小美

作者：Jacquelyn K. Beals, PhD  
出處：WebMD醫學新聞

　　April 15, 2010 — 根據線上發表於4月1日美國精神病學期刊(American Journal of Psychiatry)的研究，重度憂鬱病患比一般人更容易出現CAG重複數量增加 — 引起亨丁頓舞蹈症(Huntington’s disease，HD)的基因異常。
　　
　　在後來發生HD的病患中，更常發生憂鬱症以及衝動控制、認知症狀、躁動，但是，之前並未研究重度憂鬱異常患者的相關CAG重複。
　　
　　HD是一種自體顯性疾病，是因為HTT突變(亨丁頓基因)，只要一類變異的對偶基因就會出現臨床症狀，這個突變是一種擴大的三核甘酸重複、即C、A和G這三種核甘酸序列，代表亨丁頓蛋白質的麩胺醯胺胺基酸。
　　
　　有6- 34組重複的CAG序列者在臨床上是正常的，重複36-39組者有可能發生症狀，40組以上者會引起HD。重複的數量傾向在每次基因遺傳時增加，母系的遺傳通常會增加(較少會減少)達5組重複，父系的遺傳一般會增加平均10組重複。
　　
　　HD的其他特徵是，症狀出現在30-50歲之間，發生的年紀與CAG重複數量呈反比。第一作者、波士頓麻州綜合醫院憂鬱症臨床研究計畫、哈佛醫學院精神科助理教授Roy H. Perlis醫師在電子郵件中向Medscape表示，HD是一種典型的CAG重複異常。
　　
　　被問到何以HD症狀直到中年才會出現時，Perlis醫師解釋，這可能是一種累積效應，這也是研究動機之一，如同我們在報告中指出的，在出現亨丁頓舞蹈症典型的動作症狀前10年、甚至更早，就會出現憂鬱症狀和躁動。
　　
　　過多的CAG重複可能會干擾粒線體之二磷酸腺酶的磷酸化作用。英國倫敦國王學院精神科研究中心情感性疾患臨床講師Rudolf Uher博士向Medscape Psychiatry表示，粒線體磷酸化是每個細胞產生能量的引擎。
　　
　　Uher博士指出，當磷酸化被阻斷時，細胞功能受損，甚至連需要相當多能量的神經細胞也是，事實上，HD花了超過30年以上，這也顯示出我們腦容量的確是相當大。
　　
　　這個案例控制研究探討了重度憂鬱異常組(n = 34人)和性別、年紀、教育和種族條件相仿的健康對照組(n = 74人)之CAG重複數量的關聯，案例組有兩個人的CAG重複、36和37組，但是控制組沒有人的重複組數超過正常範圍 (費雪精確性檢定，P = .098)。
　　
　　在第二個「發現世代」中，從「Sequenced Treatment Alternatives to Relieve Depression (STAR*D)」這項多中心研究獲得1493名白人病患之DNA (自我報告)。控制組DNA來源是重複組數較少之4007名HD病患的染色體，在STAR*D病患中，DNA分析發現四種變化：36、37、38和42組CAG重複，控制組沒有人超過正常範圍(費雪精確性檢定，P = .006)。
　　
　　德國一個住院單位中，在診斷有憂鬱者的病患(n = 601人)重複進行，控制組(n = 1339人)招募自同一地區，作為神經精神研究的對照組。憂鬱症病患發現有單一種擴大重複(38組的CAG)，控制組則無(費雪精確性檢定、 P = .31)。合併這三個世代，憂鬱組有7組重複超出正常範圍，對照組則是都沒有(費雪精確性檢定，P = .001)。
　　
　　結果顯示，重度憂鬱異常病患中，「低檔」HD相關對偶基因的發生率高於預期，解釋之一是，憂鬱是後來發生HD的早期表現。另一個可能性導致更加了解「邊緣性」或「不完全外顯」對偶基因(36-39組CAG重複)，並未發現有臨床特徵，這些對偶基因可能會引起憂鬱但是不會導致HD。
　　
　　不論哪個案例，結果認為，醫師必須問重度憂鬱病患有關動作異常之家族史，並進行完整的神經學檢查。
　　
　　Perlis醫師表示，這個罕見的基因變化依舊只佔整體憂鬱風險中相當少數的部份，我強調的是，我們不建議憂鬱病患進行基因檢測，因為還相當不成熟。
　　
　　Perlis醫師結論表示，但是，我們要指出的是，憂鬱症狀出現其他許多神經異常，出現憂鬱之病患的臨床評估必須將神經症狀納入考量，因此，我們主張密切的臨床評估而非基因檢測。
　　
　　Perlis醫師接受來自AstraZeneca、Bristol-Myers Squibb、Eli Lilly、Elan/Eisai、GlaxoSmithKline、Pfizer和U.S. Pharmaceuticals Group的研究支持、顧問費用、發言費用或獎金，擁有Concordant Rater Systems LL的股票和專利。Uher博士宣告沒有相關財務關係。
　　
　　Am J Psychiatry. 線上發表於2010年4月1日。


Genetic Abnormality in Huntington's Disease More Frequent in Those With Depression

By Jacquelyn K. Beals, PhD
Medscape Medical News

April 15, 2010 — An increased number of CAG repeats — the genetic abnormality causing Huntington’s disease (HD) — is more frequent among patients with major depressive disorder than in the general population, according to a recent study published online April 1 in the American Journal of Psychiatry.

Depression, as well as problems with impulse control, cognitive symptoms, and irritability, occurs more often in patients who will eventually develop HD, but the associated CAG repeat had not previously been studied in patients with major depressive disorder.

HD results from a mutation in HTT (the Huntingtin gene) and is an autosomal dominant disorder, requiring only 1 mutant allele for clinical symptoms to be expressed. The mutation consists of an expanded "trinucleotide repeat," a sequence of the 3 nucleotides C, A, and G, that encode the amino acid glutamine in the Huntingtin protein.

People with 6 to 34 repeats of the CAG sequence are clinically normal, those with 36 to 39 repeats are somewhat likely to develop symptoms, and 40 or more repeats cause HD. The number of repeats tends to increase each time the gene is inherited. Maternal inheritance usually involves increases (or, less often, decreases) of up to 5 repeats; paternal inheritance typically involves increases averaging 10 repeats.

A further characteristic of HD is that symptoms appear between the ages of 30 and 50 years, with age at onset varying inversely with the number of CAG repeats. HD is a "prototypical CAG repeat disorder," said first study author Roy H. Perlis, MD, MSc, assistant professor of psychiatry, Harvard Medical School, and Depression Clinical and Research Program, Massachusetts General Hospital, Boston, in his email to Medscape.

Asked why HD symptoms do not appear until middle age, Dr. Perlis explained, "It may be a cumulative effect...Part of the motivation for the study, as we point out in the paper, is that depressive symptoms and irritability may be present a decade or more before the characteristic movement symptoms in Huntington’s."

The expanded CAG repeats probably interfere with phosphorylation of adenosine diphosphate in the mitochondria. "Mitochondrial phosphorylation is the engine producing energy for each cell," Rudolf Uher, PhD, MRCPsych, clinical lecturer in affective disorders at the Institute of Psychiatry, King’s College London, United Kingdom, told Medscape Psychiatry.

"When [phosphorylation] is blocked, the cell function deteriorates. And this is even more so for neural cells [that] will have high energy demands." Dr. Uher added, "The fact that it takes more than 30 years for [HD] to manifest itself is a testimony to how great the reserves of our brains are."

This case-control study investigated associations between the number of CAG repeats in a group with major depressive disorder (n = 34) and a healthy group matched by sex, age, education, and ethnicity (n = 74). Two persons in the case group had CAG repeats of 36 and 37, but no repeats above the normal range were found in the control group (Fisher’s exact test, P = .098).

In a second "discovery cohort," DNA was obtained from 1493 white patients (self-reported) from the multicenter Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. The control DNA source was the chromosome with the shorter repeat, from 4007 HD patients. Among the STAR*D patients, DNA analysis found 4 variants with 36, 37, 38, and 42 CAG repeats. None of the control group had repeats outside the normal range (Fisher’s exact test, P = .006).

Replication was performed in patients (n = 601) diagnosed as having depression from a German inpatient unit. The control group (n = 1339) had been recruited from the same region as a comparison group for neuropsychiatric studies. A single expanded repeat (38 copies of CAG) was found among depression patients but none of the control group (Fisher’s exact test, P = .31). Combining the 3 cohorts yielded 7 repeats outside the normal range among depression cohorts and none in the comparison groups (Fisher’s exact test, P = .001).

The results show a higher than expected occurrence of "low-end" HD-associated alleles among patients with major depressive disorders. One interpretation is that the depression is an early presentation of later-developing HD. Another possibility leads to greater understanding of "borderline" or "incompletely penetrant" alleles (36 to 39 CAG repeats) for which no clinical characteristics have been defined. These alleles may cause depression but not lead to HD.

In either case, the results suggest that clinicians should ask patients with major depressive disorders about their family history of movement disorders, as well as doing a thorough neurological examination.

"This rare genetic variant still accounts for only a very small amount of the overall risk for depression," said Dr. Perlis. "I would emphasize that we are not suggesting genetic testing in people with depression, which would be extremely premature.

"Rather, we wanted to point out that many other neurologic disorders present with depressive symptoms and that clinical assessment of the patient presenting with depression includes consideration of neurologic symptoms. So we’re arguing for closer clinical assessment and emphatically not genetic testing," Dr. Perlis concluded.

Dr. Perlis has received research support, advisory or consulting fees, or speaking fees or honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Elan/Eisai, GlaxoSmithKline, Pfizer, and U.S. Pharmaceuticals Group and has equity holdings in and patents for Concordant Rater Systems LLC. Dr. Uher has disclosed no relevant financial relationships.

Am J Psychiatry. Published online April 1, 2010.