PRACTICAL GENETICS
GENETICS & NEUROLOGY
AUTHOR Vasudeva Iyer , MD
There has been tremendous progress in understanding the genetic basis of many neurological disorders during the past several decades , paving the way for better insight into their molecular bases and rational management . Major advances in transforming basic research into clinical science have finally led to the availability of gene therapy for a handful of serious neurological diseases . Establishment of clinics and fellowships for specialty training in major universities has propelled neurogenetics into an attractive subspeciality .
The genetic basis of many diseases has been assumed based on the presence of positive family history and study of the inheritance patterns . During my training days , many decades ago , the only neurological disorder with known specific chromosomal abnormality was Down syndrome , which could actually be confirmed by karyotyping . In sharp contrast , I recently saw two cases of what appeared to be Charcot Marie Tooth ( CMT ) disease ( commonest form of inherited neuropathy ) with subtle differences in phenotype . It was fascinating to figure out that one had mutation in the peripheral myelin protein ( PMP ) 22 gene , while the other had it in the myelin protein zero ( MPZ ) gene .
Let us look at some of the neurological disorders where the precise genetic basis has been confirmed and then explore the exciting and long-awaited advances in therapy , which are finally starting to give a ray of hope to patients .
ROLE IN DIAGNOSIS & PROGNOSIS :
Multiple diseases that afflict different parts of the central and the peripheral nervous system , including muscles , have been proven to have a specific genetic abnormality , thanks to discoveries in the 1980-90s . Here are some examples where the gain in genetic insight has been quite impressive .
The most well-known muscle disease Duchenne muscular dystrophy ( DMD ) which is inherited as a X-linked recessive disorder , has been found to be due to mutations in the dystrophin gene ( it has the distinction of being the largest gene , containing a whopping 79 exons ) located in the X chromosome . This gene is responsible for production of dystrophin , a large cytoskeletal protein located at the surface of the sarcolemma , necessary for maintaining healthy muscle . Lack of dystrophin is considered to be the underlying cause of muscle loss in DMD . Deletion of one or more exons has been found to be the most common mutation , usually among exons 44-55 leading to a defective reading frame ( A reading frame is a sequence of nucleotide triplets that is potentially translatable into a polypeptide ). A milder form of the disease is Becker dystrophy , in which some dystrophin is still produced ; this results from in-frame deletions that do not alter the overall reading frame . Another form of muscular dystrophy , myotonic muscular dystrophy has been found to be due to abnormal repetition of nucleotide bases in the DMPK ( myotonic dystrophy protein kinase ) gene located in chromosome 19 . The severity of disease depends on the number of the abnormal trinucleotide repeats , useful information to share with the patient while discussing prognosis .
Another disease that has been the focus of many recent studies is spinal muscular atrophy ( SMA ) which is a leading cause of death from neurogenetic disease in the first year of life . It is a form of motor neuron disease that results from mutations in the SMN ( continued on page 18 ) APRIL 2021 17