Although he is a bit unsteady at times, David loves to walk. When he first started his day program, the aid assigned to him nearly gave up. Keeping up with David’s constant motion — walking — forced her to become an athlete. She looks back at the experience now in an appreciative way. David brought fitness into her life and the two of them have a deep affection for each other. They have enriched each other’s lives in very deep ways.
David was a “floppy baby”: A general medical reference to an abnormal condition of newborns and infants manifested by inadequate tone of the muscles. It can be due to a multitude of different neurologic and muscle problems. See also Hypotonia. At age one, after daily work-outs and multiple physical therapy sessions each week, David developed the strength to lift his head and arms. He gradually learned to sit up, drag himself by his arms, and then crawl. Countless hours went into each milestone. We pushed him constantly. As soon as he improved, the bar was raised. Carol used to take him grocery shopping. He would hold onto the shopping cart and step along beside it as Carol pushed the cart through the isles. One day, fascinated by a stack of bright red apples in the produce section, he let go of the cart and walked eight steps on his own. I was not there, but it must have been quite a scene: apples all over the floor and Carol holding David as she cried tears of joy. After six very long years, David began to walk on his own.
Having very low muscle tone interferes with normal growth and development in many ways. Muscle tone is important for breathing in newborns (Lopes et al., 1981). David was born prematurely and he was on a ventilator for weeks. Low muscle tone slowed his recovery. Muscle tone is important for normal cognitive development and function (e.g., Jongsma et al., 2015). Gastroesophageal reflux plagues many children with 22q13 deletion syndrome (including David) and is likely caused by low tone in the esophageal sphincter (Hershcovici et al., 2011). The most obvious problem with low muscle tone is delayed or absent walking. Walking requires stable standing, which requires sufficient tone to hold the body erect. Building strength in David’s abdominal, back and leg muscles was years of work.
What is muscle tone and what interferes with normal tone? “Muscle tone refers to the resistance that an examiner perceives when moving someone’s limb in a passive manner” (Mitz and Winstein, in Neuroscience for Rehabilitation, 1993). Normal muscle tone disappears when someone is knocked unconscious, or when the muscle itself is unable to support contractions. Diagnosing the cause of hypotonia in infants can be complex, especially in the presence of a genetic syndrome (Bodensteiner, 2008). In genetic syndromes that include both hypotonia and intellectual disability, the hypotonia is often diagnosed as “central hypotonia”: hypotonia caused by problems with the brain or spinal cord. However, the hypotonia associated with 22q13 deletion syndrome may be from multiple causes. Certainly, it is not caused by any one gene. No single gene deletion or mutation has been identified that always causes hypotonia, and no one gene is essential to cause hypotonia. There is also no doubt that infant hypotonia is far more common in children with somewhat larger deletions (Sarasua et al., 2014, figure S1).
The severe hypotonia so often seen with 22q13 deletion syndrome infants comes from multiple sources. Since finding a way to treat hypotonia could help 100s of our children, understanding all the causes might open the door to improving their lives.
Genes that directly affect synapses
If your child was seen by a pediatrician or pediatric neurologist, it is likely the physician concluded that the hypotonia was of central origin (see, Bodensteiner, 2008). Although the conclusion would be based on accepted clinical practice, it would actually require a battery of tests to rule out other sources. Without other signs of major muscle or metabolic problems, the physician may be wise to avoid additional tests. Right now, such testing is best done as part of a research study.
One obvious source of central hypotonia is a problem with synaptic proteins. Two important proteins coding genes nearly always deleted together are SHANK3 and MAPK8IP2. I have found only one published clear case where MAPK8IP2 is deleted without SHANK3 (Vondráčková et al., 2014). That patient had hypotonia, but another important gene was involved (SCO2, discussed later). There are also very few cases of SHANK3 deletions without impacting MAPK8IP2. I am not considering SHANK3 mutations, since we know mutations can be much more severe than deletions. See my earlier blog: When missing a gene is a good thing. For those who wish to consider SHANK3 mutations, we know that hypotonia with SHANK3 mutations is much less prevalent (33%) than hypotonia in 22q13 deletion syndrome (65% to 75%), whether or not SHANK3 is involved (Vondráčková et al., 2014). Thus, synaptic genes may play a role, but the jury is still out on how important they are to hypotonia.
Other genes that affect normal function of the brain
Hypotonia of central origin can be caused by other genes important to brain function. We sometimes forget that the brain must have lot of things working properly for synapses to operate. For example, the brain is about 2% of our total body weight, but it uses up 20% of the oxygen we breathe (Rolfe and Brown, 1997). So, the blood flow from the heart, nutrition from the gut and oxygen from the lungs are of critical importance to human brain function. Any missing gene that might affect the brain’s ability to burn energy will likely impact synaptic function. Note, this raises an important limitation of studies that use rats and mice. Rats have very small brains and only use 3% of the oxygen they breathe for the brain. They are not nearly as sensitive to the “energetics” of brain function.
SCO2 and TYMP are genes that are important in making full use of nutrients, oxygen and blood flow to maintain healthy synaptic operation. One copy of these genes is missing from nearly everyone with a terminal deletion. You may recall that humans and other animals normally have 2 copies of every gene. People missing just one copy of SCO2 or TYMP seem to do fine (Pronicka et al., 2013). I found a paper that investigates the role of SCO2 and TYMP in patients with an interstitial deletion of 22q13 (Vondráčková et al., 2014). The authors describe two children who are not only missing these genes from the deletion, but, tragically, the remaining gene (on the other chromosome) is mutated. That is, both copies of the gene are affected. One child has a mutation of his remaining SCO2 gene. The other child has a mutation of the TYMP gene. One child died before age 2. The other is 12 years old and is going downhill. Over 95% of children with terminal deletions of 22q13 are missing one copy of SCO2 and one copy of TYMP. We do not know how much these genes contribute to infant hypotonia in 22q13 deletion syndrome, but if a child has a life-threatening failure to thrive, he or she should be tested for SCO2 and TYMP mutations. There are potential treatments (Casarin et al., 2012; Viscomi et al., 2011).
Unfortunately, there are many genes deleted in 22q13 deletion syndrome that might impact normal brain function. My earlier blog pointed out that 95% of people with 22q13 terminal deletions (including ring 22) are missing at least 10 genes that operate in the brain (Understanding deletion size). ALG12 is a gene critical for allowing cells to recognize each other. Loss of both copies of ALG12 produces a severe disorder (CDG-Ig) that can include hypotonia, as well as moderate to severe intellectual disabilities and seizures. Loss of one copy by itself is not pathological, but loss of ALG12 along with other genes could have a big contribution to hypotonia. CELSR1 is an example of a gene that could worsen the impact of ALG12. We know that larger deletions are more likely to cause serious hypotonia (Sarasua et al., 2014, figure S1). CELSR1 is associated with deletions larger than 4.5 Mbase. CELSR1 along with ALG12 is a one-two punch to the development of normal synaptic pathways. Both are important for the intricate organization of brain cells during early development. What about a 1-2-3 punch? I have already discussed RABL2B (Is 22q13 deletion syndrome a ciliopathy?). RABL2B is used in primary cilia, which are also responsible for guiding neuronal organization during early brain development.
There are other genes deleted in 22q13 deletion syndrome that are important to maintain healthy brains. I will cover some of these in future blog postings. However, I would like to look now at genes that might act outside the brain to cause or exacerbate hypotonia.
Genes that affect the muscles
It is probably no surprise that hypotonia can come from problems with the muscles. Muscle cells share a lot in common with the neurons of the brain. They rely on electrical activity, they have a junction with the nerve that is very much like a synapse and they require lots of blood flow and energy. Sitting very near the synaptic genes and missing in over 95% of children with 22q13 deletion syndrome, is a gene that is crucial to the energy supply of muscles, CPT1B. CPT1B is like the shovel for an old coal-burning steam engine. It grabs the coal and throws it into the steam-engine’s firebox. Technically, it helps transport fatty acids into the mitochondria for the generation of ATP. ATP interacts with muscle actin and myosin to power muscle contraction.
Genes that affect the nerve fibers leading to the muscles
SBF1 is one of about 70 genes associated with Charcot-Marie-Tooth (CMT) disease. (CMT has nothing to do with teeth. It is named, in part, after Howard Henry Tooth.) CMT is a demyelinating disease (Baets et al., 2014). Myelin is a fatty tissue that wraps around the nerves. It is the insulator that makes sure electrical signals traveling down the nerve fibers reach the muscles quickly. Demyelination, the loss of myelin, leads to weakness and muscle dysfunction. CMT is a degenerative disease. It usually appears in the 20s and starts with leg weakness. How the loss of SBF1 might interact with other genes lost with 22q13 deletion syndrome is not known. SBF1 may not contribute to infant hypotonia, but it is something to consider if weakness starts to occur early in adulthood. Like many of the genes described here, SBF1 is missing in over 95% of patients with 22q13 terminal deletions.
I have provided just a few examples of genes that are known to be involved in hypotonia. In my own review of the genes of 22q13 deletion syndrome, I have only looked closely at 34 of the approximately 200 genes that can be deleted. I have focused on the distal-most genes, those that affect the overwhelming majority of our children. Even looking at just this small selection, we begin to see the complexity of a chromosomal deletion. Focusing on just one or two genes may seem like a way to simplify the problem, but it steals the opportunity to understand what is happening to our children. The more we get to know 22q13 deletion syndrome, the more we can find opportunities to make things better.
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