AGS is a rare, inherited disorder that affects the brain and immune system. It typically causes severe neurological symptoms, such as developmental delays, intellectual disability, movement problems, and in some cases, seizures. It is often mistaken for a form of childhood encephalitis or other neurological disorders.

There are two forms of AGS: an early-onset form and a later-onset form. Symptoms for both begin in infancy, but at different times.

AGS is caused by mutations in certain genes, which affect the immune system's ability to respond to viral infections. These genetic mutations lead to abnormal immune responses that cause inflammation and damage to the brain and other organs. It is inherited in an autosomal recessive pattern, meaning both parents must carry one copy of the mutated gene for their child to inherit the disorder. However, there are some cases where there can be a spontaneous mutated gene 

AGS is caused by mutations in one of several genes. Researchers have identified at least nine genes associated with AGS, which include:

• TREX1

• RNASEH2B

• RNASEH2C

• RNASEH2A

• SAMHD1

• ADAR

• IFIH

• LSM11

• RNU7-1

Gene mutations associated with AGS are normally passed through families in a recessive pattern of inheritance. You require one associated gene from each parent to develop AGS.

Less commonly, AGS may develop due to sporadic mutations that occur without a family history.

AGS common symptoms include:

• Severe developmental delay or regression

• Intellectual disability

• Motor problems (e.g., spasticity, poor coordination)

• Seizures

• Skin rashes (similar to lupus)

• Hearing loss

• Vision problems

• In some cases, brain abnormalities (e.g., calcifications)

At 2.5 years old we noticed a change in Hailey and her abilities. A once, chatty energetic two year old was losing her ability to speak. It was slow at first and came off as having lazy speech. She also started falling a lot more when she was walking. Our concerns were often dismissed by doctors due to her age. “She is still young”, “she is trying to keep up with her older brother”. No one had the concerns we did. I have to be honest in another life I would have accepted these answers as valid and probably would have continued on thinking that she would eventually make improvements. I probably would have been satisfied. Thank goodness we didn’t.

Symptoms of early-onset AGS

Infants with early-onset AGS have jittery behavior and poor feeding ability from birth. They also have neurological and liver abnormalities at birth, which can be detected through imaging tests. Early-onset AGS is the more serious form of the syndrome. The symptoms can become more severe over time, and can include smaller head size (microcephaly), liver inflammation, seizures and skin rashes.

Loss of myelin in early-onset AGS often leads to permanent damage to brain function, and to severe lifelong intellectual and physical disabilities.

Symptoms of later-onset AGS

Babies with later-onset AGS develop and behave normally for their first few weeks or months. When symptoms appear, they may include:

• Intermittent, unexplained fever

• Irritability or inconsolable crying

• Skin problems, including chilblains (rash, lesions, or swelling on fingers, toes and ears that get worse in cold weather)

• Weak or stiffened muscles

• Feeding difficulties

• A decline in growth of the head

• Developmental delays

• Seizures

In later-onset AGS, these symptoms may last for several months. They then generally lessen and stabilize, but may leave persistent neurologic difficulties. Additionally, the immune dysfunction associated with AGS can affect many other organs of the body, sometimes in a life-threatening manner. This can include the lungs, the liver, the heart, the skin, blood cells and the kidneys.

Hailey presented as a typical developing, happy little girl meeting her milestones at appropriate ages. Looking back on her medical history now, she did used to have intermittent fevers. They were not high and would not last long but nonetheless they were there. At 1.5 I also noticed large lymph nodes that were not going away. She had blood work done, met with two infectious disease doctors and after she turned 2 we had an ultrasound done to rule out anything serious. Doctors said “sometimes you just have large glands”. Knowing what I know now, that was her body showing signs of the immune system attacking itself.  We also noticed while on vacation that she was walking with a limp but only for a few hours. We though she had hurt her foot running around without shoes. She was seemingly fine after that. Then we noticed the slow decline in her language. A previously chatty and energetic two-year-old had begun to experience a decline in her speech abilities. Initially, this change was subtle and presented as a lack of clarity in her speech. We thought she was being lazy and not pronouncing words as clearly as she once did. Her verbal skills continued to decline. Additionally, there had been an increase in the frequency of falls while she was walking. She was still tiny and had little legs so we kept thinking her walking would get better. Orthopedic did not see any cause of concern with her walking and it was chalked up to her just trying to catch up to her older brother. Bottom line, trust your gut and always get more opinions.

AGS diagnosis typically involves:

• Clinical evaluation of symptoms (developmental regression, neurological issues, etc.)

• Blood tests and genetic testing to identify mutations in genes associated with AGS

  • (e.g. There are currently nine genes identified in which mutations give rise to AGS. They are labeled as such: AGS 1-9.

  • The mutations for AGS 1-5 are inherited while the mutations for AGS 6-7 can be spontaneous events.

• Brain imaging (e.g. MRI) to detect characteristic brain changes like calcifications.

There are various treatments available for AGS to alleviate symptoms and enhance comfort for affected children. Due to the diverse range of symptoms exhibited by children with AGS, treatment plans must be tailored to the individual needs of each child.

Some children may require interventions for respiratory difficulties, while others may need assistance with feeding. It is also essential to monitor children with AGS for the following conditions:

·         Signs of glaucoma, which should be assessed through annual testing

·         Diabetes insipidus and hypothyroidism

·         Cardiac and pulmonary issues, including pulmonary hypertension and inflammatory cardiomyopathy

·         Blood cell abnormalities, particularly concerning platelets, which may increase the risk of bleeding

·         Vascular issues in the brain

·         Gradual skeletal problems, such as scoliosis and joint dislocations, which may be linked to motor impairments associated with AGS

Many children diagnosed with AGS find physical and speech therapies beneficial in addressing the weaknesses resulting from neurological damage.

The Aicardi-Goutieres Syndrome Advocacy Association (AGSAA), alongside AGS specialists and families, strongly supports the use of a category of medications known as "JAK inhibitors" to alleviate the effects of AGS disease activity. Research indicates that children with AGS, regardless of their age or level of neurological severity, can potentially gain from baricitinib treatment, leading to enhancements in their quality of life and the achievement of developmental milestones. Long-term commitment is necessary for baricitinib treatment, and the benefits may not be immediately visible. The main objective of this treatment is to protect against brain damage; maintaining stability is considered positive progress.

The process of JAK inhibition is complex, necessitating careful observation for any changes or significant immunosuppression-related events, and usually requires a multidisciplinary approach. AGS is a serious and intricate condition that demands proactive treatment strategies.

Yes, AGS is generally considered a progressive disorder. The symptoms may worsen over time, with increasing developmental delays, motor difficulties, and neurological decline. However, the rate and severity of progression can vary widely between individuals.

AGS is a very rare disorder. Its exact prevalence is not known, but it is estimated to affect fewer than 1 in a million people worldwide. It is most often diagnosed in infancy or early childhood.

There is currently no cure for AGS. Treatment focuses on managing symptoms and improving quality of life. This may include therapies such as physical therapy, speech therapy, medications, and other interventions to address specific symptoms.

Yes, AGS is inherited in an autosomal recessive manner. This means that both parents must carry one copy of the mutated gene, but they typically do not show symptoms. When both parents are carriers, there is a 25% chance with each pregnancy that the child will inherit two copies of the mutated gene and develop AGS.

Changes (pathogenic variants or mutations) in several different genes are known to cause AGS. AGS is most commonly inherited in an autosomal recessive fashion (mother and father are both carriers for the harmful gene variant), but the disease can also result from a de novo (new) gene variant in the child or from autosomal dominant inheritance from one parent.

We did meet with the genetics team and have genetic testing but not right away. Once Hailey was hospitalized, her team of doctors wanted to confirm her suspected diagnosis. This was after her MRI, EEG, and lots of blood work. Most doctors typically aim to eliminate potential issues and gain clearer guidance before proceeding with genetic testing. I have been told by genetic specialist that if every person was tested for genetics everyone would come up positive for something.

Broad testing without clinical direction could yield false positives or incidental findings that may cause more harm than good.

Overall, genetic testing is a crucial step in the diagnosis of Aicardi-Goutières Syndrome (AGS).

Here’s why:

1. Genetic Cause

AGS is a genetic disorder typically caused by mutations in one of several genes, including

TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1, among others. Identifying a mutation in one of these genes is often necessary to confirm the diagnosis.

2. Clinical Overlap

The symptoms of AGS—such as developmental delay, microcephaly, intracranial calcifications, and chronic CSF lymphocytosis—can mimic other neuroinflammatory or congenital infections (like TORCH infections). Genetic testing helps distinguish AGS from these mimics.

3. Treatment and Prognosis

While there’s currently no cure, knowing the exact genetic mutation can guide:

Prognosis: Some mutations are associated with more severe or earlier-onset forms.

Research participation: Some clinical trials target specific genotypes.

Family planning: Important for assessing recurrence risk in future pregnancies.

4. Early Intervention

Early diagnosis through genetic testing can prompt: Symptomatic treatments, Supportive therapies, Surveillance for complications.

Hailey is the hardest working little girl we know. In addition to school services which include speech, occupational therapy, and physical therapy, she gets PROMPT speech therapy, physical therapy, and aquatic therapy outside of school.

Research into AGS is ongoing, particularly focused on understanding the immune dysfunction associated with the disorder, as well as potential therapies that could modify the disease's progression. Some studies are investigating the use of antiviral drugs or immunomodulatory therapies, but more research is needed.

A key component of Hailey’s Grace mission is to facilitate the advancement of research, enabling clinical trials and novel medical innovations to progress in the pursuit of a cure for AGS.

I highly recommend finding a care team to meet your child’s specific needs. My best advice it to start at CHOP (Children’s Hospital of Philadelphia).  At this hospital, the care for your child will be managed by our Leukodystrophy Center. Our team, which includes various specialists, offers cutting-edge diagnostic testing, thorough clinical care, and access to the most recent treatment options, while also exploring innovative therapeutic possibilities.

Clinical trials could be an alternative as well. Currently, there are multiple clinical trials focused on AGS taking place at the Children’s Hospital of Philadelphia. Please consult your doctor to see if these trials might be suitable for your child.

Various patient advocacy groups and foundations exist to support families affected by AGS, providing information, resources, and support networks. Some well-known organizations include:

• AGSAA- Aicardi Goutieres Syndrome Advocacy Association

• NORD- National Organization for Rare Diseases

• The United Leukodystrophy Foundation

• Hailey’s Grace- my hope is for this to be a platform to help others navigate their journey and provide support.

Don’t give up. If you feel something is not right, your probably on to something. Every story I hear of a child with a confirmed diagnosis starts the same- being dismissed, and misdiagnosed. In my opinion the best way to start would be to see a neurologist and address your concerns. If your not satisfied with what your being told, see another one! We sought out three neurologist before someone had concerns and gave us the answers we needed.

Coping with AGS can be challenging for families, as the disorder often requires intensive medical care and management. Support groups and organizations for rare diseases can provide families with emotional support, resources, and connections with others facing similar challenges. It’s also important to work with healthcare providers to create individualized care plans for the affected child.

The BelieveWell program offers complimentary therapy sessions with a licensed mental health counselor, specifically designed to assist individuals under the psychological strain of caring for a loved one with a rare disease. The emotional toll experienced by caregivers is profound and can manifest as a significant daily stressor.

I learned about We Believe in a Cure, a nonprofit organization dedicated to finding a cure for the rare disease FOXG1, from my sister. Her fiancé, a mental health professional, partnered with We Believe in a Cure to provide therapeutic support for caregivers. Unbeknownst to me, I would soon find myself in need of these invaluable services.

Contact info@webelieveinacure.org to learn more!

https://www.webelieveinacure.org

Becoming more involved in the Aicardi-Goutières Syndrome (AGS) community can be deeply rewarding and impactful. Here are several ways you can get engaged:

1. Join AGS Support Groups and Organizations

The Aicardi-Goutières Syndrome Advocacy Association (AGSAA): This is one of the most active AGS-focused organizations. You can join their network to connect with families, patients, and advocates.

Look for Facebook groups or online forums (e.g. RareConnect) dedicated to AGS where you can share experiences, ask questions, and offer support. I am personally a member of “Aicardi-Goutières Syndrome Support Group” on Facebook.

2. Participate in Fundraisers and Awareness Campaigns. AGSAA and similar groups often organize events for Rare Disease Day, which is on February 29th. Click our Events Page to see our Fundraisers as well.

3. Attend Conferences and Webinars

Many rare disease organizations host educational events where you can learn about AGS research, treatments, and advocacy opportunities. The Global Genes and NORD (National Organization for Rare Disorders) communities often include AGS in their discussions.

4. Advocate for Policy and Research

Get involved in rare disease advocacy with groups like EveryLife Foundation, which pushes for better legislation and funding for rare conditions.

Consider becoming a patient advocate or sharing your or your loved ones story to raise awareness among healthcare providers and policymakers.

5. Support Research

Donate to or fundraise for AGS research, or participate in patient registries and natural history studies that contribute to understanding the condition. Donating specifically to Hailey’s Grace also contributes to these efforts.

6. Connect Locally

Reach out to local hospitals, genetic counselors, or rare disease clinics to see if they have AGS patients or initiatives you can support. Sometimes even hosting a local meet-up for AGS families can have a big impact.