A wrinkle in the time of mitochondrial medicine

Jaime-Dawn E. Twanow. A Wrinkle in the Time of Mitochondrial Medicine. Pediatric Neurology. 2017; 68:1-2.

Madeleine L'Engle, an author best known for the Newberry Medal winning A Wrinkle in Time , became enamored with mitochondria after a physician friend gave her journal articles introducing her to the organelle.  At the time, L'Engle was writing the companion youth fantasy novel, A Wind in the Door . Her six-year-old protagonist, Charles Wallace, presents with an increasing oxygen requirement, worsening cardiac function, and new-onset seizure. Over the past several months, his family had noticed progressive fatigability, pallor, coagulopathy, and cold intolerance.  In 1973, when A Wind in the Door was published, this fulminant and complex illness was unknown. Today, we have the ability to provide a diagnosis for the family—mitochondrial disease…

Although L'Engle was imagining a child's progressive disease course because of “mitochondritis,” Spiro et al.  were studying a father and son with confirmed myopathy, loosely coupled oxidative phosphorylation, and reduced cytochrome b content. Examination confirmed focal neurological findings, progressive ataxia, and dementia. Researchers were certain that the energy production of the muscle mitochondria was decreased; however, the relationship between the structural and functional mitochondrial abnormalities and the patients' clinical presentation remained unclear…

Viewing Charles Wallace's medical history through a modern lens reveals a recognizable disease pattern. He had an atypical developmental course, with late speech, above average intelligence, and ongoing social difficulties, raising the suspicion of high functioning autism.  Exercise intolerance manifested during a walk with his sister, who noticed “that he was breathing heavily, as if he had been running, though they had not been walking rapidly.” As his acute illness progressed, imminent cardiorespiratory failure loomed and his mother “prop(ped) him up on pillows to ease his labored breathing.” The rhythm of Charles Wallace's mitochondria serves as a metaphor for his pulse, interrupted by arrhythmia: “a faltering. A missed beat.” His family held vigil at his bedside, perhaps most concerned by his “convulsions” and “delirium”—the neurological manifestations of his disease.

 

Concerned about scientific accuracy, L'Engle requested that members of the Emory University Immunology Department review A Wind in the Door before publication.   Interestingly, her book predicted the relationship that science could not prove in 1973. In mitochondrial disease, the mitochondrial defect is the principal problem. As so eloquently stated by Charles Wallace, who had insight into his disease, “each of our mitochondrion has its own built-in system to limit the rate at which it burns fuel,” and “if anything happened to our mitochondria, we'd die.” 

The late 1980s marked the beginning of the molecular era of mitochondrial medicine, with the identification of maternally inherited disorders caused by mutations in mitochondrial DNA. Subsequent characterization of nuclear DNA mutations, inherited in a Mendelian fashion but with deleterious effects on mitochondrial function, began in the mid-1990s. Although next-generation sequencing has facilitated successful diagnosis of increasing number of patients, the clinical presentations of mitochondrial disease remain diverse and variable.  Even today, physicians may be unable to pinpoint Charles Wallace's mitochondrial defect or genetic abnormality, and no treatment has demonstrated a significant effect.   We cannot echo the reassurances of his steadfast family doctor, who encouraged the family that Charles Wallace would “be completely recovered in a day or so.”  Mitochondrial diseases are typically progressive, with cumulative disability, and lead to early death. 

I first became acquainted with Charles Wallace when I was an eight-year-old girl, naive to the existence of mitochondria or their cellular significance. Years later, as a sleep-deprived child neurology resident, I exited the room of a critically ill patient, and Charles Wallace unexpectedly came to mind. My second reading of the fantasy novel, informed by a biology major and medical training, confirmed my suspicion. The character, indeed, had a mitochondrial disease; however, his presentation was incongruent with the scientific and clinical knowledge of the early 1970s. L'Engle's powerful insight into the interplay between cell function and disease foreshadowed the complexity and severity of modern mitochondrial disease.

Now, as we move forward in the era of mitochondrial medicine, A Wind in the Door is a reminder of the impressive progress that has occurred in this young field. Born of a love of science and the power of imagination, Charles Wallace is an ambassador, furthering understanding and generating empathy for his still incompletely understood disease.

Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less. Marie Curie