22q13 Deletion Syndrome: hypotonia

A Sunday walk with David

Originally created 29 August 2015
Updated 28 November 2021
Available in Portuguese  https://pmsbrasil.org.br/sindrome-da-delecao-22q13-hipotonia

The joys of walking

Although he is a bit unsteady at times, David loves to walk. David began a day program after high school and he was assigned an aid new to the program. After one month the aid nearly quit! Keeping up with David’s constant motion — usually walking — forced the aid to become an athlete. After working with David for twelve years, she looks back at the experience in an appreciative way. David brought fitness into her life and the two of them developed a deep affection for each other. They enriched each other’s lives in many ways. Health from walking was an important one.

David has 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome (PMS). David, like many others with PMS, was born 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 of therapy in a clinic and at home went into each milestone. We pushed him constantly for six years. Each time he improved, we “raised the bar”. Once David gained strength and basic skills, his mom, Carol, would exercise David at the grocery store by having him hold onto the side of the shopping cart as she pushed. One day, fascinated by a stack of bright red apples in the produce section, David let go of the cart and walked eight steps on his own to reach the stack of applies. Carol was caught completely by surprise. David reached the apples and everything ended up on the floor. The store staff came running and found Carol holding David, crying tears of joy. After six very long years, David had learned to walk on his own. Now, David I go on weekend walks together (see photo). Every time I walk with David, it warms my heart to watch him

Hypotonia 

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 PMS (including David) and is likely caused by low tone of the esophageal sphincter (Hershcovici et al., 2011). Other gastrointestinal problems likely result from muscle tone problems of smooth muscles. The most obvious problem with low muscle tone, however, 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 took years of work.

What is muscle tone and what interferes with normal tone? For skeletal muscle, “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 PMS 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 for 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 in infants with PMS may arise from multiple sources. Since finding ways to treat hypotonia could help children with PMS, understanding the causes will open the door to improving their lives.

Genes that directly affect synapses 

If your child with PMS 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 the additional tests that would be necessary. Right now, such testing is best done as part of a research study.

Which genes might contribute to low muscle tone of central origin? One obvious source of central hypotonia is a problem with synaptic proteins. For chromosomal deletions of 22q13.3, two proteins coding genes are nearly always deleted together: SHANK3 and MAPK8IP2. I have found only one published clear case where MAPK8IP2 and more proximal genes were deleted without impacting SHANK3 (Vondráčková et al., 2014). That patient had hypotonia. Thus, hypotonia can be caused without impacting SHANK3. What is lacking in PMS research are more studies of children with so called interstitial deletions. (See my blog: PMS, IQ and why interstitial deletions matter). Generally, hypotonia created by the deletion of SHANK3 is less than with deletions of any larger size. If we include pathogenic variants of SHANK3, we know that hypotonia with a SHANK3 variant is much less prevalent (33%) than hypotonia in patients with terminal deletions of 22q13.3 (65% to 75%), whether or not SHANK3 is involved in the deletion (Vondráčková et al., 2014).

Genes that affect brain development

In PMS, hypotonia of central origin is likely caused by the genes essential to normal to brain development. A review of PMS genes showed that 18 genes that are deleted in PMS patients are associated with brain development (Mitz et al., 2018). Of these, 10 genes are associated with reproductive fitness (e.g., necessary for normal health) based on their “pLI” scores: SHANK3, MAPK8IP2, PLXNB2, TUBGCP6, BRD1, TBC1D22A, CELSR1, SULT4A1, TCF20 (see Supplementary Table S2 of Mitz et al.). Since that study, The gene PHF21B has been added to the list as an epigenetic regulator of development (Basu et al., 2020). Thus, genes across the nearly entire 22q13.3 region associated with PMS are critical genes that participate in normal brain development. Any, and likely all, contribute to both the intellectual disability and the hypotonia of PMS.

Genes that may affect the environment of the central nervous system

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 process energy in the mitochondria may impact synaptic function. Note that studies of rats and mice might be misleading. The rat brain, for example, uses only 3% of the oxygen they breathe for brain function. These mammals are not nearly as sensitive to the “energetics” of brain function as humans. The genes of 22q13.3 used by mitochondria appear to have a mixed impact on people with PMS (Frye et al., 2016). Beyond hypotonia of central origin, the same genes that affect the energy supply for the central nervous system can affect muscles directly. Muscles come in three flavors, skeletal, cardiac and smooth. They are all major users of energy.

SCO2 and TYMP are two mitochondrial PMS genes that are lost with relatively small deletions of 22q13.3. Individuals missing one copy of SCO2 and/or one copy of TYMP seem to do fine (Pronicka et al., 2013). However, if the remaining copy of either SCO or TYMP has an unusual variant, the results can be profound (Vondráčková et al., 2014). Of greater concern for most people with terminal deletions of 22q13.3 is the SULT4A1 gene. SULT4A1 is one of the few genes that has been implicated in intellectual disability and hypotonia based on a study of interstitial deletions. Recently, it has been shown the SULT4A1 protein is crucial for mitochondria function in the brain.

Conclusions

Most clinicians will conclude that hypotonia in children with PMS is of central origin. This is a good assumption, but further research is needed to look for more direct effects on muscle. There is strong evidence that many PMS genes contribute to central hypotonia, and central hypotonia occurs with all genotypes of PMS (see The four types of Phelan McDermid syndrome). On average, larger deletions lead to greater hypotonia. Developing broad and effective treatment for hypotonia will require understanding more about each gene’s contribution to maintaining healthy muscle tone (see 22q13 deletion syndrome: the hope of precision medicine).

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