What Is SKS (or MINDS)? What is mTOR?
Smith Kingsmore Syndrome, also known as MINDS (Macrocephaly-Intellectual disability-Neurodevelopmental Disorder-Small thorax syndrome)
Finding out that your child has a rare disease is devastating, but we need to stay focused on what we can do now and what's ahead of us.
Although SKS presents a variety of tough symptoms to cure, there are things we can do now and in the future. Here is the big picture I see.
1. Name, Symptoms, Prognosis
*Citation and links are coming later. **My observation
Smith Kingsmore Syndrome is a rare neurological disorder mainly characterized by large head (macrocephaly), intellectual disability and (or) seizures. It is caused by mutation of mTOR gene. MTOR gene has many variants under some subcategories, and causes a variation in symptom sets, even within the same variant**.
Elizabeth's mTOR variation might not exactly fit in the current definition of SKS.
Dr. Mirzaa has categorized many mTOR variants, mainly by brain abnormalities and intellectual disability levels (*2019), and SKS Foundation together with Cincinnati Children's Hospital is currently collecting and updating statistics, so please join their registry to help them understand more about this rare syndrome.
A large portion of SKS patients belong to one variant, and its symptom sets are described in Dr. Kate-Tatton's article. (2021*)
The second largest group includes two Mosaic variants, and one of them is Elizabeth's. The details of her variant are in Dr. Mirzaa;s 2 articles (*)and her case study by a team of Undiagnosed Diseases Network.(*2018)
The definition of the syndrome name for mTOR mutation or its subcategories might need some clarification in the future.
For now, for convenience, I talk about mTOR mutations in general with updates of general idea I get from talking and meeting other parents and patients. Symptom type and severity vary a lot even within the same mTOR variant.
The most need support through their life but a few seem to have become more independent.
Although mTOR has many functions in our body, most of problematic symptoms are limited to neurological, behavioral and developmental issues.
Most them have "overactivated" mTOR (gain of function) instead of opposite (loss of function ) with small head.
The most common features seems to be large head, intellectual disability and autism. Overgrowth of head starts before or after birth and together with overgrowth of body, it usually slows down around age 5. Body size seems to become average as they grow. Autism might start earlier in life and language and social skills might regress when Autism starts. Some of their stemming is a little different from typical Autistic stimming. Early interventions such as ABA therapy is helpful.
Common features are epilepsy, ADHD, sleep issues, low muscle tone, flexible joints, club feet, a strange way of walking, curly hair, and special facial features. For some, epilepsy starts as infants, toddlers or teenagers, and others don't have it.
Other common feature is brain abnormality, such as polymicrogyria (too many wrinkles), one or both sides of the brain may be enlarged (hemimegalencephaly or megalencephaly), or the fluid-filled spaces near the center of the brain (ventricles) may be bigger than normal (ventriculomegaly). hydrocephalus, less white matter of brain, malformation of corpus callosum (mid divider part of brain), etc.,
Other features are: swallowing issues, tongue tie, elevated optic nerve without intracranial pressure , undergrowth.
Symptoms to be Cautious: Although mTOR mutation is one of the common mutation in cancer and well studied in oncology, there seem to be no need to worry about cancer for SKS. For some SKS, uncontrolled epilepsy, pneumonia due to aspiration of food and drink, low blood glucose level, can be dangerous.
See Description of SKS at Med Line Plus of National Institute of Health
Smith-Kingsmore syndrome is a neurological disorder characterized by a head that is larger than normal (macrocephaly), intellectual disability, and seizures. In some people with this condition, the ability to speak is delayed or never develops. Some children with Smith-Kingsmore syndrome have features of a behavioral condition called attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder, which is characterized by impaired communication and social interaction. Structural brain abnormalities may also be present in affected individuals. For example, one or both sides of the brain may be enlarged (hemimegalencephaly or megalencephaly) or have too many ridges on the surface (polymicrogyria), or the fluid-filled spaces near the center of the brain (ventricles) may be bigger than normal (ventriculomegaly).
Many people with Smith-Kingsmore syndrome have unusual facial features, such as a triangular face with a pointed chin, a protruding forehead (frontal bossing), widely spaced eyes (hypertelorism) with outside corners that point downward (downslanting palpebral fissures), a flat nasal bridge, or a long space between the nose and upper lip (long philtrum). However, not everyone with Smith-Kingsmore syndrome has distinctive facial features.
3. mTORC1 and mTORC2
4. Network of Signaling Pathways
If one of the medicines work well, that'll be nice, but ultimately, we'd like to edit the gene itself, which is reaching to a reality in the near future. Currently, delivering the treatment to brain is being researched.
Antisense Therapy might become more practical sooner, but the treatment might be repeated every few month, and I'd imagine it would be a challenge to determine balance how much activities of mTOR to inhibit or how much activities of which mTOR Complexes to inhibit for each mTOR mutation variant.
DNA Editing would be the one time and permanent treatment to replace a mutated part of DNA with a correct one, and the treatment for a single-gene like mTOR mutation would become available sooner, but it's harder to develop a treatment for a single variant with single or a very small number of patients.
I think one treatment to replace a long chain of DNA that includes every patient's variant would be ideal, but it needs more time to make it possible.