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What is Fragile X?


What is Fragile X
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Diagnosis


I leaned against the kitchen bench and teased the envelope open, chatting to my husband about my day. Our two daughters, 8 and 5, were drawing at the dining room table as Jon cooked dinner. The receptionist at the medical centre had given me the envelope as I passed her desk on my way home, saying something about blood test results. Our eldest daughter had been tired recently, so our pediatrician had referred her for bloods to check her iron levels. The genetic screening tests he had mentioned were far from my mind as I looked at her blood results which showed deficiencies in iron and vitamin D.


I turned the page still downloading to Jon- how many clients I had seen- whether I thought I had been able to help them. I started reading: ‘FMR1 CGG TRIPLET REPEAT ASSAY: Assessment of the number of CGG triplet repeats…This patient has one full mutation allele (320 repeats) and one normal allele (23 repeats). This result is supportive of a diagnosis of Fragile X syndrome. A FMR1 CGG repeat expansion in the full mutation range (200+ repeats), accounts for >99% of Fragile X Syndrome. A full mutation typically results in hypermethylation of the promotor region, and subsequent reduction in fragile X mental retardation protein 1. Clinical presentation of females with a full mutation is highly variable ranging from normal intellect to intellectual disability, which is seen in about 50%. This individual is at risk of having children affected with Fragile X syndrome… This genetic test result may have significant medical implications for this individual and their relatives, therefore referral for genetic counselling is recommended.”


I went quiet. Bizarre thoughts popped into my mind: I must not be understanding the medical jargon correctly. I suddenly wanted to send the results back and wind back time to when I had no knowledge of this- as if I could undo what I was reading. I read the page again. Maybe hypermethylation was a good thing? ‘Hyper’ usually meant over the top? I read again, trying to justify, but my eyes kept being drawn to the phrases ‘mental retardation’, ‘intellectual disability’ and ‘significant medical implications’. I mutely handed the results to Jon.


I called my mum. She answered the phone happily and asked after us. After I explained she half-whispered, ‘No, she doesn’t’, a mixture of disbelief and voodoo- hoping to undo what had already been done. We cried and she prayed for us. We cried to our friends. I stayed up researching the syndrome. Then I went to bed.


That night was the beginning of what felt like months of little sleep. Whenever I closed my eyes, visions of my daughter, horribly deformed and disabled, came to mind. I could feel my sympathetic nervous system responding- floods of adrenaline, waves of ice-cold sensations, shakes, nausea, and heart palpitations. Night after night, I lay in bed- using all the techniques I had learned training as a psychologist, trying to calm my fight or flight system. But the threat was so powerful, and the value so great that I had placed on my children being beautiful and successful, my deep breathing was overwhelmed by my powerful belief: This was not going to be ok. Ever. My daughter will never be ok.


That was the beginning of my foray into the world of Fragile X.


What is Fragile X Syndrome?


Like I discovered from my daughter’s pathology report, Fragile X syndrome is a mutation of a single gene- the FMR1 gene. Every cell contains thousands of genes that give instructions to our body about all manner of physical and psychological characteristics- whether we will have a widow’s peak or our father’s flat feet.


The FMR1 gene is made up of a DNA sequence called ‘CGG’. At certain intervals we also have an AGG sequence that acts like a fence post- keeping the CGG repeats in between these AGG sequences in the right place. The small CGG DNA sequence normally repeats between 5-44 times. This number of repeats keeps it functioning well, sending the protein it makes to our brain to help us develop intellectually. A small proportion of those with this normal gene have fewer AGG fence posts to secure the CGG repeats, and this can lead to the gene becoming less stable.



I guess this was the case in my family. It meant that when the FMR1 gene was passed on from my grandma to my dad, it repeated a bit more than normal, giving my Dad 79 repeats instead of the normal 5-44. Then, when my dad passed the gene to me, I got 74 repeats. It seems strange that I received less repeats than my dad, however, the best explanation I have heard for this is that the gene has some instability. Therefore, when passed on it can act in a random manner. There are a few psychological and medical difficulties that can come with being a carrier or a premutation with between 55-200 repeats of the gene that I will explain later.


When I passed the gene to my daughter, it expanded from 79 to 320 repeats. When the gene expands to over 200 repeats, generally the body switches it off. That is because each little DNA sequence (CGG) gives an instruction to the body, but when there are over 200 instructions, the body cannot handle the information and silences it for efficiencies sake. This sounds somewhat adaptive, but unfortunately that means that the person does not receive the protein the gene makes. This protein is needed for typical intellectual development.



Prognosis


When I began researching Fragile X, I found that the information available was frequently about the presentation of boys with the condition. It seemed to me that the authors then appeared to generalise their description of the syndrome to girls as if girls are basically similar in presentation. This is not the case. Even with the wide variety of estimates for the presence of an intellectual disability in girls, the rate is generally not over 50%, meaning that we know at least 50% of girls have a Low-Average or Average intelligence. This is very different to the male presentation, of whom nearly all are much more severely intellectually affected. I found the information available about girls to be generally pessimistic and frightening.


Why is Fragile X different in girls?


The reason that Fragile X presents quite differently in girls is that girls have two X chromosomes (XX). This means that although the faulty Chromosome has silenced the much-needed protein, the girl also has a healthy chromosome that is producing the protein. Theoretically, that means they receive 50% of the protein they need, as opposed to a boy who is XY, and receives 0%. There is no FMR1 gene on the Y chromosome, hence the name Fragile X.


Genetic Skewing


For girl with Fragile X, something called genetic skewing can also happen, which explains the wide range of cognitive presentations of Fragile X in girls. As my genetic counsellor Carolyn said to me: “A very small proportion of girls with Fragile X Syndrome can become doctors and lawyers”. The reason for this is that the body randomly selects which chromosome to draw each gene in the body from with each cell it produces. If it chooses to pick the healthy X 90% of the time for the FMR1 gene, then the girl may present with minimal or zero learning difficulties or other challenges. Conversely, if the body chooses the unhealthy X 90% of the time, this may mean that a girl presents at a similar level of functioning to a boy with Fragile X, as they have almost none of the protein they need.


For this reason, although we have since found out that both my daughters have a full mutation (over 200 repeats of the gene), they present quite differently. For example, as soon as my eldest daughter went to preschool, I was asked to get a developmental assessment which led to a diagnosis of Global Developmental Delay (often a precursor to an intellectual disability diagnosis which cannot be made reliably until age 5). Since then, we have been saddled with more diagnoses like unwanted cargo- Severe Receptive Language Disorder, Autism Spectrum Disorder, Attention-Deficit Hyperactivity Disorder, Dyslexia, and a Specific Learning Disorder in Mathematics. The Fragile X diagnosis brought together an underlying cause for these disorders. We already knew that Amelie had several challenges.


For my younger daughter, her preschool noticed some language delays and attentional difficulties, however, otherwise she seemed to be developing normally. I speculate that we may not have found out that she had Fragile X except for the Cascade genetic testing that occurred as part of understanding the extent to which the syndrome affected our family. It appears that my youngest daughter Adelaide is functioning more on the healthy X that my husband gave her, than on the unhealthy one I gave her. This is genetic skewing in action.


Cognitive Profile


I find the cognitive profile of girls with Fragile X fascinating. How all the seemingly disparate aspects of a ‘typical’ profile fit together is above my paygrade, however, one aspect that seems to hang many of girls’ difficulties together is something called executive functioning. Executive function is a term used to describe many of the functions of our Prefrontal Cortex. This part of our brain sits just behind our foreheads and is responsible for problem solving, logic, attention, organisation, planning and the ability to predict the consequences of our actions. When I look at most of the common difficulties of girls, they often seem to relate to these processes. Often, girls with Fragile X will have co-occurring attentional difficulties, sometimes diagnosed as ADHD. They also have difficulties planning, problem solving and thinking ahead. Organisation can also be challenging. All of these functions originate in our pre-frontal cortex. Difficulties related to executive function such as reading complex social situations, solving maths problems, and visual-spatial processing (which may contribute to the dyslexia we see in some girls) are also often present.



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