力不足過動症 ； 多巴胺 ； 耶魯抽動嚴重度量表 ； 放射免疫分析法

並列摘要

Tourette syndrome (TS), a common childhood-onset chronic neuropsychiatric disorder, is among spectrum of tic disorders. The cardinal features of TS are motor and phonic tics that wax and wane in severity. The pattern of inheritance in Tourette syndrome is polygenic with varied penetrance. Some TS patients have other co-morbidities, such as attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), self-injurious behaviors and sleep disturbances. The pathogenesis of tics or Tourette syndrome is not elucidated clearly so far. Abnormalities in basal ganglia, cortico-striato-thalamo-cortical circuits, dopaminergic systems and hypothalamic-pituitary-adrenal axis (HPA axis) are considered to be possabile mechanisms.
Nociceptin/orphanin FQ (N/OFQ) is a kind of heptadecapeptide and its receptor—N/OFQ peptide receptor (NOP receptor)—distributes widely in human organs, especially central nervous system. Most dopominergic neurons express NOP receptors and activation of NOP receptors by N/OFQ reduces dopamine release. N/OFQ also modulates the activity of HPA axis. Based on previous facts, we propose that N/OFQ may play a role in the pathogenesis of tic or Tourette syndrome. Therefore, we conducted a study to investigate the plasma N/OFQ levels in children with TS or transient tic disorders (TTD) and normal children as controls.
From Oct, 2007 to Oct, 2008, our study recruited 30 children with TS, 9 children with TTD and 10 children as normal controls. The diagnosis of TS or TTD was based on DSM-IV and patients’ severity of tic symptoms were evaluated by the Chinese edition of Yale Global Tic Severity Scales (YGTSS). We detected plasma N/OFQ levels by radioimmunoassay. Our study revealed that TS chidren had higher plasma N/OFQ levels (137.9±23.6pg/ml) than normal controls (25.6±4.9pg/ml) and TTD children (19.1±4.2pg/ml) with statistical significance (p=0.001).N/OFQ levels in TS children also showed significantly negative correlation with motor YGTSS scores (r=-0.54, p=0.002), especially with motor numbers (r=-0.51, p=0.004).
Thirteen TS children were also diagnosed with ADHD. Slightly higher plasma N/OFQ levels, though not statistically significantly, were found in pure TS children than those with ADHD (164.7±36.8 v.s. 102.7±23.5pg/ml, p=0.33). The N/OFQ levels of TS children without ADHD were negatively correlated with motor tic numbers (r=-0.50, p=0.04). On the other hand, N/OFQ levels in TS children with ADHD were not only negatively correlated with motor YGTSS scores (r=-0.57, p=0.04), but also positively correlated with phonic complexity scores (r=0.57, p=0.04).
Our study demonstrated that TS children have higher plasma N/OFQ levels than normal controls. Due to the fact that N/OFQ negatively regulates dopaminergic system in the central nervous system, it is very likely that the elevation of plasma N/OFQ in TS children is a result of compensation for dopaminergic hyperactivity. Moreover, that N/OFQ levels in TS children were negatively correlated with motor tic symptoms may be explained by the model of tonic-phasic dopamine release. That is, higher N/OFQ level inhibits higher degree of phasic dopamine release and reduce more motor tic symptoms. Our study also revealed that children with pure TS had relatively higher plasma N/OFQ levels than those with ADHD. Both groups showed negative correlation between motor tic symptoms and N/OFQ levels. However, N/OFQ levels in TS children with ADHD were also noted to have positive correlation with phonic tic complexitiy scores. N/OFQ may have affect on ADHD but further study to clarify is necessary.
Our study is the first one to investigate the association between clinical symptoms of Tourette syndrome and N/OFQ. It is also the first study to obtain the normal range of N/OFQ levels in normal children. N/OFQ may be applied in animal models of Tourette syndrome for further elucidation of its physiological and pharmacological effect on pathogenesis of tics in the future.

並列關鍵字

Tourette syndrome ； tic disorder ； attention deficit hyperactivity disorder ； Nociceptin/orphanin FQ ； dopamine ； Yale global tic severity scale ； radioimmunoassay

參考文獻

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