The phone rings and the geneticist give you the most heart-breaking news a parent should ever hear. “The genetic test confirmed the presence of a mutation on the MECP2 gene; I am sorry to say, your daughter has Rett Syndrome”.

For my family and I, my sister is the one who received the news first from the geneticist. It was late night for her, and early morning for us in Canada. As soon as my sister managed to hold her tears and get her voice back, she made the infamous call. From the first hello, I knew it. My heart sunk and I flipped screaming. Soon after the nervous breakdown wore off, my sisters and I, thousands of miles apart, held our phones and did the same google search “What is the life expectancy of Rett Syndrome?”.

We all got the same result to our common question. The first search result you will most probably get is “While it is known that Rett syndrome shortens lifespan, not much is known about specific life expectancy rates for people with Rett syndrome. It generally depends on the age when symptoms first begin and their severity. On average, most individuals with the condition survive into their 40s or 50s” as per Boston’s Children Hospital website.

Upon further research on the Life Expectancy Rett Syndrome sufferers, I came across the website of the American-Based Rett Syndrome foundation – the International Rett Syndrome Foundation. According to their website: “Due to the rarity of RTT, very little has been published about life expectancy.  Data from the Natural History Study have determined that a girl with RTT has a 100% chance of reaching age 10, a 90% chance of reaching age 20, a greater than 75% chance of reaching age 30, a greater than 65% chance of reaching age 40, and a greater than 50% chance of reaching age 50. As improved nutrition and overall care are provided, these probabilities are expected to improve.”

However, 6 months into the world of Rett Syndrome, I realize that this is far from the truth. Is the person conducting those studies in touch with the Rett Syndrome community? How is the information collected? Is it statistically acceptable to exclude cases who do not fit the story we are trying to convey? Is it ethically okay to cancel the girls who die before the age of 10?

In the last 8 months, the Rett Syndrome community lost Korrie Sanders at the age of 7, the Canadian Rett Syndrome community lost Amelia Algar at the age of 8 (Amelia is the twin sister of Keira Algar who also had Rett syndrome and passed away at the age of 6 back in 2021). Averi Roberts who passed away (according to her publicly available obituary at the age of 6); and the list goes on. This is not 100% of girls surviving to reach the age of 10. Those are girls who died from Rett Syndrome related complications in less than 8 months. Those girls are not outliers, and they should never be excluded!

If we expand our search, we will also see that, on average, every month about 2 or 3 girls from the Rett syndrome community pass away before they reach the age of 19. This information is only based on families residing in the United States and Canada AND who are public about their Rett Syndrome journey, are sharing their children’s death on Rett-Syndrome pages, or publicly via obituaries. What about the girls in the Middle East, Europe, Australia, South America, and Africa?

The Official Cause of Death

According to the Natural History Study conducted on Rett Syndrome, Rett girls have a very high chance of survival into their 30s.  As defined by Liu et al. (2022); a natural history study is an observational study that is designed to track the natural course of a rare disease such as Rett Syndrome. One key requirement for a significant study is to be “comprehensive and granular”. Unfortunately, as said above, that is not our experience. So, why are all those girls not making it into the statistics? One potential hypothesis is the inaccurate registration of cause of death on the death certificate, and medical/ hospital records.

The cause of death is usually reported on the official Death Certificate. For Rett Syndrome girls, its almost never written as “Rett Syndrome”. Girls who pass away, usually do from complications caused by Rett Syndrome. The causes can be Respiratory Issues, Epilepsy – Uncontrolled Seizures, Heart or Liver Failure, Pneumonia, Viral Infections including Influenza / Covid-19, or simply Sudden Unexplained Death. Most of those causes would probably not amount to death if they happened in a typically healthy child (i.e. lack a MECP2 disorder).

Therefore, if we officially look at Rett Syndrome as a cause of death, we will probably find no registered death cases. This is not the whole story. Once we take the omissions into account, and acknowledge those families, the statistics would change. The rate of death before the age of 20 is not as uncommon as the google search or the Natural history study make it seem.

Typical Vs Atypical Rett Syndrome

“Most girls live into their 40s or 50s”, “50% reaching age of 50”. Where are those girls/ women?

It is well known that Rett Syndrome like almost any other genetic disorder is a spectrum. The course and severity of Rett syndrome is determined by the location, type, and severity of the MECP2 mutation, as well as the process of random X-inactivation, and the presence of modifier genes. Rett Syndrome patients can be either belonging to the Classic Rett (Typical Rett Syndrome) or the Variant Rett (Atypical Rett Syndrome).

The clinical phenotype of Rett Syndrome females ranges from those females who can purposefully use their hands; hold their iPad, type on their iPad using their fine fingers, ski and skate, run and hike, and occasionally speak and verbalise their needs. However, on the other side of that spectrum, lies the Classic Rett Syndrome cases, most were never able to crawl or walk, use their hands, require a feeding tube, have tremors, and uncontrollable seizures. The difference in their capabilities determine both their quality of life and life span.

Scientifically speaking, I argue that Rett Syndrome is one wide spectrum. There are two types: Typical and Atypical. In the Typical category there is a spectrum of capabilities and features, and the atypical category has its own spectrum. The gene is the same, the mutations and phenotype is very different. We can not classify a girl who can’t crawl or bear weight with one who can do gymnastics and go skiing. We can not classify a girl who can not move her hands with one who can run while holding her iPad. We also can not classify one whose prognosis is constantly deteriorating with one who is told by her therapists that “her gross and fine motor skills are improving”.

However, if we decide to go ahead and classify them under the same umbrella for simplicities sake and to avoid “offending” them; we must be extremely cautious when it comes to discussing quality of life and life expectancy. We can not assume that they have the same chance of survival and life expectancy.

Why does it matter?

Back in December 2023 – one parent wrote on a Rett Syndrome Forum about the importance of differentiating between the types of Rett Syndrome. Their argument was based on how the difference in Rett Syndrome phenotype and the disease prognosis impact the quality of life long-term, the urgency of finding a cure and the life expectancy. They also wrote why we should be very careful to make it clear that a girl who runs and skis is not the typical face of Rett Syndrome. Within seconds of her post, they were verbally attacked and accused of invalidating the experiences of girls with Atypical Rett Syndrome. An hour later, the post was deleted by the group admin.

While a female with Atypical Rett Syndrome is expected to have a “50% chance of living into her 50s” as per the study (which we personally disagree with), that is almost never the case for a lady with classical Rett.

If we sit and reflect on the Facebook post, we see that the urgency to find a cure for a girl who can type on her iPad and say some words is most definitely not the same as that for a girl who never know what standing feels like, or what it means to eat using her mouth.

The day we start differentiating between the two categories, and acknowledge that their life expectancy varies significantly, we would be able to address the differences in urgency. Let’s start by acknowledging that not 100% of the girls make it to the age of 10, and not 50% of the Rett syndrome girls make it beyond their 50s. It is only then; the world can start to acknowledge that Rett syndrome can indeed be terminal and the urgency to find a cure is the same as that of a terminal illness.

Additional Notes:

1. Boys (with a Rett Syndrome diagnosis) are intentionally excluded as the information on their life expectancy is different. (They are excluded from this discussion but never forgotten)
2. We are only discussing MECP2 Disorders
3. We are excluding patients with CDKL5 and FOXG1 syndromes which were previously described as Rett Syndrome Variants

Disclaimer: This article is based on our personal observations and personal opinions.

References used:

Rett Syndrome. National Organisation for Rare Disorders. Available at https://rarediseases.org/rare-diseases/rett-syndrome/ . [Accessed February 15, 2024]

What is Life Expectancy? International Rett Syndrome Foundation. Available at https://www.rettsyndrome.org/about-rett-syndrome/faqs/# . [Accessed February 15, 2024]

What’s the long-term outlook for my child?. Boston Children’s Hospital. Available at https://www.childrenshospital.org/conditions/rett-syndrome#. [Accessed February 15, 2024]

Xiol, C., Vidal, S., Pascual-Alonso, A., Blasco, L., Brandi, N., Pacheco, P., Gerotina, E., O’Callaghan, M., Pineda, M. and Armstrong, J., 2019. X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients. Scientific reports, 9(1), p.11983.

Liu, J., Barrett, J.S., Leonardi, E.T., Lee, L., Roychoudhury, S., Chen, Y. and Trifillis, P., 2022. Natural History and Real‐World Data in Rare Diseases: Applications, Limitations, and Future Perspectives. The Journal of Clinical Pharmacology, 62, pp.S38-S55.