If you ask me what is wrong with David, I don’t think I can answer the question without making a laundry list of problems, deficits and other issues. He has 22q13 deletion syndrome – that is what’s wrong. Some of his problems almost killed him. Someday, that risk may return. In the meanwhile, his biggest problem is learning new knowledge and skills. Can we make learning more efficient for our children? To investigate this question, we need to understand more about how individual and groups of genes can affect the brain.
I have written blog posts on specific issues (cancer, ulcerative colitis, hypotonia) and other issues in the context of individual genes. Individual genes can impact many parts of the body. A single gene may have multiple functions, an effect called “pleiotropy” (plahy-o-truh-pee). We are often concerned with the primary impact of a gene more so than the secondary issues. For example, CTFR is a cystic fibrosis gene. Its impact on the lungs is very damaging, but it also impacts other parts of the body.
Many 22q13 deletion syndrome genes are pleiotropic. We must look carefully at all the potential effects of a gene. Why? Because, so many genes are lost in 22q13 deletion syndrome that subtle effects can add up. When I read the scientific papers on a gene, I spend a lot of time comparing the subtle effects of this gene with all the others. I look for cases where multiple genes have subtle effects on the same organ. By definition, 22q13 deletion syndrome is a chromosomal deletion syndrome. It is not a monogenic syndrome as some have suggested. I recommend using the name “Phelan-McDermid syndrome” if you want to combine SHANK3 mutation syndrome with 22q13 deletion syndrome. See: Introduction to 22q13 deletion syndrome and How to fix SHANK3.
Pleiotropic effects come in two flavors. Either the gene has one function, but in different parts of the body, or the gene can do more than one function. CTFR, is not a 22q13 deletion syndrome gene, but it provides a useful example. It is the most common cystic fibrosis gene. CTFR is involved in making secretions (fluids used in the body). CTFR mutations are most important in the lungs, but the gene also causes faulty secretions in the digestive tract, and elsewhere.
CELSR1 is a 22q13 deletion syndrome gene. Over 40% of our children are missing this gene. Like CTFR, one function affects many different parts of the body. If one copy of CELSR1 is mutated, the most serious result is a neural tube closure defect (e.g., spina bifida or other spinal cord problems). Mouse studies of Celsr1 show that it participates in helping cells organize into physical patterns so that cells can operate as a group. Celsr1 is involved in early development by organizing certain cells into functioning tissues (Feng et al, 2012). However, the central role of CELSR1 in adult brain function was only discovered last year (Schafer et al, 2015).
During development, Celsr1 mutations can interfere with the organization of many different cells (Boutin et al, 2014). For example, ventricles are nourishing fluid lakes inside the brain. Cilia, cells with tiny hairs, line the ventricles of the brain and stir the cerebrospinal fluid (CSF) along its path through the ventricles. Stagnation of the CSF fluid is dangerous. Disordered cilia from Celsr1 mutations cause inefficient motion. In humans, stagnant CSF may have accumulating impact over years.
Very different cells with cilia are used in the ear to hear sounds. CELSR1 mutations disrupt the orientation of “outer hair cells,” responsible for hearing at low sound levels. Cilia are responsible for other body functions, as well, like keeping the airways clear and digesting food. Given its impact on different organs, CELSR1 is pleiotropic.
When someone asks me what is wrong with David, one of the first things I say is he struggles to learn. David is aware and interested in his environment, but he knows trying to learn anything new is difficult. My last blog discussed SHANK3 and its impact on learning that involves the ventral striatum in the brain. Mutations in CELSR1 disrupt a different kind of learning, learning that is unique to the hippocampus of the brain. Only two areas of the brain are able to grow new neurons. One of these areas feeds the new neurons into the dentate gyrus of the hippocampus and has a subtle, but critical effect on learning . Mutation of rodent Celsr1 disrupts the orientation of these new neurons in the hippocampus. This disruption interferes with building proper connections (Schafer et al, 2015). Thus, children with deletions greater than 6 Mbase are likely have problems with “pattern separation,” the very subtle learning process that prevents new learning from interfering with old knowledge (Johnston et al, 2015). The concept of pattern separation has arisen through complex mathematical learning models.
How can we take this information on CELSR1 and translate it into treatments? There are several paths. First, we would like someone to study a mouse missing one complete copy of Celsr1 (heterozygous knockout mouse) to make sure the effects seen in the current mice are not simply mutation effects (see Gene deletion versus mutation). There is a scientist in Belgium, Fadel Tissir, who has a “null” mouse (no copies of the gene), but has not reported any studies with a heterozygous knockout mouse yet. Second, we need to find out about outer hair cell loss and its potential impact on hearing. Perhaps someday we can arrange for a medical histologist to examine the cochlea (hearing organ) from a 22q13 deletion syndrome organ donor. Third, we need genetic testing (sequencing is best) on all patients missing CELSR1 to identify cases where the remaining CELSR1 gene is mutated. A mutation on the remaining CELSR1 gene could unmask recessive traits in a way that may be very informative.
Finally, if we really want to understand our children’s learning problems, we need to: 1) engage people involved in computational models of learning, and 2) study patients with interstitial deletions. Interstitial deletions will allow us to study genes in better isolation. These patients may be higher functioning, which is ideal for careful testing (see How to fix SHANK3). As the new studies start to bear fruit, we can then use the results to target our teaching methods. Right now parents, teachers and our children are frustrated with how poorly our children learn. Imagine how much better it will be when we know how to maximize learning for each child based on their genetic report. I dream of seeing the next generation of children with 22q13 deletion syndrome having all the benefits we never had for David. Let’s take lesson planning into the 21st century!
arm22q13
Previous blogs
How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?
Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction
arm22q13 
Logan has an interstitial deletion and an adjacent microduplication. I wouldn’t say he is “high functioning” per say, but he definitely hasn’t been effected medically as many others seem to be. Thank you for this article. I often struggle trying to “explain” Logan to new teachers/therapists and how best he learns. My biggest struggle is with speech therapy. He gets it 3 times a week at school, we did private speech for a while with little or no progress, he has some signs he uses and is learning to use a communication app somewhat. I often wonder should we continue with private speech and hope it clicks one day or are we just throwing money at a problem that just can’t be “fixed” purely because of the genetics behind it? That’s what keeps me up at night (among MANY other things!) but to date, no therapist/doctor can answer that question 😦
LikeLike
Amy,
I know you are a great mom. Many of the same things kept me up at night. We paid for therapies and we worked on everything a lot at home (which I am sure you do). David recognizes some signs and knows how to select photographs to communicate, but he never uses these modes. I talk to him and tell him a lot of things that presumes he understands spoken language. One problem with many of our kids is that they demonstrate only a small percentage of the knowledge they possess. I don’t know what to say about private therapy, but I do recommend continuing to push the use of a communications app. You might have to force him to use the ap when he does not want to. It is far easier to read Logan’s mind than to make him ask electronically. With hard work and, perhaps, magic, Logan will start thinking of the communications ap as a useful tool, rather than an annoyance.
Andy
LikeLike