Sangita Jain’s life revolves around reading and research. Not for any academic pursuit, but to provide informed care to her two sons, aged 11 and 9, affected by Fragile X Syndrome (FXS) — the leading inherited cause of mental retardation. She has learnt to redefine her life, but each quiet glance at her younger son rakes up a sense of guilt — she could have prevented the second FXS case in her family had she been rightly advised by doctors.
Ten years ago, when she sought medical advice from paediatricians about her hyperactive son, doctors suggested he would be better off with a sibling and less pampering. Ironically, two years later — when her younger son was one — both boys were diagnosed with FXS. Like millions of other parents around the world, Sangita found herself struggling to rear children with a congenital disorder which has no effective cure.
But new research in laboratories scattered across India, the US and the UK have bolstered hope that devastating congenital brain disorders may indeed be cured. A group of scientists from the National Centre for Biological Sciences (NCBS) and National Institute of Mental Health and Neurosciences (Nimhans) in Bangalore, and Massachusetts Institute of Technology in Cambridge, US, has shown for the first time that FXS symptoms in mice can be reversed.
The study, reported in last week’s issue of the Proceedings of the National Academy of Sciences (PNAS), suggests that inhibiting a certain enzyme in the brain could be an effective therapy for countering the debilitating symptoms of FXS as well as some autism cases in children. FXS is tied to a mutation in the FMR1 (fragile X mental retardation) gene found on the X chromosome (and hence mothers are the carriers) and can cause mild learning disabilities to severe autism, explain the scientists.
| Sumantra Chattarji of the National Centre for Biological Sciences
Reversal of symptoms of neurological disorders offers hope for scientists to revisit some of the diseases and look for cures where none seem to have existed before. In February this year, a group of researchers from Stanford University reported in Nature Neuroscience that they were able to reverse symptoms of Down’s Syndrome in mice. The researchers used a long-discarded drug — PTZ, known to cause seizures in some people — with two other compounds, which together interfered with the ion channels in brain cells. These channels are responsible for causing the cognitive impairment in Down’s Syndrome.
In the same month, two groups reported in PNAS and Science that they could partially, if not fully, reverse the symptoms of Rett Syndrome, the most severe form of autism, in mice.
From mice to humans may be a long haul, but scientists agree these findings force them to reconsider the view that the brain can hardly be repaired after birth. And while there may be other ways to treat these disorders, scientists pinpoint — as in Down’s Syndrome and FXS studies — the road to the clinic never looked shorter.
In the FXS study, scientists genetically engineered mice to exhibit FXS and its symptoms including hyperactivity, purposelessness, repetitive movements, attention deficit and difficulty with learning and memory tasks. They later identified that the enzyme p21-activated kinase (PAK) affects the number, size and shape of connections between neurons in the brain. These connections between neurons are formed by small protrusions called “spines” which are spread on neuron branches called “dendrites”. The number and shape of dendritic spines are crucial for normal brain function, says Sumantra Chattarji, a co-author of the study from NCBS.
People affected by FXS have more dendritic spines in their brains — with each being longer and thinner — than in non-affected individuals. “Our analysis shows that inhibition of the activity of PAK helps reverse the abnormalities in their spine number and structure,” says Chattarji.
The study is conspicuous because PAK inhibition also restored electrical communication between neurons of the FXS mice which, in turn, corrected their behavioural abnormalities, says Shankarnarayana Rao, another co-author from Nimhans.
However, the most heartening finding is that the expression of the gene that inhibits PAK occurs in the third week after birth, suggesting that neuronal abnormalities in the Fragile X mice are reversed after they appear. This implies that PAK inhibition can reverse already established mental impairments in FXS children. “It is very exciting because of the treatment implications,” says Randi J. Hagerman, medical director of the M.I.N.D. Institute at University of California in Davis and a noted FXS researcher.
According to the Centers for Disease Control and Prevention in Atlanta, FXS affects 1 in 4,000 males and 1 in 6,000 females. The prevalence of autism ranges from 1 in 500 to 1 in 166 children. FXS could provide an entry point to autism treatment as it causes about 2 to 6 per cent of all autism.
“In most parts of the world, about 1 in 130-250 women are carriers of FXS with a pre-mutation and about 1 in 800 males are carriers. The prevalence is probably the same in India but we don’t know for sure,” notes Hagerman.
And it might not be known for some more time. In a country where finding adequate reading material on FXS (in different languages) is as difficult as parents owning up that their child suffers from some development impairment, only a large-scale public campaign can increase awareness and wash away the social stigma.
“Parents call me for quick guides and flyers on FXS. But they call anonymously and most often it’s followed by a painful silence,” says Shalini Kedia, a Mumbai resident who has set up the FXS Society of India. Both Kedia and Jain admit they receive calls from parents, particularly mothers, who are often fearful of broaching the subject even with their husbands.
Perhaps moved by the larger social implication of such genetic disorders, Chattarji has decided to extend his boundaries — from neurobiological research to medical education and a nationwide network of quality screening clinics. He is collaborating with Hagerman, Kedia and others to start a pilot project to train people and make diagnostic kits available in India. On the other hand, he is pushing the drug industry to make PAK inhibitor a leading drug candidate.
Training at various levels alone could work wonders. “As the disease shows wide variation in expression, diagnosis is a little tricky,” admits Dr G.K. Chetan, department of human genetics, Nimhans.
While autism, still a black box biologically, has garnered some attention in India, FXS remains in the shadow.