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View from inside: Tália's story

2020; Springer Science+Business Media; Volume: 43; Issue: 2 Linguagem: Inglês

10.1002/jimd.12165

1573-2665

Shanalle Bacarese‐Hamilton, Andrew Bacarese‐Hamilton,

Metabolism and Genetic Disorders

It was the 28th June 2007. I lay, surrounded by my family, with newborn Tália in my arms. She was home. She had made it to this point, she was a fighter and I was blessed with the most beautiful gift. My husband and I live on the Costa del Sol, in a small coastal town called Sabinillas. Together we run our own real estate business which we set up together in 2003 and have three beautiful girls - Tara (18), Natasha (16), and Tália (12). Our youngest daughter, Tália, has mitochondrial disease. My pregnancy had been difficult. I bled at 24 weeks and thought I had lost her. I was put on bed rest, diagnosed with intrauterine growth retardation and I had felt very little movement for the entirety of the pregnancy. It was so different from my two previous pregnancies. When Tália did not turn and I was scheduled to have a C-section, I found myself praying and willing her to get to D-day. Despite our concerns Tália weighed just over 2.3 kg and had a good Apgar score 9, 10, 10. The first 6 weeks went smoothly. Her two sisters, Tara (6) and Natasha (4), showered her with affection and our family felt complete. Tália was a good baby—she nursed well, slept and barely fussed. In hindsight, I realise that she was almost too good. After the first 6 weeks, things started to go downhill. Tália developed gastrointestinal reflux. I remember nursing her and sleeping with her propped upright against me for months on end just willing the milk to stay in and to avoid the projectile vomit. Tália stopped putting on any weight—even on a good week, the scales would barely change and while trying to top up my breast milk, we hit a few barriers—Tália refused to take a bottle, she seemed to have difficulty swallowing and she suffered severe failure to thrive. The weight stayed quite static, going up a few grams 1 week and then down again the next. We tried every teat that existed to get her to feed but in the end, we used a syringe to try and top up feeds and I would use a spoon and spend hours trying to get more calories into her. It would take me 3 hours to feed her 60 ml of baby cereal. It became evident that we needed to move quickly. There were days when I feared that tomorrow would never come. If I had been offered to give her a feeding tube at this point of time, I would have accepted it wholeheartedly.Tália was hypotonic and did not meet initial milestones such as holding her head up, picking up toys, smiling. More alarming was that on several occasions, her eyeballs would roll around in her sockets—it would really terrify us. Her body trembled often, and she failed to gain basic reflexes. She had trouble with regulating her temperature and would turn purple in the cold and become listless in the heat. We were failing to meet key milestones. The doctors suggested that we wait until she was 3-4 months before testing. Tália and her cousin, both 15 months old. Little did we imagine that we were about to embark on the biggest journey of our lives, a journey that took us across the globe—to Barcelona, the UK, Hong Kong and the US. One by one we ticked off a list of syndromes including Microcephalic osteodysplastic primordial dwarfism (MOPD), Prader Willi, Williams Disease, Cerebral Palsy, Cystic Fibrosis among many others. At the onset of searching for a diagnosis, I had been confident that one would be made immediately. However, one day, it suddenly hit me that this may not be an easy case to solve, that it could take years to get an answer, that this ache of uncertainty might be my only constant. How would I cope with this and deal with not knowing? Would I become the crazily obsessed parent, searching for answers, not knowing where to turn? My initial response was to go out and search with a focus and energy that I did not know existed—I pulled out biology books, surfed the net, scrutinised everything but each revelation opened a whole new web of symptoms and possibilities. When I was first told that my child had a rare condition, one so rare that many doctors were unable to guide me in the right direction, I felt as though I was blindfolded. I could not even begin to see the way forward. I was totally overwhelmed. Once I realised that I could not move forward like this, I accepted the truth and started to look for some direction. What stood in front of me was a complex maze, with so many different paths and so many different decisions to be made. Which path should I take? It seems surreal, the world as I knew was no longer. I felt lost, alone and unqualified to make important decisions. In reality, I could choose to either sink or swim. It is not until I fully embraced our situation, that I could really move forward and become Tália's greatest advocate. Life had a funny way of knocking me into reality. Three tragedies pulled me out of the abyss: witnessing my Dad slip away from cancer at only 60 while Tália lay by his side; losing my uncle 2 months later; and then watching my cousin lose her 3-year-old son to meningitis. I realised that death can happen to anyone at any time and I chose to embrace my life and the love that surrounded me. This was our journey and I decided to make the most of the cards I had been dealt. As my husband would always say, the journey is not about getting to the destination, but about enjoying the ride along the way. Therefore, we entered a more balanced phase in our lives - one not only dedicated to finding a diagnosis, but also to living each day to the fullest. We started with basic blood tests. Each doctor, no matter where in the world, was baffled—Tália was always referred to as an interesting case. A simple blood test is traumatic. It was, and still is hard taking blood from Tália—difficult to find a vein and a real art to get enough blood out. Each time, my husband and I have to physically pin her down so that the nurses can take her blood. The process is emotionally draining. One particular occasion comes to mind. It was our last day in the United States, after numerous attempts the nurse had managed to take out enough blood, and then, in an instant, the nurse dropped the test tube and the blood spilled all over the floor. I have never cried so much. The MRI results did not show anything specific. Microcephaly was confirmed and revealed a global lack of white matter in her brain. Clinicians debated whether there was retardation in the myelination but no real conclusion was reached. I will never forget the day of the MRI test. Tália was given a minimal amount of anaesthesia to make her sleep. We anticipated that she would wake up half an hour later. However hard we tried, we could not wake her up. We tickled her toes, chatted to her, sang songs to her and splashed water on her face, but she would not wake up. It took 7 hours for her to finally open her eyes. We had our family praying across the globe and thankfully our fighter came through for us again. Initial genetic testing did not give us any answers either—the microarray (US), telomeric testing (UK) and karyotype (Spain) all came back normal. The only real hint was the elevated lactic acid in Tália's blood. An endocrinologist in Marbella started to suspect a metabolic condition. This turned out to be our first real lead. I started to research metabolic illnesses online and this is when we started narrowing it down to mitochondrial disease. A spinal tap confirmed high levels of lactic acid and pyruvate in the cerebro-spinal fluid. We were referred to San Joan de Deu Children's Hospital in Barcelona, where we were told by a Metabolic Specialist that she strongly suspected mitochondrial disease and wanted to test for pyruvate dehydrogenase deficiency (PDD). Tália was prescribed Carnicor, CoQ10, and Thiamine and it was suggested we try the ketogenic diet. I realised that time was not on our side. Infants born with PDD often do not make it through their first few years. We decided to go on a family holiday to Portugal to enjoy the moment, to make memories, to show Tália and her sisters a great quality of life. We came home to skin biopsy results that cleared Tália of PDD. We were thrilled. Even though we had no answers, not knowing at this point meant that anything was possible, and I refused to give up. We returned to Barcelona for a muscle biopsy. The muscle biopsy was performed under a local anaesthetic—we did not dare give her a general one after our experience with the MRI. Just 6 weeks after the passing of my father, we were in Barcelona, listening to Tália shriek as the biopsy was done. The muscle biopsy confirmed that Tália had multiple complex deficiencies in the respiratory chain. At this point, I came to know Professor Julio Montoya at the University of Zaragoza, who became my greatest guide, friend and has continuously been there for me. He undertook the genetic analysis on the muscle biopsy and sequenced Tália's mitochondrial DNA. We thought that we had reached jackpot when he discovered a new mutation in A5514G—however, this was short-lived as it was then found in me, in homoplasmy. Technology started to advance over the years and it became clear to me that we needed to do an exome analysis. However, the costs were extremely high at the time. I started to explore options and finally after much research found an association called Rare Genomics. After various skype calls, translation of medical notes to English, they helped to get us onto a clinical study at Scripps, La Jolla in the United States—we were the first family outside the US to be accepted onto the study. The exome came back with the results we had been waiting for. Finally, on 5th January 2015, we received a diagnosis—compound heterozygous mutations in TIMM22.1 We had found the needle in the haystack. Tália was one of a kind, the only one in the world to be officially diagnosed with mutations in this gene. The next step was to confirm that this was the leading cause of Tália's condition through functional tests. Confirming this was more complex than initially expected. Getting the blood to the US in the form it was required was impossible and we hit a wall. Two years later, I was lucky to meet two research teams at Euromit and in 2018, a paper was published in Human Molecular Genetics.1 It had taken us 11 years to get a confirmed diagnosis. Tália is currently 12 years old. She is nothing short of a miracle. Slowly, with lots of therapies she has started to reach milestones we never thought she would meet. She started to walk at 4 1/2 years and whilst non-verbal, at 9 years she started to type on a computer. Today she is vocalising a lot more and beginning to string words together. She understands both English and Spanish and whilst she has global developmental delay, her cognitive ability has improved greatly. Tália continues to have severe failure to thrive—at 12 years old, she weighs only 16 kg.While there is no cure for Mitochondrial Disease, we cannot underestimate how impactful physiotherapy, yoga therapy and speech therapy are to a person's quality of life. Social integration is also key. I am sure that the turning point in Tália's life came at age 4 when she started at a mainstream school with a personal aide. Being with other children gave her that inner self-motivation that I would never have been able to give her on my own. Living with Mito is a balancing act. Tália has a small budget of energy and it is our job to try to maintain it at a constant level. As a family, we need to prioritise what is important and ensure that she has the energy to do those things. Factors that deplete her energy include sickness, fasting, certain medications, travelling, extreme weather conditions, over-stimulation, and environmental factors such as pollution, noise, smoke and bright lights. Tália's health can rapidly decline in an instant. She can be running around one day and have a metabolic crash and be hospitalised the next. Rapid Decline in 48 hours. The search for answers can seem lonely at times. We were thrust into a new world. Living on the beach, in a remote Spanish village, meant that in the first years of Tália's life, the internet was my saviour. It was my contact with the outside world and my way of communicating with others in the same position. I joined forums and turned to US sites like “Mitoaction.org” and “UMDF.org” to find out more about Mitochondrial disease. Being part of these groups helped me both from a practical and psychological point of view. I struck a bond with strangers across the world going through similar experiences. Finally, when I discovered AEPMI, the Spanish national Mito association, I embraced the opportunity to be part of this group. I am not really sure how it happened, but today I am vice president of AEPMI. Representing AEPMI at international meetings and events has been therapy for me. As I have crossed the globe to represent them at International Mito Patients (IMP) Meetings (mitopatients.org) and Euromit, I have realised how lucky we patients are. By coming together on a global level, we can make a real difference, build up critical mass and work together to improve quality of life for patients, no matter where they happen to be in the world. So many of those working to build global solutions and making a difference are themselves Mito patients or parents, many who have already lost children to the disease. They have been my inspiration and role models. My eyes have been opened. So much is happening behind the scenes. I am humbled to see doctors and researchers dedicating their lives to trying to find a cure for Mito. I always love to tell this to other patients, because, while we do not yet have a cure, the fact that so many professionals are working on our behalf, is enough to give us hope. More and more different national research groups are collaborating on international levels. Patient representatives are being invited to share their experiences and to take part in medical conferences. I have often been asked what the impact that a child with a rare disease has on the family. Having a strong family foundation is key. A child with special needs can really change the dynamics. All members of a family need to pull together to find balance. Tália has taught us all about unconditional love. While hard at times, those glimpses of the love and the strong bond that our girls share, surpass everything else for my husband and me. Of course, we are all affected by Tália's illness—everyone has a different way of expressing it and where possible, I think it is healthy to have family discussions and include the girls in key decisions. I feel extremely proud of our girls—they have used their experience positively, to build awareness for Tália and for children with disabilities as a whole. They have shared their experiences by doing a TEDx talk, writing songs, participating in a documentary on our journey with Mito,2 and organising events.Obviously, there are times when the strain of trying to juggle so many balls gets to us all. We are often exhausted—running a business, being carers at home and trying to be good parents. The financial burden can also be overwhelming. Tensions can run high and it is easy to take it out on those you love most in the world. Despite some turbulent moments, we share the same values and goals and we grow into a stronger unit each time. With the best will in the world, we try very hard to give all three girls the same amount of attention, but in reality, it is not really possible. Tália has more physical needs and sometimes it is what it is. The girls have grown to understand this, and now they often take over and look after their sister. We have been lucky to have family support—my mother has been instrumental and is like a second mother to my girls. We do not know what the future holds. We are entering into unknown territory as Tália goes into puberty. One thing we have learnt, though, is that whilst we can try to plan, we need to enjoy each day to the fullest. The unconditional love that we experience every day and the joy and meaning that Tália has brought to our family has made this journey a truly special one. Not a day goes by that I do not thank the universe for this wonderful gift.