本帖最後由 lsc0019 於 2009-8-16 00:27 編輯
作者：Susan Jeffrey
出處：WebMD醫學新聞
July 31, 2009 — 一項發表於7月30日新英格蘭醫學期刊的病例報告指出，一種全新的症候群稱為天門冬氨酸－麩氨酸載體異構蛋白1（AGC1）缺陷，以腦部大腦半球整體髓鞘形成不足為特徵，這代表神經元的粒線體，將天門冬氨酸排出的能力不足，這可能妨礙正常髓鞘形成。
瑞典斯德哥爾摩Karolinska機構Karolinska大學醫院外科與分子醫學部門及先天性疾病中心的Anna Wedell醫師向Medscape神經學表示，我們發現一種新症候群以及一個新髓鞘生成不足的病例。
Wedell醫師附帶表示，在AGC1缺陷中，我們顯示AGC1的功能喪失，這造成令人驚奇的表現型。這個載體蛋白被認為是神經細胞產生能量所需，但是這位病患教導我們，這對鄰近寡樹突膠細胞製造髓鞘來說是相對重要的。
他們的病例報告發表於7月30日的新英格蘭醫學期刊。
【延遲發育】
這個病例描述了一位3歲女孩，她是第一胎，與另外一位瑞典病患是遠親。分娩過程並沒有問題，且到出生後5個月時發育都是正常的，之後她開始表現出精神運動功能發育遲緩。作者們表示，這位病患於7個月時開始發生癲癇，且在3歲8個月最後一次檢查時，她的精神運動功能並沒有進一步發育。血清中氨胺酸與天門冬氨酸濃度都在正常範圍。
他們寫到，這位病患無法繼續在沒有支撐下坐著、爬行、或是牽著維持站著的姿勢。她發生嚴重的抽搐，以及全身性的過度反射。其癲癇以carbamazepine與levetiracetam治療。
Wedell醫師與其同事們追蹤這位病童，於8個月、16個月、與2歲9個月時的核磁共振造影（MRI）顯示大腦半球整體缺乏髓鞘，腦幕上容積下降。然而，灰質仍然是相對閒置的，基底核與腦幹相對未受影響。
在基因學上，這位病童被發現在溶質載體家族25、第12成員、以及SLC25A12基因發生同型合子錯義突變，SLC25A12基因解碼AGC1蛋白。AGC1這個突變版本的功能分析顯示，這個基因的功能被破壞了。
作者們表示，粒線體AGC1對於神經元具專一性，且提供細胞質天門冬酸鹽。作為蘋果酸鹽－天門冬酸鹽交換鍊的一部份，他可以促進細胞質NADH進行粒線體氧化作用，這被認為在提供中樞神經系統（CNS）神經元能源上是重要的。然而，這個病例的髓鞘化低下，代表天冬門氨酸從神經元粒線體排出，使得髓鞘無法正常生長。
Wedell醫師表示，雖然僅有一個病患，但是這已經由過去報告過的基因剃除老鼠模式支持，所以回到那個老鼠模式，我們可以釐清那些分子機轉。罹患非常嚴重白質腦病變的兒童多了一個診斷，但是這闡明了其中的生化學。
【與自閉症有關？】
Wedell醫師表示，另一項使其發現吸引人的理由是，解碼突變AGC1蛋白的基因已經被證實與自閉症有關。
她指出，病患與控制組受試者們的相連性研究，以及有自閉症家族的連結研究已經將重心落在這個基因，且因為這個原因，瞭解這個蛋白質正常地在中樞神經系統當然會是很重要的，且我們可以從這個新的症候群中學習。所以在那個情況下，這具有全面的重要性。
她表示，當從自閉症中發現與AGC1的關係，這被假設與可能是因為能量製造功能受損，而得到與自閉症相同的部分，但是這代表那可能是錯的。或許這與髓鞘形成不佳有關，但那是非常不同的機轉。這相當令人興奮。
這項研究由瑞典研究委員會、Karolinska機構、斯德哥爾摩郡委員會、Ministero大學、義大利人類蛋白質組網絡、Apulia地區神經科技經費贊助。作者們報告沒有相關利益衝突。
Mutation in AGC1 Deficiency Linked to Abnormal Myelin Formation
By Susan Jeffrey
Medscape Medical News
July 31, 2009 — A new case report in the July 30 New England Journal of Medicine unveils a novel syndrome called aspartate-glutamate carrier isoform 1 (AGC1) deficiency, characterized by global hypomyelination in the cerebral hemispheres of the brain, and suggests that impaired efflux of aspartate from the mitochondria of neurons can stymie normal myelin formation.
"We found this new syndrome and a new cause of hypomyelination," Anna Wedell, MD, PhD, from the Center for Inherited Metabolic Diseases and the department of molecular medicine and surgery at Karolinska University Hospital-Karolinska Institutet, in Stockholm, Sweden, told Medscape Neurology.
In AGC1 deficiency, "we show that the function [of AGC1] is abolished, and that causes a surprising phenotype," Dr. Wedell added. "This transporter was thought to be required for energy production in the nerve cells, but this patient teaches us that it's rather important for the adjacent oligodendrocytes to make myelin."
Their case report appears in the July 30 issue of the New England Journal of Medicine.
Delayed Development
The case described is of a 3-year-old girl, the first-born child of distantly related Swedish parents. Delivery was uncomplicated, and development was normal for the child until about 5 months of age, when she began showing delayed psychomotor development. Seizures began at 7 months, and as of her last exam at 3 years, 8 months, she has had essentially no further progress in psychomotor development, the authors note. Plasma levels of glutamate and aspartate were within the normal range.
"The patient cannot sit without support, crawl, or be pulled to a standing position," they write. "Severe spasticity has developed, with generalized hyperreflexia. The epilepsy is treated with carbamazepine and levetiracetam."
Dr. Wedell and colleagues followed the child over time, with magnetic resonance imaging (MRI) done at 8 months, 16 months, and 2 years 9 months of age, and saw a global lack of myelination in the cerebral hemispheres, with reduced supratentorial cerebral volume. However, the gray matter was relatively spared, and the basal ganglia and brainstem relatively unaffected.
Genetically, the child was found to have a homozygous missense mutation in the solute carrier family 25, member 12, gene SLC25A12, which encodes the AGC1 protein. Functional analysis of this mutant version of AGC1 showed its activity was abolished.
Mitochondrial AGC1 is specific to neurons and muscle and supplies aspartate to the cytosol, the authors note. As a component of the malate-asparate shuttle, it enables the mitochondrial oxidation of cystolic NADH, which is thought to be important in providing energy to neurons in the central nervous system (CNS), they write. The hypomyelination in this case, however, suggests that impairment of the efflux of aspartate from neuronal mitochondria prevents the normal formation of myelin.
"There's only 1 patient, but this has been supported by a knockout mouse that has been reported previously, so going back to that mouse, we can clarify those molecular details," Dr. Wedell said. "It's 1 additional diagnosis to consider in these children who have a very severe leukoencephalopathy, but also it sheds light on the biochemistry."
Link to Autism?
Another reason their findings are interesting is that this gene that encodes the mutant AGC1 protein has been shown to be associated with autism, Dr. Wedell said.
"There are both association studies in patients and controls and linkage studies in families with autism that have landed on this gene, and for that reason it's of course very important to know what this protein does normally in the CNS, and that we can learn from this syndrome," she said. "So in that context, it's of more general importance."
When the association with AGC1 was found in autism, she said, "it was assumed that it was due to impaired energy production that you get the autistic component, but this could indicate that maybe that's not correct. Maybe it has to do with suboptimal myelin formation, and that's a very different mechanism. It's quite exciting."
The study is supported by grants from the Swedish Research Council, the Karolinska Institutet, the Stockholm County Council, the Ministero dell'Universita e della Ricerca, the Italian Human ProteomeNet, and Apulia Region Neurobiotech. The authors report no conflict of interest.
N Engl J Med. 2009;361:489-495. |
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