本帖最後由 lsc0019 於 2009-11-16 21:14 編輯
作者：Jacquelyn K. Beals, PhD
出處：WebMD醫學新聞
October 28, 2009 (檀香山) —一篇新研究提供異常能量代謝是有些泛自閉症障礙(autism spectrum disorders，ASDs)者的潛在機轉的證據。該報告發表於美國人類遺傳協會(American Society of Human Genetics)第59屆年會，評估一大群疑似粒線體疾病者的ASD盛行率，總論粒線體疾病與細胞核缺損的關係，發現有證據指出，能量代謝受干擾是ASD中某特定類別病患的潛在病理機轉。
ASDs定義為缺乏社交互動、認知與溝通技巧不佳、且有重複行為。3歲之前即可發現這些缺陷，認知功能、學習、注意力與感覺處理等通常也同時有缺陷。一般透過臨床觀察其發展而診斷。
自閉症目前被視為嚴重的ASDs之一，包括「待分類的廣泛性發展障礙(pervasive developmental disorder not otherwise specified；簡稱PDD-NOS)」以及亞斯伯格症候群。目前，大致上還缺乏可及早辨識的生物與基因標記。疾病控制與預防中心在2007年2月的一篇報告中，估計美國的ASDs盛行率約為每1,000名孩童有6.7例，即0.67%。
粒線體呼吸鏈疾病(Mitochondrial respiratory chain disease，MRCD)是一種複雜的雙重基因組疾病。發表者、德州休士頓Baylor醫學院分子與人類遺傳系的Lee-Jun C. Wong博士指出，超過200個基因瞄準著粒線體，所以細胞核和/或粒線體基因組的缺陷會影響到粒線體功能。這些異常可能是自體隱性或顯性疾病、與性別有關、或母系遺傳。因此，包括MRCD和ASDs都是遺傳性異型合子異常。
Wong博士向Medscape Pathology表示，粒線體是唯一含有自己的DNA細胞器。所以，要成為雙重基因組疾病，勢必與粒線體內的DNA有關。她解釋，粒線體基因組可能有原發缺陷，但是粒線體無法單靠粒線體基因組就發揮功能，還需要細胞核基因，所以一定會有交互作用。
目前的研究回顧了在Baylor醫學院粒線體診斷實驗室、與德州兒童醫院小兒基因門診接受評估的4,000名以上研究對象的紀錄。在這4,000名以上懷疑有粒線體功能不佳者之中，282人顯示有自閉症特徵(ASD)。沒有ASD者中，男性/女性之比率接近1，但是，有ASD者中，此比率為1.74。研究者也發現，疑似有MRCD和確認ASD的男性比女性多。
有ASD的282人中，14人(10名男性與4名女性)符合粒線體疾病的修改版Walker氏診斷規範。這些人的染色體微陣列分析、X染色體脆折症、安格曼症候群、蕾特氏症等檢測為陰性。與他們ASD有關的神經學特徵包括運動失調、肌張力失調、抽搐異常與發展遲緩。這14人全部都有分子或生化問題 。
14人中，8人有電子傳遞鏈異常(4人有共同的粒線體突變)；此外，2名女性有運動失調，其他問題包括細胞核基因POLG突變，此基因的功能為複製人類粒線體DNA。這14名ASD患者的其他細胞核基因突變包括SCO2、TWINKLE、SUCLA2等與粒線體DNA缺陷的其他基因。一名病患有同合子SCO2突變，也有COX缺陷；2人有原發LHON突變。
Wong博士表示，粒線體製造能量，而腦部功能需要大量能量運作；所以我們認為，如果粒線體功能不佳，腦部功能可能也無法順利運作，因此而引起ASD。
會議共同主持人、賓州UPMC匹茲堡兒童醫院遺傳醫學主任、公共衛生研究所人類遺傳學教授、匹茲堡大學醫學院小兒科教授Jerry Vockley博士接受Medscape Pathology訪問時表示，不過，ASD的診斷相當沒有特定性，幾乎每個人都可以適用。
Vockley博士表示，如果你接獲這些其他症狀與自閉症異常，你會追蹤與檢查呼吸鏈不佳嗎？絕對會！但是如果你除了泛自閉症障礙、輕微或嚴重神經腦部缺陷外什麼都沒有，也沒有其他身體方面的發現、沒有神經肌肉方面的發現、沒有乳酸中毒、代謝分析也沒有發現，是否還值得進行粒線體功能不佳檢查呢？目前沒有資料認為值得一試。
Vockley博士認為，自閉症孩童進行基本的神經代謝篩檢、以及各種血液和尿液檢查是合理的，甚至還可以進行皮膚切片檢測酵素。
但是如果你沒有任何症狀或代謝分析指向粒線體，那麼，肌肉切片是相當侵犯性的，我不認為我們有資料支持進行肌肉切片是合理的。
Vockley博士指出，問題是越來越多這兩種異常的診斷。如果你這兩者的邊緣，也就是兩者的非典型表徵，兩者都足以進行交叉評估。問題是：它們在功能上有交互影響嗎？我們目前還未研究到此領域。
Wong博士與Vockley博士皆宣告沒有相關財務關係。
美國人類遺傳協會第59屆年會：摘要62。發表於2009年10月22日。
Disturbed Energy Metabolism May Be a Factor in Some Autism Spectrum Disorders
By Jacquelyn K. Beals, PhD
Medscape Medical News
October 28, 2009 (Honolulu, Hawaii) — A new study provides evidence of abnormal energy metabolism as an underlying mechanism in some individuals with autism spectrum disorders (ASDs). The report, presented here at the American Society of Human Genetics 59th Annual Meeting, evaluated the prevalence of ASD in a large population with suspected mitochondrial disease, summarized the mitochondrial and nuclear defects, and found "evidence that there is disturbed energy metabolism as an underlying pathological mechanism in a specific subset of patients within the spectrum of ASD."
ASDs are defined by deficits in social interaction, impaired perception and communication skills, and repetitive behavior. Impairments are usually identified before a child is 3 years old, and often coexist with abnormal cognitive functioning, learning, attention, and sensory processing. Diagnosis is typically reached through clinical observation of development.
Autism is now considered 1 of several ASDs, which also include pervasive developmental disorder not otherwise specified and Asperger's syndrome. Currently, biological and genetic markers for early identification are largely lacking. A February 2007 Centers for Disease Control and Prevention report estimated the prevalence of ASDs in the United States to be approximately 6.7 children out of 1000, or 0.67%.
Mitochondrial respiratory chain disease (MRCD) is a complex dual-genome disease. Presenter Lee-Jun C. Wong, PhD, from the Department of Molecular and Human Genetics at Baylor College of Medicine in Houston, Texas, noted in her talk that more than 200 genes are targeted to mitochondria, so defects in nuclear and/or mitochondrial genomes can affect mitochondrial function. Disorders can be autosomal recessive or dominant, sex-linked, or maternally inherited. Thus, both MRCD and ASDs are genetically heterogeneous disorders.
"Mitochondria are the only organelles that contain their own DNA. So, in order to be a dual [genome disease], you have to have DNA in the mitochondria involved," Dr. Wong told Medscape Pathology. She explained that a primary defect can be in the mitochondrial genome, but mitochondria are unable to function alone with just the mitochondrial genome. Nuclear genes are also required, so there will always be interaction.
The current study reviewed the records of more than 4000 individuals evaluated by the Mitochondrial Diagnostic Laboratory at Baylor College of Medicine and the Pediatric Genetics Clinic at Texas Children's Hospital in Houston. Among more than 4000 individuals suspected of having mitochondrial dysfunction, 282 showed autistic features (ASD). The male/female ratio was close to 1 in those without ASD, but was 1.74 among individuals with ASD. The researchers also found more males than females with suspected MRCD and definite ASD.
Of the 282 individuals with ASD, 14 (10 males and 4 females) met the modified Walker diagnostic criteria for mitochondrial disease. These individuals tested negative on chromosome microarray analysis, fragile?X syndrome, Angelman syndrome, and Rett syndrome, among other tests. Neurological characteristics accompanying their ASD included ataxia, dystonia, seizure disorder, and developmental delay. All 14 demonstrated molecular or biochemical problems.
Electron transport chain abnormalities were detected in 8 of the 14 individuals (4 had a common mitochondrial mutation); in addition, 2 females with ataxia and other problems had mutations of the nuclear gene POLG, which functions in the replication of human mitochondrial DNA. Additional nuclear gene mutations among the 14 ASD individuals affected SCO2, TWINKLE, SUCLA2, and other genes involved in mitochondrial DNA depletion. One patient with a homozygous SCO2 mutation also showed COX deficiency; 2 had primary LHON mutations.
"Mitochondria are making energy, but brain function requires a lot of energy," Dr. Wong said. So we think that if you have mitochondrial dysfunction, you probably also have a brain [that does] not function very well. And that's what causes the ASD."
However, the diagnosis of ASD is "so nonspecific that you can almost apply it to anyone," observed session comoderator Jerry Vockley, MD, PhD, professor of pediatrics at the University of Pittsburgh School of Medicine, professor of human genetics at the Graduate School of Public Health, and chief of medical genetics at the Children's Hospital of Pittsburgh of UPMC in Pennsylvania, in an interview with Medscape Pathology.
"If you've got all these other symptoms and autism spectrum disorder, should you follow-up and look for respiratory chain deficiency? Absolutely!" said Dr. Vockley. "But if you have nothing but autism spectrum disease, mild — even severe — neurointellectual deficits, and no other somatic findings, no neuromuscular findings, no lactic acidosis, nothing on metabolite analysis, is it worth looking for mitochondrial dysfunction??.?.?. There are no data right now that suggest that it's worth doing."
Dr. Vockley feels that a basic neurometabolic screen is reasonable in children with autism, as well as various blood and urine tests, and perhaps even a skin biopsy for enzyme testing.
"But if you don't have anything on either symptom or metabolite analysis that points to the mitochondria, the next step is very invasive — it's muscle biopsy. I don't think that we have the data yet to say?.?.?. that's a reasonable thing to do," he said.
"The problem is that both disorders are becoming quite frequently diagnosed. If you look at the fringes of both, the atypical presentations for either, both are frequent enough that eventually they're goIng to intersect," noted Dr. Vockley. "The question is: Do they intersect functionally? And we're not there yet."
Dr. Wong and Dr. Vockley have disclosed no relevant financial relationships.
American Society of Human Genetics (ASHG) 59th Annual Meeting: Abstract 62. Presented October 22, 2009. |
|
