AbstractPompe disease (PD) is a rare autosomal recessive glycogen storage disorder that causes proximal muscle weakness and loss of respiratory function. While enzyme replacement therapy (ERT) is the only effective treatment, biomarkers for disease monitoring are scarce. Following ex vivo biomarker validation in phantom studies, we apply multispectral optoacoustic tomography (MSOT), a laser- and ultrasound-based non-invasive imaging approach, in a clinical trial (NCT05083806) to image the biceps muscles of 10 late-onset PD (LOPD) patients and 10 matched healthy controls.

摘要龐貝?。≒D）是一種罕見的常染色體隱性糖原貯積病，可導(dǎo)致近端肌肉無力和呼吸功能喪失。雖然酶替代療法（ERT）是唯一有效的治療方法，但用于疾病監(jiān)測的生物標(biāo)志物卻很少。在體模研究中進(jìn)行離體生物標(biāo)志物驗證后，我們在臨床試驗（NCT05083806）中應(yīng)用多光譜光聲斷層掃描（MSOT），一種基于激光和超聲波的非侵入性成像方法，對10例遲發(fā)性PD（LOPD）患者和10例相匹配的健康對照者的肱二頭肌進(jìn)行成像。

MSOT is compared with muscle magnetic resonance imaging (MRI), ultrasound, spirometry, muscle testing and quality of life scores. Next, results are validated in an independent LOPD patient cohort from a second clinical site. Our study demonstrates that MSOT enables imaging of subcellular disease pathology with increases in glycogen/water, collagen and lipid signals, providing higher sensitivity in detecting muscle degeneration than current methods.

MSOT與肌肉磁共振成像（MRI），超聲波，肺活量測定，肌肉測試和生活質(zhì)量評分進(jìn)行比較。接下來，在第二個臨床站點的獨立LOPD患者隊列中驗證結(jié)果。我們的研究表明，MSOT可以通過增加糖原/水，膠原蛋白和脂質(zhì)信號來對亞細(xì)胞疾病病理學(xué)進(jìn)行成像，從而比目前的方法在檢測肌肉變性方面提供更高的靈敏度。

This translational approach suggests implementation in the complex care of these rare disease patients..

這種轉(zhuǎn)化方法建議在這些罕見疾病患者的復(fù)雜護(hù)理中實施。。

IntroductionPompe disease (PD) is a rare, autosomal-recessive metabolic myopathy caused by mutations in the gene that encodes for acid alpha-glucosidase (GAA)1,2,3. Regularly, GAA catalyzes the hydrolysis of glycogen to glucose, but in PD, its impaired activity results in a generalized build-up of glycogen in metabolic active organs, such as heart, muscle and liver4,5.

簡介龐貝病（PD）是一種罕見的常染色體隱性代謝性肌病，由編碼酸性α-葡萄糖苷酶（GAA）1,2,3的基因突變引起。通常，GAA催化糖原水解為葡萄糖，但在PD中，其活性受損導(dǎo)致代謝活性器官（如心臟，肌肉和肝臟）中糖原的普遍積累4,5。

The disease progress is variable in age of onset, severity of organ involvement and degree of myopathy6. There is a differentiation in infantile (IOPD) and late-onset (LOPD) forms based on cardiac involvement, age of onset and residual enzyme activity7. IOPD patients may have less than 1% GAA activity, therefore, quickly develop severe symptoms, such as cardiac involvement, resulting in a high mortality rate by year one if untreated1,8.

疾病的進(jìn)展因發(fā)病年齡，器官受累的嚴(yán)重程度和肌病程度而異6。根據(jù)心臟受累，發(fā)病年齡和殘留酶活性，嬰兒（IOPD）和遲發(fā)（LOPD）形式存在差異7。IOPD患者的GAA活性可能低于1%，因此，如果不治療，很快就會出現(xiàn)嚴(yán)重癥狀，例如心臟受累，導(dǎo)致第一年的死亡率很高1,8。

Children and adults with LOPD have residual enzyme activity below 30%, leading to more slowly progressive limb-girdle type weakness and respiratory insufficiency9,10. Replacement therapies (ERT) are available, leading to a slower progression of cardiac and musculoskeletal involvement, prevention of deterioration of pulmonary function and increasing survival11,12,13,14.

。替代療法（ERT）是可用的，導(dǎo)致心臟和肌肉骨骼受累的進(jìn)展較慢，預(yù)防肺功能惡化并提高生存率11,12,13,14。

However, an early initiation of treatment may positively impact the overall treatment response15.The diagnosis of PD is usually established by confirmation of GAA deficiency, and confirmed by genetic testing16,17. Furthermore, PD patients require regular clinical follow-up monitoring, especially to assess the response to ERT8,9,17,18,19,20.

然而，早期開始治療可能會對整體治療反應(yīng)產(chǎn)生積極影響15。PD的診斷通常通過確認(rèn)GAA缺乏來確定，并通過基因檢測來證實16,17。此外，PD患者需要定期進(jìn)行臨床隨訪監(jiān)測，特別是評估對ERT8,9,17,18,19,20的反應(yīng)。

While rapid determination of GAA in dried blood spots is possible, enzymatic analysis is unable to discriminate between patients with PD and those individuals harboring pseudo deficiency mutations. In this regard, a tetraglucose oligomer (Glc(4)) in the urine and maltotet.

雖然可以快速測定干血斑中的GAA，但酶分析無法區(qū)分PD患者和攜帶偽缺陷突變的個體。在這方面，尿液和麥芽糖中的四葡萄糖低聚物（Glc（4））。

The raw (individual, identifiable patient) data are protected and are not available due to data privacy laws. Data sharing requests will be considered on a case-by-case basis. The processed pseudonymized imaging data can be accessed upon request and within the framework of legal regulations from the corresponding author (equivalent purposes to those for which the patients grant their consent to use the data).

原始（個人，可識別的患者）數(shù)據(jù)受到保護(hù)，并且由于數(shù)據(jù)隱私法而不可用。數(shù)據(jù)共享請求將根據(jù)具體情況予以考慮。可以根據(jù)要求并在相應(yīng)作者的法律法規(guī)框架內(nèi)訪問處理后的假名成像數(shù)據(jù)（與患者同意使用數(shù)據(jù)的目的相同）。

Access is granted directly after publication for 36 months. The contact is ki-forschung@uk-erlangen.de, and response to request will be provided within 4–6 weeks. The data will be available for 3 months. The remaining data of this study are provided in the Supplementary Information and Source Data file.

出版36個月后直接授予訪問權(quán)限。聯(lián)系人是ki-forschung@uk-erlangen.de，并將在4-6周內(nèi)對請求做出響應(yīng)。數(shù)據(jù)將持續(xù)3個月。這項研究的其余數(shù)據(jù)在補充信息和源數(shù)據(jù)文件中提供。

The study protocols and the statistical analysis plan are provided with this manuscript in the Supplementary information file. Source data are provided with this paper..

。本文提供了源數(shù)據(jù)。。

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JACC Cardiovasc. Imaging 16, 719–721 (2023).Download referencesAcknowledgementsThe research was supported by a research Grant from Sanofi Aventis (SGZ201912542) for A.L.W., R.R., R.T. and F.K. and an EU-IMI2 JU research grant (www.screen4care.eu) under the grant agreement No. 101034427 for V.D., S.M., J.Z., F.A., R.T., A.L.W., R.R. and F.K.

JACC心血管。成像16719-721（2023）。下載參考文獻(xiàn)致謝該研究得到了賽諾菲-安萬特（SGZ201912542）的研究資助。五十、 W.，R.R.，R。T、 。

The JU receives support from the European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Association. Further support was provided by the European Research Council under the European Union Horizon H2020 program (ERC Starting Grant No. 101115742-IseeG) for F.K and an Else Kr?ner Excellence Fellowship from the Else-Kr?ner Fresenius Stiftung for A.P.R.

JU得到了歐盟地平線2020研究與創(chuàng)新計劃和歐洲制藥工業(yè)與協(xié)會聯(lián)合會的支持。歐洲研究理事會根據(jù)歐盟地平線H2020計劃（ERC起始資助號101115742 IseeG）為F.K提供了進(jìn)一步的支持，并為A.P.R.提供了Else Kr?ner Fresenius Stiftung的Else Kr?ner卓越獎學(xué)金。

A.L.W. was supported by the Rahel Hirsch Program scholarship from the Charité University Hospital Berlin. The present work was performed in (partial) fulfillment of the requirements for obtaining the degree “Dr. med.” for L.T. The sponsors of the study had no influence on study design, data collection and analysis or manuscript writing.FundingOpen Access funding enabled and organized by Projekt DEAL.Author informationAuthor notesThese authors contributed equally: Alexandra L.

A、 L.W.得到了柏林Charité大學(xué)醫(yī)院Rahel Hirsch計劃獎學(xué)金的支持。目前的工作是（部分）滿足L.T.獲得“醫(yī)學(xué)博士”學(xué)位的要求。該研究的贊助商對研究設(shè)計，數(shù)據(jù)收集和分析或手稿撰寫沒有影響。資金開放獲取資金由Projekt交易啟用和組織。作者信息作者注意到這些作者做出了同樣的貢獻(xiàn)：Alexandra L。

Wagner, Roman Raming, Ferdinand Knieling.Authors and AffiliationsDepartment of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-Universit?t (FAU) Erlangen-Nürnberg, Erlangen, 91054, G.

瓦格納、羅曼·拉明、費迪南德·克尼林。作者和附屬機構(gòu)埃爾蘭根大學(xué)醫(yī)院兒科和青少年醫(yī)學(xué)系，弗里德里?！啔v山大大學(xué)（FAU）埃爾蘭根-紐倫堡，埃爾蘭根，91054，G。

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PubMed Google ScholarContributionsL.T., A.L.W., J.Z., A.P.R., V.D., R.R., and F. K. designed, performed experiments, and clinical studies. J.J., V.D., and S.S., S.M., A.S., and H.B. performed clinical studies. J.Z., M.T., U.R., Y.L., W.L., A.H., R.T., A.M., M.W., J.W., and R.H.

PubMed谷歌學(xué)術(shù)貢獻(xiàn)l。T、 ，A.L.W.，J.Z.，A.P.R.，V.D.，R.R。和F.K.設(shè)計，進(jìn)行實驗和臨床研究。J、 J.，V.D。和S.S.，S.M.，A.S。和H.B.進(jìn)行了臨床研究。J、 。

provided essential support to the clinical study. U.R., F.A., M.V., and L.S. provided essential materials or technical expertise. L.T., R.R., A.L.W., M.C., and F.K. analyzed and interpreted the data. F.K. conceived and supervised the project. L.T., R.R., and F.K. wrote the first draft of the manuscript.

為臨床研究提供了必要的支持。U、 R.，F(xiàn).A.，M.V.和L.S.提供了必要的材料或技術(shù)專業(yè)知識。五十、 T.，R.R.，A.L.W.，M.C。和F.K.分析并解釋了數(shù)據(jù)。F、 K.構(gòu)思并監(jiān)督了該項目。五十、 T.，R.R。和F.K.撰寫了手稿的初稿。

All authors edited and approved the final draft.Corresponding authorCorrespondence to.

所有作者都編輯并批準(zhǔn)了最終草案。對應(yīng)作者對應(yīng)。

Ferdinand Knieling.Ethics declarations

費迪南德·克尼林。道德宣言

Competing interests

相互競爭的利益

A.P.R. and F.K. are co-inventors together with iThera Medical GmbH, Germany, on an EU patent application (EP 19 163 304.9) relating to a device and a method for analyzing optoacoustic data, an optoacoustic system and a computer program. F.K. is a member of the advisory board of iThera Medical GmbH, Munich, Germany.

A、 P.R.和F.K.與德國iThera Medical GmbH共同發(fā)明了一項歐盟專利申請（EP 19 163 304.9），涉及一種用于分析光聲數(shù)據(jù)、光聲系統(tǒng)和計算機程序的裝置和方法。F、 K.是德國慕尼黑iThera Medical GmbH咨詢委員會成員。

A.P.R. and F.K. received travel support from iThera Medical GmbH, Germany. A.P.R., A.L.W., and F.K. report travel support from Sanofi Aventis, Germany. A.P.R. and F.K. report lecture fees from Sanofi Genzyme. F.K. reports lecture fees from Siemens Healthcare GmbH. The other authors declare no competing interests..

A、 P.R.和F.K.獲得了德國iThera Medical GmbH的旅行支持。A、 P.R.、A.L.W.和F.K.報告了來自德國賽諾菲-安萬特的旅行支持。A、 P.R.和F.K.報告賽諾菲基因酶的講座費用。F、 K.報道了西門子醫(yī)療保健有限公司的講座費用。其他作者聲明沒有利益沖突。。

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The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

本文中的圖像或其他第三方材料包含在文章的知識共享許可中，除非在材料的信用額度中另有說明。如果材料未包含在文章的知識共享許可中，并且您的預(yù)期用途不受法律法規(guī)的許可或超出許可用途，則您需要直接獲得版權(quán)所有者的許可。

To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/..

要查看此許可證的副本，請訪問http://creativecommons.org/licenses/by/4.0/..

Reprints and permissionsAbout this articleCite this articleTan, L., Zschüntzsch, J., Meyer, S. et al. Non-invasive optoacoustic imaging of glycogen-storage and muscle degeneration in late-onset Pompe disease.

轉(zhuǎn)載和許可本文引用本文Tan，L.，Zschüntzsch，J.，Meyer，S。等人。遲發(fā)性龐貝病糖原儲存和肌肉變性的無創(chuàng)光聲成像。

Nat Commun 15, 7843 (2024). https://doi.org/10.1038/s41467-024-52143-6Download citationReceived: 09 December 2023Accepted: 26 August 2024Published: 08 September 2024DOI: https://doi.org/10.1038/s41467-024-52143-6Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《國家公社》157843（2024）。https://doi.org/10.1038/s41467-024-52143-6Download引文接收日期：2023年12月9日接收日期：2024年8月26日發(fā)布日期：2024年9月8日OI：https://doi.org/10.1038/s41467-024-52143-6Share本文與您共享以下鏈接的任何人都可以閱讀此內(nèi)容：獲取可共享鏈接對不起，本文目前沒有可共享的鏈接。復(fù)制到剪貼板。

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