“Pedal, pedal, pedal. Five more minutes, come on!”  

 I am seventeen. I am struggling. This stress test is another phase of my diagnostic odyssey. I have been searching for an answer to my exercise fatigue, muscle cramps, and frequent hospitalizations. 

Ten minutes later, I am wheeled from the exam room, my legs nearly immobile. My Creatine Kinase is measured: 36,000 units per liter (with the normal range being 50-388 U/L). My muscles are breaking down. 

A few months later, I am diagnosed with Tarui disease, an exceptionally rare muscle glycogen storage disease. Tarui disease (GSD type VII, GSD7) results from a genetic deficiency in phosphofructokinase (PFK), impairing muscles’ abilities to generate energy from carbohydrates. When pushed past their capacity, PFK-deficient muscles break down, leeching proteins toxic to the kidneys into the blood. This is rhabdomyolysis, a critical condition that requires immediate medical intervention. As with many patients with Tarui disease, the damage from my first rhabdomyolysis episode predisposed me to subsequent episodes and repeat hospitalizations. It took me seventeen years, six hospitalizations, two muscle biopsies, and four evaluations at top-tier academic medical centers to achieve this diagnosis. 

Genome sequencing could avoid the diagnostic odyssey 

 I attended the NSIGHT Ethics and Policy Advisory Board’s meeting on sequencing newborns as a research associate in a joint apprenticeship between the University of California, San Francisco, Institute for Human Genetics and the university’s Program in Bioethics. But I also came to the meeting with a deeply personal perspective: I had spent nearly my entire childhood in search of a diagnosis and therefore was eager to hear the board’s discussion on how to ethically include genomic sequencing early in life. Genomic sequencing in the newborn period could have helped me avoid my diagnostic odyssey by revealing the cause of my condition shortly after birth. 

Symptoms from infancy

There was no period in my life when I was “normal”. Indeed, my symptoms may have first begun in infancy. I was unable to suckle for my first month of life, and I weighed less than my birth weight at the end of that time. In childhood, I could not keep up with my peers on the playground, struggled to walk comparatively short distances, and fatigued constantly. In second grade, I walked with my class on a field trip to a local senior center. The six-block walk was torturous. On arrival, I rushed to the restroom and vomited profusely. 

I was first evaluated at an excellent local hospital in Northern California, where I received blood tests, neurological exams, an electroencephalogram, magnetic resonance imaging, and my first muscle biopsy. After this comprehensive, months-long workup, my doctor reported, “We have no diagnosis, no treatment recommendations, and no further tests or evaluations we can perform.” Meanwhile, I continued to struggle with walking and basic daily activities. This non-diagnosis was unacceptable. 

My family arranged a consultation at a second academic medical center, this time in Southern California. There, I was subjected to another thorough evaluation, including my second muscle biopsy. After all of this, I was diagnosed with a “mitochondrial myopathy” – which is not so much a diagnosis as a broad category of diseases. 

An acceptable misdiagnosis?

With this putative diagnosis, our search seemed to have ended. A name for my condition (even if it was the wrong name) enabled me to receive accommodations in school and explain my limitations to others. This misdiagnosis was acceptable, even useful for quite some time.  

At least until I participated in a dance exercise in my eleventh-grade theater class. This short-duration, high-intensity exercise sent my neck and back into spasm. My urine turned the color of Coca-Cola, and I was brought to the hospital. My creatine kinase was measured at over 265,000 U/L. I was admitted to the intensive care unit, where intravenous lines were placed in each of my arms. Over the next week, I was pumped up with more than twenty liters of fluid—so much fluid that I couldn’t sit up on my own due to the overbearing weight on my chest. By the end of the week, I had gained and lost more than twenty pounds. After my discharge, my rhabdomyolysis recurred five times in as many months. 

An accurate diagnosis needed

It was clear that I needed an accurate diagnosis. I was referred to my third academic medical center in California. I received another battery of tests, including the exercise stress test described earlier. As I lay in the hospital with testing-induced rhabdomyolysis, the pulmonologist breezily advised me to abstain from exercise and expect to lead a sedentary life. Besides being impractical, this advice was not based on an accurate understanding of my disease. 

I was referred to my fourth academic medical center, in New York. There, at seventeen years of age, I finally received what we had been searching for my entire life: an accurate diagnosis. Genetic sequencing revealed compound heterozygous variants in the gene that causes Tarui disease. Obtaining this diagnosis was an enormous relief. I felt so glad to have an answer for my life-long quest. Despite the fact that no treatment or cure for my condition exists, understanding that my symptoms were caused by a muscle glycogen storage disease has allowed me to take a number of actions that have improved my health. 

Moving ahead with a diagnosis

​First, Tarui disease results from muscles’ inability to use carbohydrates for energy. By eating a ketogenic diet low in carbohydrates, high in fat, and with adequate protein, I have been able to drastically reduce the muscle symptoms I experience on a daily basis.

​Second, I have connected with expert patients and learned techniques for safe and healthy exercise with a muscle GSD. Four years after my diagnosis, I joined a group of people with muscle GSDs to summit Mount Snowdon, the tallest mountain in Wales, climbing to a peak of 3,096 feet over ten miles. By understanding the molecular basis of my disease, I overcame my limitations: if I exercise at a moderate pace after a lengthy warmup, muscle metabolism shifts from carbohydrates to fats, making exercise possible. 

Cofounding IamGSD

​Finally, I have joined the muscle GSD patient community and become active in the support networks, where I have learned more about my condition and shared my knowledge with others. As part of this effort, I cofounded the International Association for Muscle Glycogen Storage Disease (IamGSD) [1]. One of our ambitions is to reduce the rate of misdiagnosis and the age of proper diagnosis for individuals with muscle GSDs. To do so requires the widespread use of sequencing early in the diagnostic process. 

Many patients remain undiagnosed or misdiagnosed. For patients in the United Kingdom with McArdle disease (GSD type V), the median age of diagnosis is thirty-three years, despite median symptom onset at three years of age [2].  This thirty-year lag from symptom onset to accurate diagnosis leaves much room for error. 

Misdiagnosis causes diagnostic delay

Misdiagnosis is a common cause of diagnostic delay in people with muscle GSDs. In one survey of fifty genetically confirmed McArdle disease patients, 90 percent had a previous misdiagnosis, and 62 percent had more than one previous misdiagnosis [3].  Misdiagnosis and diagnostic delay are not consequence free. Patients may receive wrong advice, incorrect medications, harmful therapies, and unnecessary procedures. I experienced all of the above. I was advised to avoid exercise, prescribed ineffective supplements, and exposed to general anesthesia three times during my diagnostic odyssey. From my work in the patient community, I have learned of individuals with muscle GSDs who have been told to abstain from exercise to stave off muscle symptoms, have been prescribed opioid medications to treat muscle pain, leading to addiction, or have been subjected to harmful, unneeded surgery. 

​My story is one of privilege. I come from a family with high health literacy, good insurance, and the financial resources to seek out care around the country. I was evaluated at four of the most highly ranked hospitals in the United States [4].  Despite these advantages, I was not diagnosed for nearly eighteen years. How much longer might a less privileged individual live undiagnosed?