Educating children with 22q13 deletion syndrome

David is tolerant of my picture taking

Originally posted 17 July 2016
Updated 10 April 2024

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 (Phelan McDermid syndrome, PMS) – 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 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“.  We are often concerned with the primary impact of a gene more so than the secondary issues. We can learn from examples of genes from other disorders.  For example, for people with cystic fibrosis, CTFR is an important 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, many genes can be lost with PMS. 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 other genes of 22q13.  I look for cases where multiple genes have subtle effects on the same organ.

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 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 PMS gene.  Over 40% of people with 22q13 deletions are missing this gene.  Like CTFR, one function affects many different parts of the body.  If one copy of Celsr1 is mutated in a mouse, 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 was shown to be 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 identified later (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.  A previous blog post 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. (Note that SHANK3 is also important for the hippocampus.) In rodents, 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). The human hippocampus may not have exactly the same mechanism for new memories. However, children with deletions greater than 6 Mb (megabase) may 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 and needs to be studied in children with PMS.

How can we take this information on CELSR1 and translate it into treatments?  There are several paths.  First, we look forward to studies of mice 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).  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 PMS 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
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.
Understanding deletion size
22q13 deletion syndrome – an introduction