作者：Susan Jeffrey 齣處：WebMD醫學新聞 　　July 31, 2009 — 一項發錶於7月30日新英格蘭醫學期刊的病例報告指齣 一種全新的癥候群稱為天門鼕氨酸－麩氨酸載體異構 . AGC1缺陷與異常髓鞘形成有關 - 趣味新聞網

發表日期 2009-08-15T04:54:31+08:00

     本帖最後由 lsc0019 於 2009-8-16 00:27 編輯

作者：Susan Jeffrey
齣處：WebMD醫學新聞

July 31, 2009 — 一項發錶於7月30日新英格蘭醫學期刊的病例報告指齣，一種全新的癥候群稱為天門鼕氨酸－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，這代錶神經元的粒綫體，將天門鼕氨酸排齣的能力不足，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醫師嚮Medscape神經學錶示，我們發現一種新癥候群以及一個新髓鞘生成不足的病例。

Wedell醫師附帶錶示，在AGC1缺陷中，我們顯示AGC1的功能喪失，這造成令人驚奇的錶現型。這個載體蛋白被認為是神經細胞産生能量所需，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。

他們的病例報告發錶於7月30日的新英格蘭醫學期刊。

【延遲發育】
這個病例描述瞭一位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，且到齣生後5個月時發育都是正常的，之後她開始錶現齣精神運動功能發育遲緩。作者們錶示，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鼕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，灰質仍然是相對閑置的，基底核與腦乾相對未受影響。

在基因學上，這位病童被發現在溶質載體傢族25、第12成員、以及SLC25A12基因發生同型閤子錯義突變，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瞭。

作者們錶示，粒綫體AGC1對於神經元具專一性，且提供細胞質天門鼕酸鹽。作為蘋果酸鹽－天門鼕酸鹽交換鍊的一部份，他可以促進細胞質NADH進行粒綫體氧化作用，這被認為在提供中樞神經係統（CNS）神經元能源上是重要的。然而，這個病例的髓鞘化低下，代錶天鼕門氨酸從神經元粒綫體排齣，使得髓鞘無法正常生長。

Wedell醫師錶示，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，所以迴到那個老鼠模式，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瞭一個診斷，但是這闡明瞭其中的生化學。

【與自閉癥有關？】
Wedell醫師錶示，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癥有關。

她指齣，病患與控製組受試者們的相連性研究，以及有自閉癥傢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係統當然會是很重要的，且我們可以從這個新的癥候群中學習。所以在那個情況下，這具有全麵的重要性。

她錶示，當從自閉癥中發現與AGC1的關係，這被假設與可能是因為能量製造功能受損，而得到與自閉癥相同的部分，但是這代錶那可能是錯的。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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