What is AGO2/Leskres syndrome?

AGO2/Leskres (Lessel-Kreienkamp) syndrome is a rare neurodevelopmental disorder characterized by delayed motor development, seizures, problems speaking and understanding, and cognitive impairment. 

It is associated with a mutation in the gene AGO2 or Argonaute2. If you are a parent of an affected child, please know that YOU DID NOTHING WRONG! It's that important, we write it in capitals. New mutations happen naturally, and in the good cases this is how we evolve as a human species.

The syndrome was discovered by Dr. Lessel and Prof. Kreienkamp and first described in November 2020. It was named "Lessel-Kreienkamp syndrome" in early 2021 (OMIM).

Symptoms typically appear in infancy or early childhood, vary significantly in severity and cover a broad range (Lessel et al. 2020, OMIM).

Very common

• from delayed speech to nonverbal

• from mildly delayed walking to wheelchair-bound

• from mild to significant difficulties with learning and understanding information, with measured IQ as low as 47

Common

• a floppy body

• seizures, incl. West and Lennox-Gastaut syndrome

• newborn eating difficulties

• behavioral problems, e.g. autistic features, ADHD, or aggressive behavior

• dental anomalies

• brain anomalies on MRI scans

Uncommon

• heart defects

• vision problems

• breathing problems, esp. at birth, and sleep apnea

As the condition is so new, we don't know much yet about its prognosis - we want to help change that by setting up a patient registry.

It is extremely rare. Worldwide, around 50 patients have been diagnosed though the number is growing.

Given the recent discovery of the syndrome and the fact that the gene is currently not included in any gene panel, many patients are likely undiagnosed. Based on the gene length and sequence, and its dominant inheritance (a mutation in one copy of the gene is enough), scientists recently predicted that as many as 1 in 16´000 chilren may be affected. It is possible however, that some of these children are never born. Still, this means that there could be many undiagnosed children!

AGO2/Leskres syndrome is diagnosed via a genetic test: either whole genome (all your genetic material) or whole exome sequencing (only the part of your genome with instructions to make proteins).

If you had genetic testing done and don't know how to interpret the report, have a look at this great 101 Genetics webinar by ClinGen (minutes 5-30, use captions & translate for other languages): you will learn about different genetic changes (insertion, deletion, missense, nonsense, duplication, frameshift, c.1091T>C, p.Met364Thr) and common terms (likely pathogenic, variant of uncertain significance, heterozygous, de novo).

The AGO2 (Argonaute2) gene regulates other genes by silencing their expression. 

A gene is made up of DNA and contains instructions for your cells to make proteins, which play a variety of roles in your body. In the standard journey from a gene to a protein, a gene's DNA is first transcribed into mRNA, and then translated into a protein. The RNA-induced silencing complex (RISC) can stop this journey by destroying target mRNA: this silences the gene’s expression. AGO2 plays a crucial role in target recognition and silencing, and may also directly cut ("slice") target mRNAs.

One of the RNA silencing pathways, termed RNA interference, plays a fundamental role in cells and its discovery won a Nobel Prize in 2006.

Learn more about DNA, genes and proteins in this 101 Genetics webinar from ClinGen (minutes 2-5).

Learn more about the Argonaute proteins and RNA-guided gene regulation in Prof. Gunter Meister's excellent review Meister Nature Rev Genetics 2013 (email us if you can't access it).

• Regulation of gene expression via gene silencing is defective when AGO2 is mutated.

• A mutation in one of the two copies of AGO2 is enough to cause the disease ("autosomal dominant").

• The exact disease-causing mechanisms are still being studied.

Because of the mutation, the silencing activity of the RNA-induced silencing complex (RISC), which AGO2 is a part of, and the regulation of gene expression are disturbed: Lessel et al. observed faulty formation of the RISC complex and enhanced binding to target mRNAs. 700-1'500 genes out of ~20'000 (4-8%!) were up- or downregulated in patient-derived skin cells (Lessel et al. 2020). AGO2 plays a crucial role in the regulation of other genes all over the body, and in particular in the development of the brain.

Scientists believe that patients with AGO2 syndrome have less functional AGO2 protein but are still investigating this.

Humans have 4 Argonaute proteins, called AGO1 to AGO4. Very similar symptoms has been reported for children with mutations in AGO1 (Schalk et al. 2021). Also deletions in AGO1 or AGO3 have been associated with a neurodevelopmental disorder (Tokita et al. 2015).

If your family is affected by a mutation in another Argonaute gene, know that you are welcome to join our private Facebook support group too!

There is unfortunately no cure and no direct treatment... yet.

However, physical, speech and occupational therapies or seizure medication can help to manage symptoms and support the child’s development. 

A friend who headed an integrative day care told us that the worst a parent can do is to underestimate their child and to stop supporting their development. Dr. Lessel seconds this and encourages "support, support, support even if you don’t see immediate progress". And if you have enough therapies, please say so too.

If your child has been diagnosed, please reach out to us and join our private Facebook support group! Given the rarity of the syndrome, other affected families may currently know more about the disease than doctors. Or, at the very least, we are here for each other.

There is hope. Genetic therapies have made tremendous progress in the last decade and have finally come to the patient bedside.

• Two gene therapy treatments, Spinraza and Zolgensma, for the muscle-wasting disease spinal muscular atrophy (SMA) have been approved in 2016 and 2019,

• A gene therapy for Angelman syndrome, a neurodevelopmental condition, has started clinical trials,

• A repurposed drug has been approved for the rare disease Progeria and others are close to/in trial (PMM2-CDG, SLC6A1).

Rare disease communities help to push the boundaries of the possible by acting as incubators and by de-risking the early stages of drug development by:

• collecting information on disease burden and patient demographics,

• making patient tissue and animal models easily available,

• defining outcome measures,

• funding research to elucidate disease mechanisms and establishing proof of concepts for drug candidates.

Read more in our research roadmap.

Together with our scientific advisors and your support, we will work incessantly towards treatments and a cure.

We aim to pursue the following therapeutic strategies to find treatments:

1. Small molecule drugs to increase production or activity of AGO2, starting with screening already approved or developed drugs for off-target effects

2. RNA therapy to upregulate production of healthy AGO2 with a splicing antisense oligonucleotide (ASO) or regulatory element ASO

3. DNA therapy to deliver a functional copy of AGO2 (AAV-mediated gene therapy) or correct the mutation (CRISPR base editing)

Learn more about our therapeutic strategies.