David has very poor hand control and he required years to develop the balance and coordination for walking. These characteristics are common among children with Phelan McDermid syndrome (PMS), but less common and less severe among among children with SHANK3 variants. A paper recently presented at the annual Society for Neuroscience meeting (SfN2018) may explain the important difference (Modeling of NMDAr-dependent mechanism of cerebellar granular layer hyperfunctioning in the IB2 KO mouse model of autism). This research out of the University of Pavia in Italy looks carefully at a mouse missing the Mapk8ip2 gene, also called Ib2. I have written about this gene before: Which PMS genes are most associated with Autism? and Which PMS genes are most important? The new research shows that the microcircuitry of the cerebellum is greatly disrupted in the Ib2 knockout mouse.
Technical description: The evidence from recording of cerebellar granular cells indicate that NMDA receptors at synapses are dysfunctional in the Ib2 knockout mouse. The receptors are overstimulated, which disrupts the excitation/inhibition (E/I) balance of the neurons. Computer models show that the dysfunction of the NMDA receptors can explain the severe synaptopathy in the mouse’s cerebellum.
The practical result is poor cerebellar function. What does the cerebellum do? Wikipedia explains: “The human cerebellum…contributes to coordination, precision, and accurate timing…Cerebellar damage produces disorders in fine movement, equilibrium, posture, and motor learning in humans.” Sound familiar? To me, this sounds like David (pictured, above). He has problems learning any new motor task. He has problems retaining skills he has learned. His balance problems undoubtedly come from problems with his cerebellum.
Why is this problem so common among PMS children? That is easy to answer. Aside from SHANK3, MAPK8IP2 is the most frequently lost important gene of PMS. The two genes are very near each other on the chromosome and the vast majority of terminal deletions impact both genes.
It is possible that loss of SHANK3 contributes, to some degree, to the problem in the cerebellum. Shank3 is present in one cell type of the cerebellum. However, the new research shows that the major dysfunction produced by loss of Mapk8ip2 occurs independently of Shank3.
It is nice to start getting some answers. MAPK8IP2 is likely the most important PMS gene for balance and fine motor control. Even more exciting is that earlier work showed an already-approved FDA medication, memantine, improved behavior in Ib2 knockout mice. I wonder if this medication could help David now?
TCF20 may explain why some big deletions are worse than others
Current trends in SHANK3 research
Which PMS genes are most associated with Autism?
Does SHANK3 cause Autism?
We need to study interstitial deletions to cure PMS
What do we know about PMS genes?
Which PMS genes are most important?
Are children with Phelan McDermid syndrome insensitive to pain?
Looking for Opportunities
Splitting, Lumping and Clustering
Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
What do parents want to know?
Is 22q13 deletion syndrome a mitochondrial disorder?
Educating children with 22q13 deletion syndrome
How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?
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