Arising from the Doom of 'No Diagnosis No Treatment', here is the story of how Samir Sethi persevered.
The Sethi's on a family vacation. (L-R - Shafali, Samiksha, Rohan and Samir)
In the 1980's Samir Sethi could be described as a charming Punjabi lad with impeccable manners. His family had migrated from Rawalpindi in Pakistan, and by the time Samir was growing up they had set up a flourishing dry fruit business in old Delhi. With his ivy league-type education and MBA degree, Samir had no plans to be sitting in his father’s shop selling dry fruits like a ‘Lala’. However, with the untimely death of his dad, Samir was compelled to take over the family business, like the dutiful only son.
In Feb 1994, Samir was wedded to Shafali whose family had also migrated from Pakistan, from the city of Multan. Both inherited a similar value system with close cultural bonding.
In Dec 1994 the young couple were blessed with a baby girl whom they fondly named Samiksha. The pregnancy had been without incidence, Samiksha was a full-term normal baby, and now she was the centre of her family’s universe. By the time she was a year old, however, her parents sensed that she was not growing as expected for her age. Her cousin, who was exactly her age, was a ready comparison. Samiksha’s paediatrician, however, did not share their concern and so another year went by. Samiksha was still not walking or talking, but the paediatrician was still not worried as some babies could reach these milestones much later.
Unable to continue with waiting and watching, the family consulted another paediatrician. This doctor was concerned, and ordered a battery of tests, including neurological evaluation. When the EEG was done to check electrical activity of the brain, it showed that baby Samiksha was prone to seizures. These were silent seizures, like a little jerk or a slight shiver. They were happening frequently but went unnoticed. The reason Samiksha was not walking normally, and had a limited vocabulary of a few words, was due to these unseen bouts of epileptic seizures. The verdict set alarm bells ringing for the whole family. Clearly the seizures had to be controlled urgently. At age 3, baby Samiksha was put on the epileptic drug Sabril. In addition, regular speech therapy and physiotherapy were initiated.
Although alerted about the seizures, the family was left in a state of confusion and despair as there was no firm diagnosis and no clarity about the source of the seizures and the delays in Samiksha’s developmental milestones. Samir, by now, was completely seized of the underlying questions. Why these frequent seizures? What exactly was wrong? What was in store for Samiksha’s future? In his search for information Samir visited many paediatric neurologists, development specialists, and paediatricians in India, and even sent Samiksha’s reports to doctors in USA and UK for their opinion. In spite of these efforts a diagnosis was still not forthcoming.
In 2005, suspecting it to be a genetic defect, Samir visited Gangaram hospital, the premier centre for human genetics in the country. It was still early days in India for genetic testing by direct DNA sequencing, and other methods were used to infer a genetic basis, like pedigree analysis, chromosome-level defects, or biochemical tests. Nothing conclusive could be found by the available tests; hence the painful diagnostic odyssey continued.
By 2008 Samiksha’s seizures were increasing in frequency in addition to other complications due to breathing difficulties and digestive issues. Already confused and frustrated without a diagnosis, Samir received a further blow by the insensitive behaviour of Samiksha’s long-time paediatric neurologist. This, though, was going to be a game-changer for Samir through an arduous route.
Shafali and Samiksha
Inching towards a diagnosis
Although many Doctors are deservedly ‘Bhagwan ka roop’ for their patients, there are those who are all too human in their carelessness, greed, and apathy. Samir encountered an unfair share of the latter type in his journey. Samiksha had been under treatment by a paediatric neurologist for the past few years. Once when she had a particularly bad case of seizures, Samir called the Doctor for advice, expecting at least a patient hearing. The neurologist, however, behaved as though he did not recognize the caller or the patient who had been under his regular treatment. This struck a panic button in Samir and his family. What if Samiksha was in an emergency situation? They certainly couldn’t count on this doctor. So, the family switched to another paediatric neurologist who was formerly at AIIMS, New Delhi and was now in private practice. She, being a very experienced doctor, immediately recognized the symptoms to closely correspond with Rett syndrome, for which a genetic test was now available in India. She took Samiksha’s blood sample for DNA sequence testing, which would provide a confirmed diagnosis. She also changed her medication. There was a new regimen that included sodium valproate, which in addition to controlling seizures, was also a mood stabilizer.
The diagnosis at last (early 2009)
Just when the family was much relieved to have found the right doctor, Samir received a strange phone call that was to change the course of his life. The call was from AIIMS, Department of genetic medicine, to inform Samir that the blood sample they had purportedly sent for DNA testing to AIIMS had been analysed, and they should report to the hospital to discuss the results. A month ago they had, indeed given Samiksha’s blood sample for DNA testing, but it was to the doctor who had charged them Rs. 12,000 for it, not to AIIMS where they later found that the test was being done free of cost. That trip to AIIMS catapulted Samir to the world of rare genetic diseases that he never imagined he was fated to inhabit. Samiksha’s test was positive for the neuro-developmental disorder, Rett syndrome, a rare genetic disease due to mutations in the MECP2 gene. It affects mainly girls as the gene is located on the X-chromosome related to sex. Technical information can be intimidating to many, but Samir gratefully lapped it up, as it opened a doorway to view the silent world in which his darling angel lived.
After diagnosis what?
All these years Samiksha’s diagnosis had varied, depending on the best judgement of her consulting physician, from cerebral palsy to delayed development, epilepsy and so on. Finally, that uncertainty had ended and they had the correct name to describe Samiksha’s condition. It was not as though the confirmed diagnosis brought with it a confirmed treatment, but at least now they knew what they were waiting for- a drug for Rett syndrome. Besides being aware of the risk for the next pregnancy, they could now look for Rett-relevant information on the internet and learn from international parents’ groups what to expect as the disease progressed, what serious issues to look out for, what corrective measures to take. This exposure to knowledge based on real-life experiences of Rett parents gave Samir the sense of control and empowerment he longed for.
Samiksha with her cousin.
Special health issues associated with Rett Syndrome
Samir’s connection with the international Rett syndrome groups was, and continues to be, highly informative for him and his family. They learnt that disease severity and progression varied amongst children. It could depend on many factors, including the location and type of mutation seen. In general, children experience the following issues:
Impaired motor skills and communication. Children begin to lose the normal use of muscles that control movement, and communication, that manifests as loss of mobility or disturbed gait.
They are unable to communicate effectively as they lose the ability to speak, and to make eye contact. Instead, they may develop unusual eye movements like intense staring and blinking, and unusual involuntary hand movements, like repetitive clapping, squeezing, or rubbing.
Breathing problems of various types like breath holding, or rapid breathing (hyperventilation) during the day, and shallow breathing or stopping breathing (apnea) during sleep.
Disturbed Sleep patterns.
Epileptic seizures
Behavioural problems like sudden bouts of crying or screaming, or prolonged periods of laughter, or hand licking, and grasping of hair or clothing.
Other problems include intellectual disabilities, irregular heartbeat, decreased response to pain, problems with chewing and swallowing, and sideways curvature of the spine (scoliosis).
Accept and conquer
Such a slew of health issues is daunting, to say the least. The disease impairs the basic activities of life, namely walking, speaking, eating, and breathing. Undaunted however, Samir and his family took on the challenge to manage each issue as it arose. It ultimately boils down to one’s attitude. This family embraced the disease lovingly. As Samiksha lost the ability to speak they became the voice of their ‘silent angel’. She could sometimes be in extreme discomfort, for example due to a dental issue, but would be unable to communicate the problem. So, they would guess the possible causes and draw inferences from her behaviour. She needs to be fed carefully as food particles could get stuck in the trachea. She is very prone to lung infections which can become serious. Early on they realized that cough and cold with low grade fever is not to be taken lightly. Along with supportive treatments like nebulizer, it needs doctor’s examination.
Scoliosis Management
It was the year 2009 and Samiksha was entering puberty. Her parents were now extra vigilant to observe any physical, emotional and behavioural changes that could be of concern. At this time they noticed that Samiksha was beginning to develop spine bending or scoliosis. This was a common consequence of Rett, and some children could start developing it as early as age eight. Samiksha was immediately examined by an orthopaedic who advised putting her in a brace for eighteen hours a day to arrest the spine curvature. Although not without discomfort it was the best solution on offer. For the next three years, as Samiksha was growing, the brace had to be changed several times to fit her size. Finally, the scoliosis seemed to be arrested as the angle of curvature had reduced from 360 to 190. If the angle exceeds 400 it can put pressure on the rib cage and severely affect lung function. For Samiksha that danger had been averted and the brace was no longer required. Prompt management of adverse symptoms was, thus, the key.
Awareness meeting at Safdarjung Hospital.
Rett Parents Advocacy group in India - Early beginnings
Samir’s first interaction with the Department of Genetics at AIIMS, New Delhi was in early 2009 at the time of Samiksha’s diagnosis. The keen interest of AIIMS in Rett syndrome patients was because they had received a project to serve as a referral Centre for all Rett patients of north India. Consequently, they had formed an organized group of all Rett parents whose daughters had been diagnosed at AIIMS, New Delhi. This group met periodically, and that was how Samir met, for the first time, other parents of Rett daughters. It was not a happy experience. Most of the parents were highly disturbed and felt lost, confused, and disillusioned. Samir realized that the reason he was relatively calm was because he had educated himself about the disease through the websites of patient groups abroad. The empowerment that comes through rational thinking had eluded these parents as they probably lacked the means to benefit from the internet. And so, they pinned all their hopes on AIIMS. They came to the meetings with the hope of learning how to improve their child’s condition, but left none the wiser. They and the experts were clearly not on the same page. Perhaps the parents did not know what questions to ask; how to articulate their sense of hopelessness to the doctors. Samir being one of them could easily capture their insecurities and frustrations- the feelings he himself had experienced not so long ago, but which had now given way to positive action. Samir could have easily walked away from it all. He had nothing to gain from these confused parents. Besides, he had enough on his plate with a business to manage, a family to provide for, and a daughter who needed his continuous attention and care. But walking away was not even a distant thought. These parents were family, their daughters so many other Samikshas.
2009-2010 : Samir the natural leader of Rett Parents’ group
Around the time Samir came on the scene, an NGO was already operating from AIIMS. They had the contact details of a substantial number of Rett patients’ families, but they had done little to serve the community. Samir volunteered his time, and began to think about effective strategies to help the parents emerge from their gloom and start doing the needful to help their child. All his personal experiences and learnings of the past were put to good use. By 2014 Samir was the most popular parent in the group and was elected President of the Rett society, called Indian Rett Syndrome Foundation.
Samiksha at her birthday celebrations.
Samironomics to cope with an Incurable Disease
Acceptance - Only when you truly accept the condition you are in, can you hope to gain control. But the instinct for most parents in the Rett group (and, indeed in most other rare diseases) was to hide the disease, and hope that some magical treatment would emerge before the world knew about their daughter’s illness. Samir figured out the main reasons behind this reluctance to accept the obvious. a) Girl child; the social stigma associated with a mentally-challenged girl child was enormous, and would have a ripple effect on their other children as well; b) Acute financial burden; just basic management of the disease placed a significant financial burden on lower income families; c) Caregiver support; one family member was constantly required to provide care and support to the dependent child, which further added to the reluctant family’s woes. These parents were viewing their child from a lens that was completely different from how Samir’s family saw Samiksha. It was heart-breaking, and Samir decided to do his best to counsel these parents. He found that these families were not including their child in any social events, family gatherings, vacations, weddings etc. The child was being isolated, and in the process the family was isolating itself as well. A few close family members and friends who did know about the child’s condition were all too prompt to offer unsolicited advice, which was almost like a diktat. If not obeyed, the parents were accused of neglecting their child, or else the child would certainly have improved. Samir, through his own example impressed upon these families to exude confidence within, which in turn would be reflected before the world. They, or their child, had committed no crime. They were playing this game of life with the cards dealt out to them, and they were doing a superb job. As parents, they had the best interest of their child in mind. If they could make themselves reach such a level of acceptance within, the world would follow suit.
Vulnerability - The grim reality that a meaningful treatment to relieve your child’s suffering simply does not exist, can shatter the steeliest of resolves. Little wonder then that most parents are highly vulnerable to the false promises of quacks, and always need to be on their guard. Samir had himself learnt this the hard way. Once when he was visiting a temple with Samiksha he met someone who assured him that he could treat Samiksha with an Ayurvedic oil massage that was known to cure such conditions. This person visited Samir at home and handed him a list of about twenty ingredients to be procured from a particular shop. Samir decided to cross-check with a known Ayurvedic doctor to understand more about the logic of using all those ingredients. His suspicion was justified as this doctor immediately rubbished the whole thing. Those ingredients were meant for totally disparate conditions- one was for headache, another for gastrointestinal symptoms, and so on. They would collectively cost some three to four lakh Rupees. Obviously, it was all a racket to extort hapless patients and their families. This experience exposed to Samir his own vulnerability, and he warned other parents of this danger.
Sharing is caring - Unlike common diseases where information about disease management and latest treatments is more readily available, patients and caregivers of rare diseases are lonely souls living in complete isolation. Even their doctors give up on them as there is no treatment to offer. But the families have each other. The network of rare parents for their own rare disease is very strong and they care for each other by sharing valuable practical experiences. Samir proposed that the Rett parents of India should also form such an interactive group that would meet regularly and where parents could discuss their problems and fears in an open and conducive environment.
Rett Conference in Finland.
2014-2017 - Interactive sessions with Parents - The beginning of acceptance
Samir began to organize regular awareness meetings and workshops for the benefit of parents, where experts from various specializations were invited. Simultaneously, there was enough opportunity for parents to talk to one another and share their problems and solutions. In one such meeting Samir recalls that a couple of parents stood up to narrate their personal issues arising as a consequence of a child with special needs in their family. With one parent sharing his experience, it emboldened other parents as well. Soon those who were shy and reticent opened up, and the sense of isolation diminished. Interestingly, a common refrain from most parents was that, more than their child’s illness, they were suffering from unsolicited, aggressive advice from neighbours and family. They were being constantly pushed and blamed for being inadequate parents. Opening up with each other helped them to regain much-needed confidence in themselves.
Multidisciplinary meetings with Doctors and Parents - Gaining Control
As Samir began to organize regular awareness meetings, he kept evolving the meeting format so that parents could accrue more benefit. In the beginning a day-long meeting would typically include expert talks, and a panel discussion where parents could ask questions. Soon it became a mechanical exercise with little scope to discuss real-world problems of each patient with the expert clinicians. To solve this, Samir introduced a one-on-one meeting format where multiple experts were invited, from neurology, gynaecology, pulmonology etc. as needed by Rett patients. Each expert would see the child for a few minutes, and listen to their individual problems. Experts could also consult each other to suggest the best personalized treatment regimen for the child. These meetings were hugely satisfying for parents. Doctors also got a more comprehensive insight into comorbidities in Rett children.
This successful meeting format, started at AIIMS, New Delhi was soon replicated in more hospitals in Delhi; and subsequently in other cities- Mumbai, Kolkata, Bengaluru. One such multidisciplinary meeting is now organized every year in each major city. Over the years, with Samir being present in all of these meetings, he has developed close personal contacts with most of the doctors who are treating Rett syndrome patients. This helps him to put patients in touch with doctors in any part of the country.
Picnic at Railway Museum, New Delhi
Annual picnic for patients and families - Bonding and Learning
In addition to the multidisciplinary meetings, Samir organizes an annual meeting at the national level. This is a two-day meeting where patients and families from different parts of the country meet and socialize. The first day is typically devoted to academic talks by experts. On the second day a picnic is organized in a convenient public space like a park or a children’s museum. It is an opportunity for families to mingle and socialize, and for children to have a fun time. Parents learn from others by observing how other parents are managing their child, what is the child eating and how are the parents feeding her, how are they helping with her mood swings etc.
Other programs at the Indian Rett Syndrome Foundation
In addition to organizing meetings, the group undertakes many other useful activities.
Obtaining disability certificate for the child It is a cumbersome process involving multiple trips to a hospital. Samir could simplify it by organizing camps where disability certificates could be obtained in a single sitting.
Samarth (Silent Angels Medical And Rehabilitation Therapy)
This program, to provide free medicines to Rett patients, was launched in 2018 through generous funding by a donor. This was necessary to help low-income parents, who do not always get a sustained supply of free medicines from government-run hospitals, which means that the child could be without medication for long periods. The program ran successfully for a year, after which Covid-19 struck and the donor could no longer continue with funding. Currently, Samir is running this program on a limited scale through his own funds to help very needy patients.
Connecting with doctors- Perhaps the biggest service Samir does is to connect patients’ families to the right doctors. This is because of his constant engagement with doctors from all over the country who are treating Rett patients. He narrates with a degree of satisfaction that he could connect a patient’s family from Khammam in Telengana to a paediatric neurologist in Khammam itself and saved them the trouble of travelling to Bengaluru. Samir travels a lot to meet doctors, who encourage newly diagnosed patients to join their group. Having covered the major metro cities, he is now travelling to Chandigarh, Jammu and the northeastern states.
Excercise time for Samiksha!
Living happily with Rett : A peek into the life of Samiksha
Samiksha doesn’t just have a doting family, they are also very intelligent people and have ensured that, in spite of her various health problems, their ‘silent angel’ would inhabit a world of joy and possibilities. Samiksha is intrinsically a fun-loving woman. She is very social, loves to dress up, eat spicy food and go for outings. On a typical day she eats breakfast at 10 am along with the family, the same food that they eat, after which she watches her favourite show, Animal Planet on TV. From 12 to 1 pm she exercises and takes a walk inside the house. After lunch she sleeps for a couple of hours and by 5pm she is ready for a one-hour physiotherapy session. Her exercises include playing with a ball, blowing out candles (which she loves to do on everyone’s birthdays), hand exercises like unscrewing pegs from a board, putting alphabets in position, and some yoga too. From 6pm till dinner time she entertains herself by watching dance and music shows on TV. Her favourite activity is to continuously flip the pages of a glossy magazine, and eventually to start tearing out a few of them. Her favourite person in the family is her brother, Rohan, who is nine years younger than her, and with whom she can do ‘masti’. After dinner she again takes a walk inside the house. If the weather is mild, they go out for a long walk. She is always excited to meet any neighbours and greet them with her broad smile. Interestingly, the activity she most loves to do is listen to ‘bhajans’ and visit the temple. In fact, the temple is a place from where she does not want to return home. Does she feel there a spiritual connect that transcends verbal communication? She alone would know.
The dedicated father that Samir is, he tried his best to see that Samiksha could acquire some communication skills. For a number of years, Samiksha was sent to an expensive integrated school where children with special needs supposedly got education along with everyone else. However, in practice children like Samiksha were kept in a separate room, with no professional educators, and the school was a glorified day-care centre. Samir tried various speech therapy centres but it remains his regret that Samiksha could not acquire language skills, although she has obvious cognitive abilities. If her family members are un well she can sense it immediately and is deeply concerned. If she is reprimanded, she can gauge from the tone of voice whether it is being done seriously or jokingly, but she cannot verbalize her thoughts even in a few words. India lacks trained speech therapists and we are way behind the advanced countries in this area. Apart from the speech therapists working on the child, the common practice abroad is also to train the parents and caregivers so that the therapy can continue at home. It is also not an easy task to identify and retain a physiotherapist and occupational therapist who knows exactly how to break the ice with children like Samiksha and interact with them in a friendly manner to ensure compliance. The therapist should also have the expertise to identify the child’s weak spots, especially since they often have fragile bones, and make a comprehensive rehabilitation plan of exercises and therapies which would benefit the child.
Samir has reason to be satisfied that he has succeeded in providing the right regimen of physical therapy and occupational therapy to Samiksha, which has benefited her greatly. At age 29 she has retained her movement, whereas young children without regular therapy lose muscle tone and could become bed-ridden.
When parents give up and abandon the child
Samir has touched the lives of so many Rett families, counselling them, imparting courage and strength through his own example, and helping them practically by connecting them to the right doctors in government hospitals. He even provides financial support to the most needy. This has helped many families - single moms where the husband deserted the family to escape the challenge, and also vice versa. Painfully though, there have been parents who could not cope with the challenges and decided to give up on the child. Samir recalls one such family whom he had been supporting personally and was keeping track of the child. Once when a respiratory issue became serious Samir arranged to have her admitted to the hospital. She was put on ventilator, and gradually recovered. But a few days after she was discharged from the hospital Samir learnt that the child was no more. They had stopped taking care of the child at home, and the father sounded relieved that the child, who was a burden on the family, was gone. His moral justification was that one’s life span is pre-determined by a greater force before whom mere mortals are powerless. In the case of another such family the parents refused to meet Samir after the daughter was gone and asked him never to phone them again. It seems they had resolved in their family never to talk about this daughter again, and to forget her like a bad dream. Alas, bad dreams can’t be wished away; they have a tendency to lurk around and haunt us.
Efforts by Indian Rett Syndrome Foundation to bring approved drugs to India In March 2023, the drug DAYBUE (Trofinetide) was approved by the USFDA for treatment of Rett syndrome. It reduces comorbidities and improves the overall quality of life. It is not yet available in India. Samir, and others at their Foundation are actively pursuing with the drug manufacturer (Acadia) to introduce this medicine for Indian patients. At this point the drug is still being tested for efficacy and reduction of side effects; hence sales are very restricted.
They are also in discussion with the principal investigators and sponsors of gene therapy trials (currently under way for Rett syndrome in the US), to include Indian patients in their clinical research program. Samir has met company executives personally on his recent visit to the US. He has organised web-meetings with these companies so that parents and caregivers in India could directly discuss the preliminary results from the drug trials. These meetings have given parents the confidence and assurance that treatment for their children can be expected in the near future.
Samiksha with brother Rohan, on vacation.
Beyond Rett - Samir, an ambassador for all Rare Diseases
An impressive number of rare diseases have very active patient advocacy groups in India. This rare disease fraternity, while working for the welfare of patients in their own group, are also supportive of one another and for the common goals and needs of all rare diseases. Samir is at the forefront in these common activities, lobbying with government for improvements in rare disease policy, brainstorming to develop strategies for getting drugs to India, fighting for disability benefits, health insurance cover and much more. Samir is also working closely with various Centres of Excellence for rare diseases, set up under the National Policy of Rare Diseases, 2021. He is assisting these centres to implement their mandate of efficient diagnoses, treatment, and management of rare diseases.
Samir has been actively involved in the inception of a national forum called REDRESS (Rare Genetic Diseases Research Summit) to promote indigenous research in rare diseases. This forum is sponsored by the Organization for Rare Diseases India (ORDI) and the Tata Institute for Genetics and Society (TIGS). It brings together researchers, scientists, clinicians, pharma companies, drug developers, government agencies etc., at an annual meeting. Now in its third year, REDRESS fosters collaboration to accelerate research and development of therapeutics for rare diseases in the country.
Samir Sethi is, by far, the most congenial and popular person in the Indian rare disease community. Not only does he support and contribute to every rare disease event in the country, he has the diplomatic and communication skills to be a worthy spokesperson of the community especially with government agencies and policy makers.
In the world of rare diseases where disappointment is the norm, how does Samir stay so positive and optimistic? The unspoken expressions of gratitude from his ‘silent angels’ are perhaps his driving force.
ABOUT RETT SYNDROME Rett syndrome (RTT) is a rare genetic disorder leading to severe and progressive intellectual disability. It almost exclusively affects female children with an incidence of approximately 1 in 15,000. It was first characterized in 1966 by an Austrian psychiatrist Andreas Rett. The symptoms of RTT begin to appear from 6 to 18 months of age when the baby shows deterioration of motor skills, eye contact, speech, and motor control. This is followed by neurological symptoms, including anxiety, respiratory dysrhythmias, and seizures. Children lose normal mobility and ability to speak. They develop unusual eye movements like intense staring or blinking, and involuntary hand movements, like repetitive clapping, squeezing or rubbing. They could go through sudden bouts of crying or screaming, or prolonged laughter. Breathing problems include rapid breathing (hyperventilation) during waking hours, and stopping breathing (apnea) during sleep.
Genetics - The gene MECP2 responsible for RTT was identified in 1999. It is located on the X-chromosome. It is inherited in a dominant pattern, that is a single copy of the mutated gene is sufficient to cause disease, even though a second normal copy is present. More than 95% cases are sporadic, that is the mutation was not inherited from a parent but arose independently. RTT almost exclusively affects females. Since they have two copies of the X-chromosome, the presence of one normal copy of MECP2 gene along with one mutated copy allows survival of the female baby, although with severe disease. Male babies (if they receive the faulty X-chromosome) do not generally survive as they possess only one copy of the X-chromosome. Disease severity in females depends to some extent on the type of mutation and the extent to which the normal gene copy is expressed.
The MECP2 (Methyl CpG binding protein 2) gene: This gene codes for a protein that binds to DNA at CpG sequences where the C is a special nucleotide containing a methyl group. Binding of MECP2 protein to such methylated DNA in a gene has a profound effect on the activity of that gene (epigenetic regulation). If MECP2 protein loses function due to mutations, its target genes get mis-regulated. This has disastrous effects in the brain because MECP2 protein is needed in very high amounts there for neuronal development.
Treatment options - RTT, although a rare disease, has been an active area of research from the early 1980s due to the efforts of a few dedicated paediatric neurologists and parent groups. It has elicited significant pharmacological interest with more than 60 clinical trials finished or in progress. Most treatments aim to alleviate some of the symptoms and improve quality of life. As knowledge of RTT has increased, the life expectancy of females with RTT has increased several-fold, with women likely to survive till their fifth decade and beyond.
Nucleic acid-based therapies - An encouraging observation from mouse models of RTT is that the damage caused by MECP2 deficiency is reversible once expression of normal gene is restored. This makes it possible for gene replacement therapies to work, provided the MECP2 expression can be fine-tuned. Too little expression is ineffective and too much expression of this gene has adverse neurological consequences. Gene therapy is being developed to transfer MECP2 gene through adeno-associated virus (AAV) vector. When injected intravenously it can have severe liver toxicity. The AAV vector is being modified to target it preferentially to the brain, and to include DNA regulatory sequences that can modulate MECP2 gene expression and avoid over-expression.
The first gene therapy trial for RTT has already been initiated in USA by Neurogene. Their drug (NGN-401) is AAV-based gene delivery of the full-length MECP2 gene directly into the central nervous system. They have also developed a technology to avoid overexpression of the gene. Other strategies include DNA editing using CRISPR/Cas9, and RNA editing. They need optimization and reduction of off-target effects. Another approach is to reactivate the silent X chromosome to enhance expression of the normal copy of MECP2 gene. Here the possible adverse effects due to over-expression of other genes on the X-chromosome have to be considered. Thus, these strategies, although highly promising, are still works in progress.
Rehabilitation interventions - Rehabilitation has the potential to partially restore lost functions, reduce disability, and vastly improve the quality of life. To obtain maximum benefit it is essential to carry out these interventions over a long-duration each day and over a long-term. Regular physiotherapy can improve gross motor skills like walking, stair climbing, and gait. Fine motor interventions include splinting of hand and/or elbow, gentle physical interruption of hand mouthing during playing with toys, interactive game play, and operant conditioning (to induce learning through rewards and punishments). Activities like playing a musical instrument, and self-feeding can also improve hand use and reduce stereotypic hand movements.
Communication interventions - can improve choice-making skills of the child (for example choice between snacks or songs), and boost language and social communication abilities. Storybook reading, and use of assistive devices, can improve symbolic communication. Eye tracking technology has applications in language learning and has been shown to help RTT children improve their focus on a target. All these therapies require sustained effort and time from parents and caregivers to produce beneficial results. In the long-run they could make the child a happier individual and more independent.
Trofinetide - the first USFDA-approved drug for RTT - It is an analogue of the tripeptide glycine-proline-glutamate (GPE), which is an N-terminal cleavage product of insulin-like growth factor 1 (IGF-1). GPE is found naturally in the brain and has neuroprotective properties. How exactly Trofinetide helps in RTT is not known, but it is thought to work in the brain by enhancing synaptic activities, suppressing inflammation, and protecting neurons by reducing tissue damage and apoptosis. Developed by Acadia Pharmaceuticals, Trofinetide showed statistically significant improvement over placebo in a phase 3 trial conducted for 12 weeks with RTT girls and women aged 5-20 years. The drug does have side effects of concern, chief being diarrhoea, vomiting and associated weight loss. However, as a first drug for RTT it can provide much relief for patients.
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References
Panayotis N et al. 2023, State-of-the-art therapies for Rett syndrome,
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Good KV et al. 2021, MeCP2: The Genetic Driver of Rett Syndrome Epigenetics, Front. Genet. doi: 10.3389/fgene.2021.620859
Lim J et al. 2020, Rehabilitation interventions in Rett syndrome: a scoping review, Dev Med Child Neurol. DOI: 10.1111/dmcn.14565
Furqan M. 2023, Trofinetide—a new chapter in rett syndrome’s treatment, Front. Pharmocol. doi: 10.3389/fphar.2023.1284035