PRACTICAL GENETICS
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gene located in chromosome 5 , which codes for a protein essential for survival of the spinal motor neurons ( survival motor neuron protein ). In the absence of the SMN 1 gene , a backup gene called SMN 2 can produce the protein to a small extent . With lack of the SMN 1 gene , the babies fail to achieve motor milestones and often die in the first year ; however , if there are several copies of the SMN 2 gene , the disease is milder as some amount of the survival motor neuron protein is still produced . Thus , the study of the genetic profile in SMA is not only diagnostic , but also gives a hint at the prognosis . With the recent availability of targeted gene therapy , newborn screening for SMN has become routine in many states .
Genetic knowledge about the hitherto untreatable neurological disorder , Huntington ’ s disease ( HD ) is giving hope for novel treatment . HD is a monogenic disorder caused by mutations in the HTT gene , located in chromosome 4 , coding for a protein called huntingtin . There are excessive nucleotide repeats and the greater the number of repeats , the earlier the onset of disease .
GENE THERAPY
Let us look at the more exciting topic of gene therapy . The basic goal is to treat diseases at the genetic level by adding new genes to replace faulty or absent genes or by editing the faulty gene in vivo .
Gene addition is a logical step in genetic diseases , in which there is a single faulty gene , which is replaced with a healthy functioning gene . While the principle is simple , there are many hurdles in effectively getting the gene into the affected cells with the faulty gene . The healthy gene is often sent through a harmless virus or special compounds such as polymers .
Gene editing is aimed at either disrupting or inactivating the part of the malfunctioning gene , or correcting it , or inserting genetic material . A number of techniques like CRISPR-CAS9 are being tried to achieve this .
There are two neurologic diseases with currently FDA-approved gene therapies . Three pharmaceuticals have been approved for SMA . The first was nusinersen , an oligonucleotide to correct the loss of 7 th exon during RNA splicing of the SMN 2 gene , and make it function like the SMN 1 gene . It has to be given intrathecally , repeatedly and treatment has to be started early to stop progressive loss of motor neurons ; newborn screening for SMN 1 is crucial in this regard . The second drug , onasemnogene abeparvovec , delivers a working copy of the SMN gene to the motor neurons via a virus vector . It is given IV and the expectation is that a single treatment should give lasting relief . A third drug , risdiplam , is an oral form of SMN 2 splicing modifier , approved for use in 2020 . effective in increasing dystrophin production ; genetic analysis is done to locate the faulty exon and use specific ASO to skip it . Eteplirsen was the first drug to be approved for gene therapy in DMD ; it specifically skips faulty exon 51 . Exon 53 has been the main target of further development resulting in golodirsen and viltolarsen being approved by FDA in 2019 and 2020 . Casimersen was approved in 2021 for skipping exon 45 . It looks like the flood gates are open for exon skipping therapy , an exemplary example of personalized precise medicine .
The next in line is oligonucleotide for Huntington ’ s disease , trials of which are underway . Gene therapy for certain forms of CMT are also being tested . It is likely that many similar disorders will have genetic therapy in the near future . However , the three “ Darth Vaders ” of neurology , ALS ( amyotrophic lateral sclerosis ), Alzheimer ’ s disease and Parkinson ’ s disease show familial transmission only in a tiny percentage of patients . Hence , they may not be candidates for genetic therapy anytime soon . Nevertheless , extensive study of familial forms of these disorders is already yielding genetic data which may open up new therapeutic options .
The spectacular advances in molecular genetics and the increasing sophistication in gene sequencing techniques is posing a unique challenge to practicing physicians in every field of medicine , including neurology . It is becoming quite difficult to keep up with the fast pace at which the genetic basis of a given disorder is being uncovered . For the neurologist , akin to all other specialties , faced with the barrage of new developments in every disorder ( not to mention the new drugs appearing almost every few weeks for multiple sclerosis and epilepsy ), it is challenging to learn in depth about the ongoing advances in neurogenetics . It is also frustrating and embarrassing when one cannot quickly recall the causative genetic defect of a clinical syndrome at the bedside .
Neurologists are trained to aske four questions at the end of patient evaluation : Where is the lesion ? What is the lesion ? What is the prognosis ? What is the best treatment ? Perhaps we should add a fifth question : What is the genetic basis ? Fortunately , there are so many resources readily available at the click of a key to provide the answer to the last question . Periodic assimilation of genetic knowledge from published data , plus using it effectively at the bedside while evaluating each patient , should make the process easier . In this context I am reminded of Osler ’ s famous advice : “ To study the phenomenon of disease without books is to sail an uncharted sea , while to study books without patients is not go to sea at all .”
Dr . Iyer practices at the Neurodiagnostic Center of Louisville and is a retired professor of neurology at the University of Louisville School of Medicine .
DMD is the other condition where genetic therapy has been approved . Exon skipping antisense oligonucleotidses ( ASO ) are
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