Thursday 15th November I had a neuromuscular follow up with my fantastic consultant Dr Ros Quinlivan at the National Hospital for Neurology and Neurosurgery. I’ve been seeing Dr Quinlivan after I was referred to the National Rare Mitochondrial Disease Service, of which the London service is based at the NHNN, in 2015. I was born with health problems, seeing various professionals, having physiotherapy, intensive support from a colorectal nurse in my early years and some treatment, but no diagnosis, and deteriorated through childhood until I became disabled and seriously ill at the age of 14. At 15 I was diagnosed with hypermobile Ehlers-Danlos Syndrome (hEDS) as this seemed to fit the symptoms and complications I was suffering from. However, over time it became clear that I didn’t quite fit the bracket of EDS and that my condition went beyond and was very different to the typical hEDS patient, and so it was often referred to “complex” or “atypical” EDS. Then at one point someone mentioned that my presentation could be a form of Mitochondrial Disease, or at least another neuromuscular disease, and I was referred to the National Rare Mitochondrial Disease Service to investigate this, and came under the care of Dr Ros Quinlivan as part of Professor Hanna’s team. Dr Quinlivan ordered various tests, including an EMG which showed myopathy, various other tests, a muscle biopsy and planned for me to be recruited onto the 100,000 Genomes Project. I also came under the care of the Neuromuscular Complex Care Centre (NMCCC), where I have regular “MOTs” and see various professionals whilst admitted for a few days, which enabled me to cut down my medical team as I know I’ll see a cardiologist, respiratory consultant, physio and so on whilst inpatient on the NMCCC.
It took until March this year, after waiting 2 years, to have the muscle biopsy, and the results take a while to come in.
At my appointment on Thursday, I received the results (minus one test on the muscle sample which is yet to return). On the biopsy, when they looked at the sample under a microscope, it looked abnormal but nothing definitively pointing towards a diagnosis, just evidence of the myopathy. She then went onto explain about the other tests. One was that the muscle sample showed low levels/deficiency of ubiquinone, which is often a feature of Mitochondrial Diseases. Then she went onto the tests looking at the respiratory chain complexes. Whilst Complex 5 testing hasn’t been completed yet, Complexes 2 and 3 were normal and Complexes 1 and 4 were abnormal, with Complex 1 being half the level it should be. These are all signs of a Mitochondrial Disease.
However, whilst we know it is a form of Mitochondrial Disease, we do not have a definitive diagnosis as to the type of “Mito” and the underlying genetic cause, which is where the 100,000 Genomes Project comes in. I have been recruited onto the 100KGP to have my entire genome sequenced, to try and find the underlying cause of my condition and hopefully lead to a diagnosis. The 100,000 Genomes Project finds the cause for 65% of patients with a rare disease, so I am hopeful we will find a diagnosis, however even if they don’t find the cause, they will continue to work on a potential diagnosis, comparing my phenotype (symptoms/presentation/complications) with other patients and testing us collectively to see if we share a common mutation. Even if this comes too late for me, I hope it will benefit other patients in the future. I feel relived in many ways that we have some evidence of what is wrong, even without an exact diagnosis/knowing the exact cause.
What does this all mean?
Obviously, I have talked a lot of medical words and scientific things, so now I will explain what these mean.
What Are Mitochondria & What Do They Do?
Mitochondrial are organelles found in every cell of the body (except red blood cells). Mitochondria are the powerhouses within cells, they convert nutrients including glucose combined with oxygen into the energy (ATP) the cells need to function, and they produce about 90% of the energy your body needs to survive. The mitochondria have processes to convert glucose and oxygen into ATP. Mitochondria have 5 respiratory chain complexes related to energy production and processing.
Cells make up tissues and organs in our bodies, for example the heart and liver. If our cells do not have enough energy, the tissues or organs do not work properly. In much the same way, if power stations do not produce enough energy there will be areas of blackout, where parts of the country cannot function.
“The conventional teaching in biology and medicine is that mitochondria function only as “energy factories” for the cell. This over-simplification is a mistake which has slowed our progress toward understanding the biology underlying mitochondrial disease. It takes about 3000 genes to make a mitochondrion. Mitochondrial DNA encodes just 37 of these genes; the remaining genes are encoded in the cell nucleus and the resultant proteins are transported to the mitochondria. Only about 3% of the genes necessary to make a mitochondrion (100 of the 3000) are allocated for making ATP. More than 95% (2900 of 3000) are involved with other functions tied to the specialized duties of the differentiated cell in which it resides. These duties change as we develop from embryo to adult, and our tissues grow, mature, and adapt to the postnatal environment. These other, non-ATP-related functions are intimately involved with most of the major metabolic pathways used by a cell to build, break down, and recycle its molecular building blocks. Cells cannot even make the RNA and DNA they need to grow and function without mitochondria. The building blocks of RNA and DNA are purines and pyrimidines. Mitochondria contain the rate-limiting enzymes for pyrimidine biosynthesis (dihydroorotate dehydrogenase) and heme synthesis (d-amino levulinic acid synthetase) required to make hemoglobin. In the liver, mitochondria are specialized to detoxify ammonia in the urea cycle. Mitochondria are also required for cholesterol metabolism, for estrogen and testosterone synthesis, for neurotransmitter metabolism, and for free radical production and detoxification. They do all this in addition to breaking down (oxidizing) the fat, protein, and carbohydrates we eat and drink.“
What Is Mitochondrial Disease?
Mitochondrial Disease is a group of conditions affecting the function of the mitochondria, which fail to product sufficient energy for cell and thus organ function. This can have wide-ranging effects and complications as a result of that lack of energy and the related death or dysfunction of cells.
“Mitochondrial disease, or ‘mito’, is the term given to a group of medical disorders caused by mutations in mitochondria, the tiny organelles that are present in every cell in our bodies and which generate about 90% of the energy we need to live. Cells cannot function properly without healthy mitochondria, so when they fail the consequences can be serious and wide-ranging.
Mitochondrial diseases affect people in multiple ways, depending on which cells are affected. This can make the condition hard to diagnose, as symptoms often resemble those of other serious illnesses. For example, a person with mitochondrial disease may suffer from seizures, fatigue, vision and hearing loss, cognitive disabilities, respiratory problems or poor growth. Any of the body’s organs and systems can be affected including the brain, heart, lungs, gut, liver and skin.”
The 100,000 Genomes Project is a project with the aim of sequencing 100,000 Genomes, with intake closing within the last month. This aimed to sequence the genome of people with cancer and the genome of their tumour samples, as well as to sequence the genomes of people with rare diseases to help diagnose patients. This was done with the aim of creating a new genomic medicine service for the NHS – transforming the way people are cared for and offering better diagnostics. This has the potential for the emerging field of precision medicine, where treatments are tailored to the individual based on their specific genetic makeup, ensuring they are on the right treatments, treatments they will respond to best. It also has the ability to diagnose patients better, more accurately and more efficiently, especially for those who have not had a result from traditional genetic testing. Not only that, but genomic medicine also allows us to map and better understand our genes and what different genes do and why and how and why certain conditions are caused. Now the project recruitment/intake has closed, they have sequenced or are sequencing 92,297 genomes – including mine, but also my mum’s (for comparison).
Mitochondrial Disease has affected my body in many different ways. I have Chronic Intestinal Pseudo Obstruction (CIPO) due to muscle wastage and nerve degeneration in my gastrointestinal tract, affecting from top to bottom, which is why I am dependent on Total Parenteral Nutrition (TPN), as well as intravenous medications, due to type 3 Intestinal Failure, and is also why I have a venting gastrostomy (PEG) on 24/7 drainage and an Ileostomy. CIPO/Mito also affects my bladder, causing neuromyopathic bladder failure, which is why I have a Urostomy (Ileal Conduit) to bypass my bladder completely, making it redundant. I have Autonomic Neuropathy and Postural Orthostatic Tachycardia Syndrome (PoTS), meaning my autonomic nervous system, which controls all the unconscious, automatic processes in the body (including heart rate, blood pressure, respiration, digestion, urine production) is dysfunctional causing widespread problems, including orthostatic hypotension (drop in blood pressure on change of posture) and the PoTS, the latter being an abnormally high increase in heart rate upon position change from lying to sitting or sitting to standing (although I am completely non-weight bearing, so never stand anymore), and these are why I need to keep my legs elevated whilst sat up in my wheelchair, as otherwise the blood goes down to my feet, legs and lower abdomen and not back up to my brain, due to this dysfunction in the process in my body that tells my veins to constrict to push blood back upwards. I have respiratory muscle weakness, causing an elevation of CO2 in my blood (fortunately not enough to need of NIV/intervention yet), and meaning I have a weak cough and so need nebulisers and a lung volume recruitment device to help clear my chest. Mild cardiac problems. Progressive muscle weakness and atrophy. Intermittent Metabolic Acidosis. My kidneys waste fluid and substrates, and I require a high volume of fluid every day to stay hydrated, needing 5 litres intravenous fluid every day, 4 litres infused over 21 hours (my TPN) and an additional litre of fluid (Hartmann’s solution) over 10 hours alongside my PN, as well as high levels of sodium and electrolytes to try and ensure I don’t suffer electrolyte imbalances and the sodium to try and ensure I retain as much fluid as possible, trying to ‘trick’ my kidneys into reducing the wasting of fluid. Various other manifestations of Mito/neuromuscular origin. Then I also have Chronic Pancreatitis, Osteoporosis, Kyphoscoliosis, Degenerative Disc Disease, Sacroiliitis, some form of Peripheral Neuropathy and as well as the above, 4 chronic/incurable infections: E. Coli in my kidneys and Ileal Conduit, which frequently causes sepsis, as well as Staphylococcus Aureus and Pseudomonas in my PEG site and Faecal Streptococcus in my redundant bladder.
I have had symptoms from birth, I had some mild breathing problems as a baby, I had (have) weak eye muscles and had astigmatism, and I was not a very strong baby, met my physical milestones late – and even when I could sit up, then crawl, then walk, I didn’t try to move very much at all – and had a dislocated hip and developed septic arthritis in that hip age 2 (which is when they discovered the dislocation), and other niggling things, but my biggest issue was my digestive system, I had silent reflux meaning I couldn’t be laid down, mild stomach problems and severe constipation, for which I had a colorectal nurse visit me three times a week to try and manage my bowel and get it moving so I could go to the toilet, which never proved very successful, and this stopped when I went to school (the issue wasn’t better, but it wasn’t working so that support was stopped and I just got on with it). I started physiotherapy at 11 and my physiotherapist always said something wasn’t right but he didn’t know what, he couldn’t understand how I was so active and yet had very little muscle and what muscle I did have, didn’t do its job. Physio didn’t seem to make me any stronger, nor did my active life, and I progressively lost abilities, needing more help such as with dressing. Other things like my handwriting, which was once beautiful, was now scruffy and I was struggling with fine motor skills, including writing. There were things I had always needed help with too – I’d never been able to wash, brush and tie up my own hair, my mum always had to do this for me, and I used to struggle to get up off the floor, using an odd technique to get up off the floor (Gower’s Sign). Over the years, I progressively became weaker, able to do less, needing more help, until at 14 I was a wheelchair user, barely able to walk with support, needing help with personal care, my organs started failing, starting with my gut and bladder, I had a lot of pain, and my life ground to a halt. The autonomic problems were now a big issue and I quickly became bed bound, my body unable to cope with being upright, even sitting up without severe symptoms or collapsing. At 15 I started tube feeding via NG, then PEG, at 17 I started feeding into my jejunum via a PEGJ, then in May 2011 my gut had completely failed, my weight had dropped to under 7 stones (I’m 6ft1) and after suffering a heart attack and my bone marrow failing and being severely malnourished and underweight, I was started on Total Parenteral Nutrition (TPN) and had my first Hickman Line placed. My bladder was failing and I had been intermittent catheterising since age 15. Tests had diagnosed Chronic Intestinal Pseudo Obstruction, which was the reason my gut and bladder had failed. At 18 I had an Ileostomy. At 19 I had a suprapubic catheter. The day after my 21st birthday having my Urostomy (Ileal Conduit) formed. At 20 I managed to get to a point where I could sit up in my wheelchair again, albeit not all day until I received my Permobil F5 Corpus in 2015 following 3 months of fundraising, which had all the functions I needed including electric leg elevation so I could keep my legs elevated at 90˚ in front of me, helping with blood pooling and comfort and enabling me to sit up all day in my chair if I have an event or outing, albeit I still spend 90% of my time in bed. My respiratory muscles are weak as I described above but fortunately no need for NIV yet. Here I am today, 25, living with everything I have described in this paragraph and the paragraph above. I have also survived sepsis 14 times, most recently at the end of October, and overcome things I wasn’t expected to. At 17 I was told my lifespan would be shortened, and at 18 I was told I wasn’t expected to live another 5 years, but I have exceeded that by at least 2 years by reaching 25, and I have a lot of living yet to do!
The Psychological Impact Of This Latest Revelation:
I feel relieved we have some clues as to what is going on, even without a concrete diagnosis, as we have evidence of faulty processes in my cells. It’s reassuring that we’re narrowing down a diagnosis and can say it’s a Mitochondrial Disease. It’s also sad, knowing that a diagnosis won’t change my life or affect my care or prognosis. However, knowing what/why, is so powerful. Knowledge is power, as they say, and this knowledge is definitely helpful to me, to have some answers. I can say “I have Mitochondrial Disease”, even if I can’t name the specific form of Mito. This is, mentally, so powerful for us.
I hope this blog is interesting to others and may prove useful in some form or some way, somehow, now or in the future. Don’t hesitate to get in touch with me on the contact page if I can be of any help or support.