The Exhilarating World of Neurogenetics

In a short time, we have made such tremendous progress that many diagnoses are now re-categorised based on the genes and mutations rather than based on the clinical manifestations.

Several years ago, when an elderly retired surgeon in my family came to know that I had decided to become a paediatric neurologist, he candidly remarked that only lazy medical students pursue the study of the brain. In his defence, he belonged to a different era. He trained in the UK in the 1950s, successfully attained the prestigious FRCS (for Fellowship of the Royal Colleges of Surgeons) title and practiced till the late 1980s.

During those times, neurologists were viewed as kind, laid-back human beings who went around hospital wards carrying a black bag and tools that no other doctors possessed – such as the Queen Square reflex hammer. They whiled away their time, leisurely examining patients to diagnose curious diseases, only to offer empathy and a limited number of medications in turn.

The great Oliver Sacks epitomised the neurologists of that era. His elaborate case studies documented the common and the bizarre of clinical neurology. His compassion led him to dedicate a part of his life to chronic-care facilities filled with patients devastated by diagnosed and undiagnosed neurological illnesses. His artistry enabled him to use music as therapy, and more importantly write books that inspired a whole generation to pursue a career in neurology.

Much has changed since then, in part due to the success of the ‘Decade of the Brain’ campaign of the 1990s. Neurologists are now routinely successful at bringing patients out of coma unscathed or recovering those paralysed fully. In addition to the art of the neurological examination, they have easy access to scanners to make accurate diagnoses and follow it up with treatments using innovative biomedical devices and a burgeoning array of pharmaceutical agents.

The Queen Square reflex hammer. Source: Author provided

The Queen Square reflex hammer. Source: Author provided

However, the human brain remains the final frontier for health sciences today. A field that is likely to significantly help us solve the mysteries of the brain is neurogenetics. It is the study of the genes on a molecular level to understand the development and function of the nervous system – including the brain, the spinal cord, nerves and muscles. A large number of neurological diagnoses, especially in children, have a genetic basis, with a mutation causing the production of an abnormally functioning protein that is widely expressed in the diseased nervous system. Hence, the outcome of the efforts to tame neurological diseases will depend on how successful we are at neurogenetics in the years to come.

Prior to the advent of this field, a majority of the genetics-based neurological diseases were classified according to the type and severity of clinical manifestations. Take spinal muscular atrophy, for example. It is a disease very similar to amyotrophic lateral sclerosis that has afflicted and paralysed Stephen Hawking. While we don’t know what causes amyotrophic lateral sclerosis, spinal muscular atrophy is caused by a mutation of the SMN1 (Survival motor neuron 1) gene. Prior to a full understanding of the genetic basis, the disease was classified into separate categories based on the variety of clinical manifestations.

However, we now fully understand the differences in molecular level changes that account for the various clinical categories of the disease. Similarly, diseases that were lumped under one category previously because of similar clinical manifestations have now been discovered to be due to mutations in a variety of different genes. In a short time, we have made such tremendous progress that many of these diagnoses are now re-categorised based on the genes and mutations rather than based on the clinical manifestations, especially for research purposes.

And not only do we understand the genetic basis of many neurological diseases well now, we are also making rapid progress towards modulating gene function to mitigate or cure afflictions. Take the case of nusinersen, a biologic agent approved late last year by the US Food and Drugs Administration (FDA) for the treatment of spinal muscular atrophy. It is administered in the spinal fluid periodically and works by converting a protein in the body called SMN2 (Survival motor neuron 2) to SMN1, thus halting the progression of paralysis. The agent showed such positive results that the clinical trial had to be stopped on an ethical basis: so that all children enrolled in the initial study could receive the actual drug rather than some getting only the placebo.

The field of neurogenetics faces a major obstacle in that many of these are relatively rare diseases and hence are not generating enough interest. Both testing and treatments for these conditions have to pass obstacles such as a paucity of funding for research and non-authorisation by insurance agencies even after the benefit is unequivocally established. Finally, the dichotomy of the availability of such cutting-edge treatments to a handful for rare diseases and the lack of medications to treat conditions such as malaria for many others raises ethical questions pertaining to our collective responsibility on a global scale.

Jay Desai is a neurologist at Children’s Hospital Los Angeles. He tweets @southgujarati.