SKS Overview

Smith-Kingsmore syndrome (SKS) is a mutation of the mTOR gene that stops the brain from developing and functioning properly, leading to intellectual, developmental, behavioral and physical symptoms.

The specific genetic change may vary for individuals with SKS, and therefore the symptoms may also vary. The most common features of SKS are intellectual and developmental disability, large brain size, sleep disturbances, seizures and autism.

While there is a wide variation of symptoms across individuals with SKS, there’s a common experience of feeling like different parts of the body aren’t regulating like they would in a typical body. Imagine if every clock or measurement device in your life was constantly changing and often wrong – your alarm wakes you up at 1am instead of 6am, the speed of your car doesn’t change when you hit the brakes, your oven cooks at twice the temperature you intended.

That’s what it’s like to live in the body of someone with Smith-Kingsmore Syndrome. Your body systems or ‘clocks’ don’t work as they should, leading to daily challenges that impact both health and quality of life. These challenges can morph and and change over time, leaving patients and their families to manage many unknowns.

The instructions for our bodies are organized into structures called DNA. Genes are segments of DNA that give the instructions for a specific function or job.

The MTOR gene provides the body with instructions for making a protein that influences cell growth, and is especially important for brain growth and development. The MTOR gene is located on Chromosome 1, specifically location 1p36.

Changes (also called variants or mutations) in the MTOR gene can lead to hyperactivation, or “gain of function”. This hyperactivation causes affected nerve cells (neurons) grow unusually large and misshapen, leading to brain malformations, cognitive delays and epilepsy. It may also impact the proper regulation of other parts of the body.

Genetic changes within MTOR were first noted as a cause of a neurodevelopmental disorder in 2013. There is still a lot we need to learn about how the different variants impact individuals – even people with the same variant may have different symptoms. Current thinking about genetic changes in MTOR separates them into three clinical types.

• The first group includes patients with generalized brain overgrowth (megalencephaly), intellectual disability, sleep disturbances, autism, and hypotonia (what is commonly considered Smith-Kingsmore syndrome).
• The second group includes patients with diffuse brain overgrowth, abnormalities of the surface of the brain (polymicrogyria), and skin pigmentation abnormalities.
• The third group includes patients with focal changes in the brain (focal cortical dysplasia or hemimegalencephaly) causing early-onset epilepsy.

All individuals have two copies of each gene, one inherited from each parent. SKS usually is an autosomal dominant condition, which means one copy of the altered MTOR gene in each cell is sufficient to cause the disorder.

Changes in the MTOR gene are usually random events (sporadic or de novo) that happen in the egg or sperm prior to conception and are not inherited from either parent. This type of change is present in all cells of the affected individual and is called a germline variant.

There are also some SKS patients who have an altered MTOR gene in some, but not all of their cells, and this is called somatic mosaicism. This type of change is also de novo (not inherited) and occurs at some point while a baby is developing during pregnancy. MTOR gene mutations in these SKS patients can only be detected in samples of affected tissues and might not be detected in a blood or saliva sample.

Rarely, people with SKS inherit the altered gene from an unaffected parent who has a MTOR gene mutation only in their sperm or egg cells (germline tissues). This is called germline mosaicism and, although rare, it has been seen more frequently in SKS than in other diseases.

The risk of a genetic change happening in more than one person in a family is called recurrence risk. Individuals with SKS have up to a 50% chance of having an affected child.

In cases where the parents do not appear to have SKS, it is challenging to calculate the exact recurrence risk in future pregnancies – it depends on whether SKS in their child was caused by a ‘de novo’ mutation (just in the child) or germline mosaicism in the parent (only the egg or sperm of one of the parents has the MTOR mutation). Because each family and healthcare system is different , meeting with prenatal genetic counselors is recommended to understand the risks and discuss options for screening and testing.

MTOR-related disorders are extremely rare. The total patient population is still unknown, but it is estimated that there are about 10 people with MTOR gene disorders (with some MTOR mutations causing SKS) in every 10,000 individuals. However, SKS may go undiagnosed or misdiagnosed, making it extremely difficult to determine the true frequency in the general population. Based on the current understanding of this condition, SKS occurs worldwide in people of all ethnic groups.