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View from inside: Nina, Glycogen storage disease warrior.
Journal of Inherited Metabolic Disease ( IF 4.2 ) Pub Date : 2020-05-07 , DOI: 10.1002/jimd.12246
Enrique Landelino Lande Contreras

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Our daughter Nina Contreras D'Agosto is a half‐Spanish, half‐Italian 30‐month‐old baby girl.

She is also known as Nina, the Von Gierke's Warrior, and she is unique. Not only because she lives with Glycogen Storage Disease (GSD) type 1b—an inherited metabolic condition that affects one out of 1 million people—but also because during her short life, and despite all her health‐related challenges, she has been able to raise a peaceful army of thousands of “Warriors In Action” to promote awareness about her disease and to raise funds (currently around 100 000 USD) to support GSD 1b research through her website www.ninalaguerrera.org and social networks #ninalaguerrera.org.

imageNina and her Warriros In Action in her yearly charity hike to raise funds for GSD gene therapy research.

Let us tell you her story, a story of love, fight, and hope.

She was born in Portogruaro, Nina's mother's hometown near Venice (Italy), and 2 months later, we moved to Alcalá la Real, Nina's father's hometown near Granada (Spain) to celebrate Christmas. At that time, our plan was to move abroad. We are both humanitarian workers, and we have always worked in different countries around the world, so we wanted to offer Nina a future made of multi‐cultural and pluri‐language exchanges and experiences.

However, things turned out to be much more difficult than initially expected. The day Nina got her first round of vaccinations, when she was 2 months old, she had a high fever and seizures. We had to run to the Emergency Room where they did blood work. They were so alarmed about the results that they thought there had to be a mistake and repeated the tests. Again, the results were awful, so they activated an emergency protocol, and Nina went through X‐ray, ultrasounds, and a spinal tap.

Nina's liver was enlarged, and her immune system was not fine. Some indicators were pointing to a possible bacterial infection, but some others (growth retardation, high uric and lactic acid) did not have an explanation at that time. It took 3 months to get an official diagnosis; first, it was clinically suspected and, later, confirmed through a genetic test.

imageNina the Warrior

It was an extremely hard time for us. Having our first and only 2‐month‐old baby girl diagnosed with an ultra‐rare, chronic, and very serious disease was the worst thing we had ever experienced. All the plans for a bright future abroad were over, and a huge battle in the dark against something unknown started. Our lives were changed forever, and our whole world crumbled without even time for mourning, a luxury you cannot afford with GSD type 1b. We needed to get hands‐on immediately to learn and to provide daily care as a little mistake in the treatment could be fatal and kill Nina.

GSD 1b is a very challenging disease. Patients are not able to convert glycogen into glucose, and they can quickly go into severe hypoglycaemia (which can lead to coma, brain damage, or death). Their only source of glucose is the one that they receive either from food or directly in blood through an IV. Their neutrophil count and functionality are lower than it should be, so they are prone to recurrent infections, and inflammatory bowel disease (IBD, Crohn‐like disease) will develop at some point in their life. Infections such as gastroenteritis and IBD make GSD 1b patients’ blood sugars very unstable, sometimes going down to zero and needing an IV to avoid death. On the top of all that, the lack of proper metabolic control has many other negative consequences.

Despite all these challenges, initially, we were told that GSD 1b could be treated in our countries following the existing guidelines. A diet with meals every 3 hours supported by cornstarch (a slow‐absorption carbohydrate, which helps have more stable blood sugars during longer periods), daily Granulocyte‐colony stimulating factor (GCSF) injections to increase the neutrophil count and vitamin E to improve neutrophil functionality, mesalazine to treat the IBD, and a long list of medicines (vitamin D, iron, calcium, probiotics, omega 3, multivitamins, etc.) to address the consequences of the lack of proper metabolic control could be enough for Nina to survive and be somehow stable.

However, Nina's case turned out to be a very severe and complex one: we had to feed her every 40 minutes during the day and with continuous feeding during the night. Despite this very demanding feeding schedule, she was often suffering unexplained hypoglycaemias. GCSF and vitamin E did not prevent several serious infections.

She had a very significant absorption problem, and even with strict monitoring, she went through unpredictable emergency situations in which she had seizures, one coma, and needed IVs, spending most of her short life admitted in hospitals. Even these long hospital stays were a risk considering the possibility of hospital‐acquired infections, potential human errors due to the complexity and rarity of the disease and its treatment, serious difficulties in setting up IVs, and so on.

During this time, our phone alarms used to ring dozens of times during the day and the night as reminders of feed times, medicines, injections, supplements, and so on. Our mood depended on the stability of Nina's blood sugars. If that was not enough, much work had to be done to train Nina to eat homemade food by mouth so that, at some point, she could get rid of the nasogastric tube and eat solid regular food. We are still struggling with it, but we know that, at some point, we will get there.

Even if it is hard to believe, thanks to our family's efforts and Nina's strong and positive spirit, she is growing up as a very happy baby, playing, singing, laughing; there has never been any sign of intellectual growth retardation, and actually, everybody says she is very smart.

In order to achieve that, Nina needed at least two people fully dedicated to her care 24/7. We were exhausted because of the demanding treatment and the stressful situation made worse by deprivation of sleep and proper rest at night while managing Nina's hypoglycaemias.

We had to request extended unpaid leave from our jobs to find the time and energy to devour GSD guidelines to know the disease, to take care of Nina, and to find the time to get in touch with the two best GSD experts in the world. We succeeded, and actually, Nina spent her first birthday with one of them, and the second one with the other. Maybe it was pure coincidence, but we like seeing it as the best possible presents she could ever have: these two doctors are not only excellent and brilliant professionals but also very beautiful and kind human beings who have done much to support us.

imageNina's second birthday during a hospital stay in The Netherlands with her parents and grandma

Given the severity of Nina's case, at some point, there was the need to go for a hospital admission abroad, in The Netherlands, to follow an innovative, experimental, and off‐label treatment. It was a complex and beautiful “odyssey” to which we were entitled based on the European Union Directive 2011/24/EU on patients’ rights in cross‐border healthcare. We were very much supported by the doctor who would be treating Nina, by some members of the Italian health authorities, and by the European Reference Network for Hereditary Metabolic Disorders. It was amazing teamwork and an excellent example of cross‐border healthcare within the European Union.

We are extremely thankful to all of them for all the genuine efforts they made to ensure that Nina could get the best possible treatment, which was based on a publication by Veiga‐da‐Cunha et al (PMID: 30626647) followed up by a very recent article by Wortmann SB, Van Hove JLK, Derks TGJ, et al. "Treating neutropenia and neutrophil dysfunction in glycogen storage disease 1B with an SGLT‐2‐inhibitor" published by Blood (doi: 10.1182/Blood 2019004465).

Before going to The Netherlands, the leading doctor informed us about the treatment, its expected benefits, and its relative contraindications. We were convinced that the benefits would outweigh the risks, so we went for it.

The preparation and implementation of the trip were intense, full of heavy workload and stressful. Apart from the regular arrangements we all do for a normal trip, we had to travel with plenty of medical supplies, we had to be ready for a possible emergency, we needed much paperwork, and we still had to control Nina's blood sugars and feed her every 40 minutes (in the car, in the plane, in the taxi, at the hotel reception, etc.) However, we were so full of hope that everything would go smoothly, and we managed to get to our destination safely.

Once we were there, we started the treatment with the introduction of a new medicine called empagliflozin, taking several measures to ensure safety and having designed a contingency plan. Empagliflozin improved Nina's neutrophil count and, more importantly, their functionality. As a wonderful consequence, her absorption problem started disappearing as her neutrophils were in a better position to fight the potential bacteria in her digestive system. Finally, Nina was able to tolerate cornstarch, something which helped her have much longer fasting periods.

At that stage, we had different options: to have meals followed by cornstarch during the whole day (approximately 6‐8 meals in 24 hours) or to have these meals during the daytime (3‐4 meals) and continuous feeding during the night. It was also possible to establish a schedule so that these meals were given at specific times every day or to go for an anticipatory dietary approach and basically feed Nina whenever her blood sugars were down to around 72 mg/dL or 4 mmol/L.

Today, we are back home, and Nina is doing much better. Her blood sugars are more stable; we chose the dietary anticipatory approach, and her meals take place every 3 to 4 hours (with a little snack in between). Her immune system is strengthened, she eats a little bit better by mouth, she has grown a few centimetres in height, and she has lost some weight (a positive thing considering she was overweight).

imageNina enjoying nature

We also have a very nice memory of our hospital stay. We felt welcomed and were listened to with plenty of kindness. We were invited to multidisciplinary meetings to discuss Nina's case, and our opinion was genuinely considered to design the way forward. The centrality of the patient approach worked at its best.

Once in a while, we still have some difficult days: sometimes, out of the blue, Nina needs more frequent meals to remain stable, and her blood sugars drop faster. There are endless possible reasons behind these episodes: growth spurts, teeth coming out, a virus, a bacterial infection, even a nightmare. It can take us a few days to know what is going on, and sometimes, we never know what really happened. We just go through it, hoping it will not last long, getting ready for a possible emergency but also trying our best to avoid a hospital stay. In any case, these periods are also much less challenging than they used to be before the new treatment.

GSD 1b remains a very challenging disease, but at least, we have greatly improved our situation. We hope that, as Nina grows up, things will become even easier, and maybe after some years, she will be in a position to receive the enzymatic and gene therapies being developed in the research we are supporting.

We would love for other GSD1b patients with similar challenges to be as lucky as we have been and have access to the best possible healthcare for their respective cases. At this stage, it is still a bit challenging; it takes time to implement a new treatment and to build the scientific evidence before it becomes available to most patients. But we will hopefully get there as soon as possible, and we will try to start supporting initiatives in this way through www.ninalaguerrera.org. Please do not hesitate to visit our website and social networks if you wish to collaborate.

To conclude, we would like to say that we have no words to express our endless gratitude to every person and institution implied along this process, which vastly improved our quality of life, and to all those who have given Nina so much love and so much hope during all her life. Family, friends, “Warriors In Action”, other GSD families, researchers, doctors, nutritionists, nurses, nursing assistants, liaison nurses, speech therapists, physiotherapists, pedagogues, hospital play centre staff, admins, pharmacists, cleaning and kitchen staff, associations, and other entities.

We have always believed very much in research, and we are supporting it as much as we can. We believe this story is a good example of how the new findings of research put together by an awesome medical team can really make a difference in people's lives.

Thanks to them, we are finally able to enjoy our daughter as a family, and we have gone from feeling like Nina's nurses to truly becoming Nina's parents.

imageNina, Marta and Lande



中文翻译:

从内部看:Nina,糖原贮积症战士。

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我们的女儿 Nina Contreras D'Agosto 是一个半西班牙半意大利的 30 个月大的女婴。

她也被称为冯吉尔克的战士尼娜,她是独一无二的。不仅因为她患有糖原贮积病 (GSD) 1b 型——一种遗传性代谢疾病,影响着百万分之一的人——而且因为在她短暂的一生中,尽管她面临着所有与健康相关的挑战,她已经能够通过她的网站 www.ninalaguerrera.org 和社交网络#ninalaguerrera.org 筹集数千名“战士在行动”的和平军队,以提高对她的疾病的认识并筹集资金(目前约为 10 万美元)以支持 GSD 1b 研究。

图片Nina 和她的 Warriros In Action在她每年的慈善远足中为 GSD 基因治疗研究筹集资金。

让我们告诉你她的故事,一个关于爱、战斗和希望的故事。

她出生在尼娜(Nina)母亲在威尼斯(意大利)附近的家乡波尔托格鲁阿罗(Portogruaro),2 个月后,我们搬到了尼娜(Nina)父亲在格拉纳达(西班牙)附近的家乡阿尔卡拉·拉雷亚 (Alcalá la Real) 庆祝圣诞节。当时,我们的计划是移居国外。我们都是人道主义工作者,我们一直在世界各地的不同国家工作,所以我们想为 Nina 提供一个由多元文化和多语言交流和体验组成的未来。

然而,事实证明事情比最初预期的要困难得多。妮娜在接受第一轮疫苗接种的那一天,在她 2 个月大的时候,她发高烧和癫痫发作。我们不得不跑到他们做血液检查的急诊室。他们对结果感到非常震惊,以至于他们认为肯定有错误并重复了测试。再次,结果很糟糕,所以他们启动了紧急方案,尼娜接受了 X 光检查、超声波检查和脊椎穿刺。

妮娜的肝脏肿大了,免疫系统也不好。一些指标指向可能的细菌感染,但其他一些(生长迟缓、高尿酸和乳酸)当时没有解释。花了3个月才得到正式诊断;首先是临床怀疑,后来通过基因检测证实。

图片尼娜战士

对我们来说,那是一段极其艰难的时期。我们的第一个也是唯一一个 2 个月大的女婴被诊断出患有一种极其罕见、慢性且非常严重的疾病,这是我们经历过的最糟糕的事情。海外美好未来的计划全部结束,一场与未知事物的暗中大战开始了。我们的生活永远改变了,我们的整个世界都崩溃了,甚至没有时间哀悼,这是 GSD 1b 型无法承受的奢侈品。我们需要立即动手学习并提供日常护理,因为治疗中的一个小错误可能会致命并杀死 Nina。

GSD 1b 是一种非常具有挑战性的疾病。患者无法将糖原转化为葡萄糖,他们会迅速进入严重的低血糖(这可能导致昏迷、脑损伤或死亡)。他们唯一的葡萄糖来源是他们从食物中或通过静脉注射直接从血液中获得的葡萄糖。他们的中性粒细胞计数和功能低于应有的水平,因此他们容易反复感染,并且在他们生命中的某个阶段会发生炎症性肠病(IBD,克罗恩样疾病)。肠胃炎和 IBD 等感染使 GSD 1b 患者的血糖非常不稳定,有时会降至零并需要静脉注射以避免死亡。最重要的是,缺乏适当的代谢控制还有许多其他负面后果。

尽管存在所有这些挑战,但最初我们被告知可以按照现有指南在我们的国家处理 GSD 1b。每 3 小时进食一次,辅以玉米淀粉(一种缓慢吸收的碳水化合物,有助于在较长时间内保持更稳定的血糖)、每日注射粒细胞集落刺激因子 (GCSF) 以增加中性粒细胞计数和维生素 E 以改善中性粒细胞功能性、治疗 IBD 的美沙拉嗪和一长串药物(维生素 D、铁、钙、益生菌、欧米茄 3、多种维生素等)来解决缺乏适当代谢控制的后果可能足以让 Nina 生存并以某种方式稳定。

然而,Nina 的情况却是一个非常严重和复杂的案例:我们不得不在白天每 40 分钟给她喂一次食,而在夜间连续喂食。尽管有这个非常苛刻的喂养时间表,她还是经常遭受不明原因的低血糖症。GCSF 和维生素 E 并不能预防几种严重的感染。

她有一个非常严重的吸收问题,即使有严格的监测,她也经历了不可预测的紧急情况,她癫痫发作,昏迷,需要静脉注射,在她短暂的一生中大部分时间都在医院里度过。考虑到医院获得性感染的可能性、由于疾病及其治疗的复杂性和罕见性导致的潜在人为错误、设置静脉注射的严重困难等,即使这些长时间的住院治疗也是一种风险。

在此期间,我们的手机闹钟白天和黑夜都会响起数十次,提醒您喂食时间、药物、注射剂、补充剂等。我们的情绪取决于尼娜血糖的稳定性。如果这还不够,还需要做很多工作来训练尼娜用嘴吃自制的食物,以便在某个时候她可以摆脱鼻胃管,吃普通的固体食物。我们仍在为此苦苦挣扎,但我们知道,在某个时候,我们会到达那里。

即使难以置信,在我们家人的努力和妮娜坚强积极向上的精神下,她正在成长为一个非常快乐的婴儿,玩耍、唱歌、欢笑;从来没有任何智力发育迟缓的迹象,实际上,每个人都说她很聪明。

为了实现这一目标,Nina 至少需要两个人全心全意地 24/7 全天候照顾她。由于要求严格的治疗,我们筋疲力尽,而在控制 Nina 的低血糖症的同时,由于晚上缺乏睡眠和适当的休息,压力情况变得更糟。

我们不得不申请延长无薪假,以便有时间和精力阅读 GSD 指南以了解疾病、照顾 Nina,并有时间与世界上最好的两位 GSD 专家取得联系。我们成功了,事实上,妮娜和他们中的一个一起度过了她的第一个生日,第二个和另一个一起度过。也许这纯粹是巧合,但我们喜欢把它看作是她所能拥有的最好的礼物:这两位医生不仅是优秀和才华横溢的专业人士,而且还是非常美丽和善良的人,他们为我们做了很多工作。

图片尼娜与父母和祖母在荷兰住院期间的两岁生日

鉴于 Nina 病例的严重性,在某些时候,有必要到国外去荷兰住院,以进行创新的、实验性的和标签外治疗。这是一个复杂而美丽的“奥德赛”,根据欧盟关于跨境医疗中患者权利的指令 2011/24/EU,我们有权参加。我们得到了治疗 Nina 的医生、意大利卫生当局的一些成员以及欧洲遗传性代谢疾病参考网络的大力支持。这是令人惊叹的团队合作,也是欧盟内部跨境医疗保健的一个很好的例子。

我们非常感谢他们为确保 Nina 获得尽可能最好的治疗所做的所有真诚努力,这是基于 Veiga-da-Cunha 等人 (PMID: 30626647) Wortmann SB、Van Hove JLK、Derks TGJ 等人最近发表的文章。“用 SGLT-2 抑制剂治疗糖原贮积病 1B 中的中性粒细胞减少症和中性粒细胞功能障碍”,Blood发表(doi:10.1182/Blood 2019004465)。

在去荷兰之前,首席医生向我们介绍了治疗方法、预期益处和相对禁忌症。我们确信收益大于风险,所以我们选择了它。

此次行程的筹备和实施工作紧张,工作量大,压力大。除了我们为正常旅行所做的常规安排外,我们必须携带大量医疗用品旅行,我们必须为可能出现的紧急情况做好准备,我们需要大量文书工作,我们还必须控制 Nina 的血糖并给她喂食每40分钟一趟(车上、飞机上、出租车上、酒店前台等),但我们满怀希望,一切顺利,顺利到达目的地。

到达那里后,我们开始使用一种名为 empagliflozin 的新药进行治疗,采取多项措施确保安全并设计了应急计划。Empagliflozin 改善了 Nina 的中性粒细胞计数,更重要的是改善了它们的功能。一个奇妙的结果是,她的吸收问题开始消失,因为她的中性粒细胞处于更好的位置来对抗消化系统中的潜在细菌。最后,尼娜能够忍受玉米淀粉,这有助于她有更长的禁食期。

在那个阶段,我们有不同的选择:全天先吃玉米淀粉(24小时内大约6-8餐)或白天吃这些餐(3-4餐)并在夜间连续喂养。还可以制定一个时间表,以便每天在特定时间提供这些膳食,或者采用预期的饮食方法,基本上在 Nina 的血糖降至 72 mg/dL 或 4 mmol/L 左右时喂食。

今天,我们回到了家,妮娜的情况好多了。她的血糖更稳定;我们选择了饮食预期方法,她每 3 到 4 小时进餐一次(中间有一点点心)。她的免疫系统得到加强,她的嘴巴吃得更好一点,她的身高增加了几厘米,她的体重减轻了一些(考虑到她超重,这是一件好事)。

图片妮娜享受大自然

我们也对我们的住院有着非常美好的回忆。我们感到受到欢迎,并被善意地倾听。我们被邀请参加多学科会议来讨论 Nina 的案例,我们的意见被真正考虑用来设计前进的道路。患者方法的中心地位发挥了最佳作用。

偶尔,我们仍然会有一些艰难的日子:有时,突然间,尼娜需要更频繁地进餐以保持稳定,她的血糖下降得更快。这些事件背后有无数可能的原因:生长突增、长牙、病毒、细菌感染,甚至是噩梦。我们可能需要几天的时间才能知道发生了什么,有时,我们永远不知道真正发生了什么。我们只是经历了它,希望它不会持续很长时间,为可能出现的紧急情况做好准备,同时也尽力避免住院。无论如何,这些时期也比新治疗之前的挑战小得多。

GSD 1b 仍然是一种非常具有挑战性的疾病,但至少,我们已经大大改善了我们的情况。我们希望,随着 Nina 的成长,事情会变得更加容易,也许几年后,她将能够接受我们正在支持的研究中正在开发的酶和基因疗法。

我们希望其他面临类似挑战的 GSD1b 患者像我们一样幸运,并为他们各自的病例获得最好的医疗保健。现阶段,还是有点挑战的;在大多数患者可用之前,实施新疗法并建立科学证据需要时间。但我们希望尽快到达那里,我们将尝试通过 www.ninalaguerrera.org 以这种方式开始支持倡议。如果您想合作,请随时访问我们的网站和社交网络。

最后,我们想说,我们无法用言语来表达我们对这个过程中所暗示的每一个人和机构的无尽感激,他们极大地提高了我们的生活质量,以及所有给予 Nina 如此多的爱和如此多的人希望在她的一生中。家人、朋友、“行动中的勇士”、其他 GSD 家庭、研究人员、医生、营养师、护士、护理助理、联络护士、语言治疗师、物理治疗师、教师、医院游戏中心工作人员、管理员、药剂师、清洁和厨房工作人员、协会, 和其他实体。

我们一直非常相信研究,我们会尽可能地支持它。我们相信这个故事是一个很好的例子,说明了一个了不起的医疗团队将研究的新发现如何真正改变人们的生活。

多亏了他们,我们终于能够像一家人一样享受我们的女儿,我们从感觉像妮娜的护士变成了真正成为妮娜的父母。

图片尼娜、玛尔塔和兰德

更新日期:2020-07-10
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