The root cause of most disorders of the nervous system often lies with defective genes
LONG perplexed by the causes of more than a thousand brain disorders, neuroscientists are now increasingly finding that genes are often the culprits. Delving deep into the brain's molecular structure, scientists have identified the genetic defects that are responsible for 40 disorders of the nervous system and have a good idea of where the flaws for several other afflictions lie (Science, Vol 262, No 5134).
Interestingly, scientists have been able to identify the actual changes in deoxyribonucleic acid (DNA) -- the molecule that contains genetic information -- that cause these disorders (See box). DNA is made up of four chemicals known as bases or nucleotides. Each gene is a long pattern of bases arranged in sequence, some of which are repeated.
Sometimes, for reasons not yet understood, the base sequences go awry and this leads to neurological disorders. So far, scientists have uncovered four types of genetic disorders that cause neurological afflictions: when the occurrence of repeat base sequences is higher than normal; when a single base is flawed; when protein-producing genes are defective, and when mitochondrial genes (those found outside a cell's nucleus) mutate.
If the occurrence of repeated base sequences is above normal, a person is affected by a disease. The higher the number of excessive repeat sequences, the more severe the disease (See box). Moreover, if a person inherits genes with more repeated sequences, the chances are that he or she will fall prey to the disease earlier than a person with fewer repeated sequences. The number of repeated sequences can also increase from one generation to the next.
Scientists reckon alterations in DNA repeat sequences occur either because of defective eggs and sperm or during cell division in the course of growth. In the former case, all the cells of an individual would carry the gene defects, but in the latter, only some cells would be affected. This, says Joseph B Martin, professor of neurology at University of California in San Francisco, could explain the wide variation in the severity of symptoms of several inherited neurological diseases.
Genetic defects in even a single base can result in faulty transmission of nerve impulses, leading to diseases characterised by muscle contractions and periodic paralysis.
Researchers now also say some neurological disorders are due to defects in certain genes that produce proteins vital in the early development of the brain. These proteins control the migration of nerve cells from their site of origin to their location in the adult brain. A defect in them interferes with the normal maturation of specific cells, which are then unable to function.
Not only are defective DNA in a cell nuclei responsible for neurological disorders, those in mitochondria -- small structures outside the cell nucleus -- also cause certain diseases. Interestingly, mutations in mitochondrial DNA can be inherited only from the mother because paternal genetic contribution is limited to DNA found in the nucleus of the sperm.
Research indicates that with age, the frequency of defects in mitochondrial DNA increases and this may contribute to such diseases as Parkinson's, a nervous system disorder associated with trembling of limbs.
The advances in the diagnosis of neurological diseases pose new challenges for both doctors and patients. Doctors are using knowledge of DNA sequences to determine whether people have a predilection for certain diseases. Presymptomatic genetic testing, first developed for Huntington's disease, has now suddenly become possible for a myriad of other neurological disorders.
But, warns Martin, several ethical concerns need to be addressed. He is especially worried about proper counselling of patients on the implications of testing and the need to help them make difficult decisions to cope with the test results.
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