TANGO2: Simple Guide + Podcast

Everything to know about TANGO2, from the experts.

Podcast

Author and Contributing Experts to this Guide include:

Seema Lalani Clinical Geneticist
Jayme Gilmore Pediatric Physical Therapist
Lindsey Messerschmidt Licensed Speech Pathologist LinkedIn
Sheena Byerly Genetic Counseling Student LinkedIn

TANGO2 Disease

Dr. Seema Lalani, a clinical geneticist at Texas Children's Hospital, and a faculty member in the Department of Molecular and Human Genetics at Baylor College of Medicine. She was part of a team at Baylor who first characterized TANGO2 in 2016 and is currently on the board of the TANGO2 Research Foundation.

Jayme Gilmore, a pediatric physical therapist who received her doctorate in Physical Therapy from Eastern Washington University. Jayme has worked directly with TANGO2 patients in addition to working with adults and children who have a variety of orthopedic, neurological, general surgical and cardiac conditions.

Lindsey Messerschmidt, a licensed speech pathologist and a mom of three children born with TANGO2. She currently works as a family resource coordinator for families with children with developmental delays. Lindsey remains active in the TANGO2 community and has co-founded a TANGO2 Parent Support Committee.

What is TANGO2 disease?

TANGO2 Disease is a rare genetic disorder caused by changes in both copies of the TANGO2 gene that causes it to not function properly. Patients can experience sudden changes in their metabolism such as low blood glucose levels, increased blood lactate levels, and slightly elevated blood ammonia levels.

This constellation of features is called acute metabolic crises and often occur after an individual is sick or has not eaten for a long period of time.

During a metabolic crisis, patients can experience muscle weakness, changes in the way they walk, a confused mental state, a breakdown of muscle tissue, and changes in the heart’s rhythm. The exact presentation can vary between patients.

TANGO2 is an abbreviation for Transport and Golgi Organization 2 Homolog and is sometimes referred to as TANGO2-related metabolic encephalopathy and arrhythmias.

TANGO2 is an encephalopathy meaning that it is also a brain disease and can also cause neurological problems, developmental delays, intellectual disabilities, seizures, hearing loss, low thyroid function and trouble coordinating movements. The neurological symptoms are seen even when an individual is not experiencing a metabolic crisis, but can vary from person to person.

At this time there is currently no cure for TANGO2. However, there are treatment options to help manage the signs and symptoms.

“This is a rare disease that affects multiple organ systems including the brain, heart and skeletal muscles. Children can present with life-threatening episodes of cardiac arrhythmia and muscle breakdown which is called rhabdomyolysis,” said Dr. Seema Lalani, a clinical geneticist at Texas Children's Hospital, and a faculty member in the Department of Molecular and Human Genetics at Baylor College of Medicine. She was part of a team at Baylor who first characterized TANGO2 in 2016 and is currently on the board of the TANGO2 Research Foundation.

“Children can have acute episodes of crises, and these crises can be described as a state where their blood sugar drops, they have great abnormalities, they have altered mental status, and they end up in the emergency room. Frequently they are in coma when they arrive and often, they require intensive care unit admission for managing their cardiac arrhythmia and rhabdomyolysis.

“Unfortunately, some children have passed away during their acute episode, so it is a serious disorder. And children who survive continue to have significant health challenges. They can have difficulty walking, slurred speech, they can have seizures, intellectual disability, and hypothyroidism. These children also continue to have this risk of rhabdomyolysis and metabolic and cardiac decompensation which can be life-threatening,” added Dr. Lalani.

“It is a life-long condition. What makes it worse is that you cannot predict if a child will ever develop a metabolic crisis or die suddenly from a cardiac cause, so it's really difficult for families.”

What Causes TANGO2 Disease?

TANGO2 disease is caused by variations (changes) in the transport and Golgi organization 2 (TANGO2) gene 1.

The cells in our bodies contain genetic information called DNA. Throughout DNA there are sections called genes, which encode for proteins, which carry out many important functions in our bodies.

Our genes play a role in determining our hair color, height, and even health status. When there are harmful changes in our genes that cause it to not function correctly, this can lead to different diseases and disorders.

Because it is a relatively recently identified disease, researchers aren’t absolutely sure what the protein produced by the TANGO2 gene does. Without knowing the exact underlying biological problem, it is difficult to work on developing cures and treatments.

This is why the majority of management options are focused on the specific sign or symptom.

That being said, we do know that if someone inherited two non-working copies of the TANGO2 gene, one from their mother and one from their father, then they will experience the signs and symptoms of the condition. However, the exact signs and symptoms will vary from person to person, causing patients to experience varying severity 2.

“Because it's such a newly-discovered genetic disorder, like many new conditions, there are several unanswered questions. For example, ‘What causes disease at a cellular level?’ or “What treatment would work?’ or “How do we prevent the medical concerns?’” said Dr. Lalani.

“So, we really don't know what causes the life-threatening cardiac arrhythmias and recurrent muscle breakdown in these children, and we don't know how we can prevent them. As of yet there are no established evidence-based studies to propose best medications or supplements or diets that can reduce morbidity in these children,” she added.

What are the Symptoms of TANGO2 disease?

There are still many things researchers don’t understand about TANGO2.

Although core symptoms have been identified, the small number of cases and lack of large clinical studies have hampered efforts to fully understand TANGO2.

Researchers do know that TANGO2 is a variable disease, meaning it affects each person differently. Not all people with the condition will have all symptoms, and they will vary in severity.

For some patients, the first signs and symptoms of the condition occur in the form of an acute metabolic crisis. This is a quick period of rapid changes due to changes in an individual’s metabolites.

For TANGO2 patients this could be low blood sugar, increased levels of lactate and/or ammonia. During this period, patients might also present with muscle breakdown which releases a substance called creatine kinase.

High levels of muscle tissue in the urine can cause damage to kidneys which can be very serious 3. While in a metabolic crisis, patients can experience muscle weakness, a loss of coordination (ataxia), changes in the heart's rhythm, an altered mental state, and potentially enter a coma.

Changes in the heart’s rhythm (arrhythmias) can lead to sudden unconsciousness, cardiac arrest, and in some cases, sudden cardiac death. The heart can develop cardiomyopathy making it harder to treat the arrhythmias.

Because of this all children with TANGO2 should be evaluated by an electrophysiologist who has expertise in heart arrhythmia and cardiomyopathy disorders.2

Neurodevelopmental problems are also common. Some Individuals with TANGO2 disease will have differences in the structure of their brain.

However, regardless of the results of brain imaging, some level of intellectual disability has been observed in almost all affected individuals. Other neurodevelopmental problems can include: seizures, problems coordinating voluntary movements, clumsiness and an unsteady way of walking, and difficulty with speech. These features can occur outside of a metabolic crisis 4.

In approximately, one-third of patience, Hypothyroidism, which is a low functioning of the thyroid, can also occur. The thyroid secretes hormones that regulate the body’s metabolism such as the heart rate, body temperature, and blood pressure.

Hypothyroidism can produce fatigue, dry skin, constipation, increased sensitivity to cold, unintended weight gain, muscle weakness, and hoarseness.

Other symptoms of TANGO2 may include:

  • exaggerated or heightened reflexes
  • temporary misalignment of the eyes where one or both eyes are turn outward away from the nose
  • a few individuals have been diagnosed with optic atrophy
  • sensorineural hearing loss which takes place when the nerves in the ear cannot properly send sound to the brain
  • A variety of seizure types, including generalized myoclonic and atonic seizures
  • generalized cerebral atrophy
  • Difficulty swallowing 5
  • delayed gastric emptying with gastrointestinal dysmotility 6
  • overactive reflexes and a series of involuntary, rhythmic, muscular contractions and relaxations
  • dysarthria (motor speech disorder characterized by poor articulation)
  • stroke

Prevalence and Risk Factors of TANGO2 Disease

TANGO2 disease is an extremely rare condition. Estimates put diagnosed cases at anywhere between 30 and 400 cases since the condition was first discovered a few years ago 7.

“It was such a recently diagnosed condition, we didn't know anything about it until 2016. So, honestly, we don't know how many families are affected,” said Dr. Lalani.

“But through the TANGO2 Research Foundation we are aware of about 100 families worldwide, and some of these families have had multiple children affected.

“Regarding ethnicity, we've seen that all ethnicities are affected, Europeans and Hispanic populations are more affected because both populations have this common genetic variation that can predispose to TANGO2 disorder. Through the Foundation, we are aware of families from Saudi Arabia, Germany, France, Italy, Sweden, Australia, the USA, Canada, and South America, so it affects children worldwide.

“As doctors are more able to recognize TANGO2 I think more children will be getting diagnosed,” added Dr. Lalani.

Diagnosis of TANGO2 Disease

Recognizing clinical signs and symptoms, a detailed patient history, and genetic testing are all important in determining a diagnosis of TANGO2 disease.

If your physician is suspicious that the child may have TANGO2 they will likely order genetic testing for this gene. They will need a sample from the patient, usually blood or saliva.

Molecular genetic testing can detect variation in the TANGO2 gene known to cause TANGO2 disease. The physician may order a single gene test, looking at only TANGO2, a panel test which looks at a number of genes associated with the patient’s signs and symptoms, or an expanded test, called exome sequencing, that looks at all of the protein-encoding genetic information.

All of these options could potentially result in a diagnosis of TANGO2 disease.

Once the TANGO2 variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic diagnosis are possible. Parents of an affected child, should undergo genetic testing to identify which harmful change they carry.

Should the family decide to have another child, then there is a 25% chance that each subsequent pregnancy will also be affected with TANGO2 Disease.

“Many children with TANGO2 disease were initially identified through exome sequencing. This is a test where approximately 20,000 genes are sequenced in the hope of finding the disease-causing change in the genome,” said Dr. Lalani.

“Since its description in 2016 we now know that the disease manifestation can be very specific, and I feel that we have come to a point where we can see a child and just test for TANGO2 as a single gene.

“For example, if I see a young child in the clinic who has difficulty walking, has slurred speech and has a past history of very high CK level which indicates rhabdomyolysis, and if that child has had cardiac arrhythmia in the past that required hospitalization, I would just test him for a single gene TANGO2.

“There's also one interesting fact about TANGO2 and that is the gene is in the critical region of DiGeorge deletion of 22q11 deletion, so children who have DiGeorge already have one copy of TANGO2 missing. So, if the second copy has a mutation in it, then children with the DiGeorge syndrome can also have the manifestation of TANGO2 disorder which would be muscle breakdown, cardiac arrhythmia, that generally are not seen in 22q11 deletion,” added Dr. Lalani.

Can TANGO2 Disease be Cured?

No. Signs and symptoms can be managed through effective treatments, but currently there is not a cure for TANGO2 disease.

Treatment and Care Options for TANGO2 Disease

There are always two sides to the treatment of a rare disease like TANGO2. Care providers and parents must join together to ensure the most effective treatment possible.

To gain greater insights as to what care for TANGO2 disease actually looks like from both sides of the care spectrum, we talked to Jayme Gilmore and Lindsey Messerschmidt.

Gilmore is a pediatric physical therapist who received her doctorate in Physical Therapy from Eastern Washington University. She has worked directly with TANGO2 disease patients in addition to working with adults and children who have a variety of orthopedic, neurological, general surgical and cardiac conditions.

Lindsey Messerschmidt is a licensed speech pathologist and a mom of three children born with TANGO2 disease. She currently works as a family resource coordinator for families with children who have developmental delays.

She also remains active in the TANGO2 disease community and has co-founded a TANGO2 Parent Support Committee.

NOTE: These interviews were conducted separately but combined to give a better overall impression of both sides of the treatment spectrum. They have also been edited slightly for clarity and length.

Messerschmidt. Our two children have TANGO2 disease. Our son Daniel is five and our daughter, McKenna, is four. We also had another son named Jackson who passed away at the age of three in 2015 from TANGO2 disease.

My husband Brad is working as a financial advisor. His job is really flexible so that's really, really nice having medically complex kids.

All three of my children have been affected differently, yet they do have really similar symptoms. Jackson was just really severely affected and his disease progressed very quickly.

When I'm talking with someone about what TANGO2 is like, is that it's kind of similar to ALS or Lou Gehrig's disease, except with ALS there's this very steep slope of disease progression, and in TANGO2 disease I would say the progression is not as steep and that it's more of this kind of gradual up and down trajectory with, of course, this general decline throughout life.

Gilmore: Not all kids with TANGO2 are able to sit or are able to walk. Danny and McKenna both can, and so now we're working on more higher-level balance and coordination skills. Both go to Seattle Children's frequently with a huge team over there that really look at whole body care.

That is so important with a genetic syndrome to make sure that they're getting everything that they need.

Messerschmidt: What's different about Jackson from my other kids is that his disease progression was just so fast. We don't know why and we may never know why, but he was born healthy, and he began with symptoms around two to four months of life.

By the time he was one year old, he was unable to hold his head up, roll over, or sit. He had catastrophic seizures, and severe gastroparesis. He had a lot of feeding issues with a feeding tube, and over the course of MRIs you could see substantial cerebral volume loss.

One thing that all people who met Jackson or saw him would say is just how happy he was, and this was really true, but just below this was a little boy who was suffering really severe pain and we couldn't figure out why.

I remember one time a nurse came in, Jackson was in the hospital, and she had to document what number on the pain scale did we think he was at? He had quite a bit of pain meds on board at that time and we couldn't even answer the question.

We were trying to console him and she just had to look away because she was starting to cry seeing him in that much pain and not being able to help him. So, by the time he passed away in 2015 at the age of three, we had no diagnosis.

Talking about Jackson is so much different than talking about Danny and McKenna. Although Danny and McKenna have similar symptoms, the severity is just not near as much as Jackson experienced.

Gilmore: My first experience with TANGO2 was my first week at Stepping Stones Pediatric Therapy in Spokane. In July of 2017, I met my two friends, Danny and McKenna. Danny was a couple of months from turning three-years-old at the time, McKenna was just over 15-months-old.

Messerschmidt: We started the whole quest for a diagnosis in early 2012 when Jackson started showing symptoms. We did various panels based on his symptoms which eventually led us to whole exome sequencing, and I believe the first time that was completed was in 2012. But in 2012 TANGO2 disease wasn't even recognized as a disease yet, so nothing popped up on any of the whole exome sequencing that was completed.

We had it done four times, and the fourth time happened in 2016. Luckily, we had started the process two months after TANGO2 disease was recognized. So, in 2016 we did get our answer in September, that all three kids have this rare disease called TANGO2 disease.

Messerschmidt: For all three kids, their first symptoms were overall different in severity, just in different degrees around the same time.

With Jackson, I knew almost right away, I just knew something's off. I had that weird gut feeling.

With my other two children it was a lot more gradual and maybe by the time there was truly obviously something wrong, they were probably closer to one. So, there was like three different symptoms that I really noticed, and it was right around, I would say, two to five months of age.

There was, in all of the kids, kind of this sudden onset, gastrointestinal symptoms. It was like sudden onset acid reflux, and right about that time they also started having trouble feeding. It was like they would be drinking fine and then all of a sudden they would fatigue and just stop, but they weren't satisfied.

That really concerned me, but acid reflux is a super common symptom in infants, so we took our kids to the pediatrician, and switched formulas, and tried medications. But nothing worked, and if anything, it just seemed like they were getting worse.

That was the first symptom. The second early symptom that I really noticed was their muscles and coordination.

So, sometime around six to 12 months it became apparent something was wrong. Some days they would appear really coordinated, they'd be holding their heads up, rolling over, moving normally.

This would be followed by days on end where we wouldn't see them roll over, that they were looking around as much, and their head control just wasn't as good as it had been days prior.

That was really difficult for us to document as parents, and difficult for us to communicate with pediatricians because the symptoms were so fleeting.

The third thing that we noticed was just weird neurological abnormalities. Sometimes they would experience nystagmus. Out of nowhere their eyes would kind of look like they were dancing.

And you can imagine a parent taking their kid to the pediatrician. and I'm telling them, "Oh, their eyes are dancing." And by the time they look, the nystagmus has essentially resolved, and they're like, "Oh, we don't really see..."

The other neurological thing that Danny, McKenna and Jackson all experienced was a seizure by the time they were 15 months of age. Very different epilepsy types, very different levels of severity, but they all had a seizure by the time they were 15 months of age.

Gilmore: Danny was ambulatory already when I started to work with him. He was struggling with surface changes, stairs, standing on one leg. A year later we were working on jumping, riding a tricycle, ball play, throwing and kicking a ball to enhance family and peer interactions.

When I first started working with McKenna, her main means of locomotion were rocking on her knees.

She was having a substantial number of drop seizures that were increasing the longer that I worked with her. That really eliminated safety, her independence and progression of milestones.

We never knew when another drop seizure would come, and therefore interrupt her mobility, interrupt her play, and interrupt her confidence.

She was able to stand independently on her own up to 10 seconds at that point, but we did see a regression in that because the uncontrolled seizures. There was a point when the EEG caught 300 seizures in a 30-minute period, and so she was limited in safety, constantly dropping down when we would work on different skills.

Messerschmidt: Danny and McKenna both have epilepsy. They both have eating tubes and both have developmental delays. They really struggle to communicate and talk, but they run, they play, they jump, and they climb.

Danny is really interested in lawn tools, especially the lawnmower. He wants to mow the lawn every day, all the time, and he's really motivated by that, and he's really kind of funny.

McKenna, she's really interested in cleaning everything and she's got a little spray bottle that she carries around with her and a rag and she's scrubbing things, always trying to clean and she really loves taking care of her baby dolls. She's very nurturing.

Both of my kids are so social. Talking with other TANGO2 families it's kind of a theme among all of the kids. They're really social, they're very happy, they have a lot of joy.

And that is especially true for Danny and McKenna. You might look at them and not really immediately even realize that anything is wrong.

And even if you did realize, "Oh, they're developmentally delayed, something's off," you certainly wouldn't realize or be able to see that they're living with this fatal condition called TANGO2.

Gilmore: We used specific tools to help McKenna further progress her motor skills, but really it was the medication change that helped us. Neurology and Metabolics were going back and forth, with which medications were appropriate for her. All the ones that they had tried were not working previously.

They finally tried a medication that Metabolics was unsure about based on the liver function, but neurology ended up kind of winning out based on her function and how much it was impairing her quality of life and any sort of progression towards walking on her own.

So, that new medication was probably like summer of 2018. In November of 2018 she had her first normal EEG for a 45-minute period, and then all of a sudden just took off, which was so cool to witness.

Gilmore: McKenna started ambulating with the use of a grocery cart for 50 feet. She was able to ambulate with just minimal assist from me for up to 15 feet prior to losing her balance.

At the end of November, just a month later, she was taking up to 11 steps independently. By December she was ambulating independently, rising to stand in the middle of the floor on her own.

She really took off and that just reiterated the importance of the medical team and therapy team communicating together to regulate systems.

If we didn’t regulate procedures, I anticipate we probably would have continued to see regression rather than her great progression as soon as we got the seizures regulated.

Gilmore: Once she did start to learn to stand on her own, we used orthotics. Specifically for McKenna, we used supramalleolar orthosis.

The abbreviation is SMO, and they helped her significantly progress in her weight-bearing activity and independent upright mobility. What they do is really improve the ankle in the foot, or the distal alignment of the lower extremity, to provide a more stable base to rely on for a dynamic movement for that independent ambulation.

Gilmore: The therapy methods and treatment we use for TANGO2 have a broader application to other types of patients. We do use specific pieces of equipment for McKenna to progress her specifically, but these have applications for a variety of patients regardless of diagnosis or syndrome.

We really do like to give them a stable base of their feet so that they can activate more appropriate muscles, approximately, and therefore progress their motor skills.

Gilmore: Another piece of equipment we use with McKenna because of all of her seizures is the Danmar Soft Shell Protective Helmet. We modified it a little bit for her because she seems to go forward with her drop seizures a lot, so in order to protect her from extreme cervical extension and worry of spinal cord injury after a drop seizure, we did have our local orthotist add some things on the helmet in order to protect her from further injury.

McKenna also benefitted from a Rifton gait trainer to help with her independent ambulation prior to having that postural control or stability to do it on her own. This piece of equipment is a walker but it also has a chest harness and a pelvic harness to help develop that control prior to having it on their own.

Having her chest in a pelvic harness allows her to weight-bear through her feet but also prevent the injury from dropping so close to the ground because those harnesses are helping to hold her upright.

Gilmore: We use equipment or play structures that generally promote more flexor activation rather than extensor activation. Kids all develop their extensor muscles first, but especially when kids have feeding difficulties and G-tubes which we often see in kids with TANGO2 based on their energy that's required for digestion.

These extensor motor patterns become dominant and preferred. They seem to have difficulty activating their flexor muscles, their pectoral muscles for reaching for a toy, their abdominals for a postural control, or rolling or climbing.

So we introduce equipment that allows them to practice climbing with more of a forward lean like a ladder to a slide, peanut balls to activate their core and to maintain an upright posture with less mass to manage, and trampolines to balance out the flexor-extensor muscle imbalances of the lower extremities.

The other thing that I've used on both of them is a Rifton adaptive tricycles. These are super helpful, cool pieces of equipment that help the kids to learn reciprocal motion. It's a wider base tricycle with a pulley system for the feet to make it easier to propel.

There are straps to hold the feet on the pedals, and it has a lower center of gravity for safety and a low gear ratio to make pedaling easier.

If a kid is not able to ambulate and they're wheelchair dependent, it's really important to get a lightweight wheelchair to make it easier on mom and dad. It's really important to have a good seating system in there to make sure that there is a good cushion for lack of skin breakdown.

We don't want any bedsores or anything if they can't stand up or walk on their own, so that's really important.

Gilmore: Danny and McKenna both walk, they both run. I struggle to catch up with them a lot. They both jump, they kick a ball on command, they throw a ball, intentional release can be somewhat tricky, but they both can throw a ball…They’re both making consistent progress and that's ideally what we want to see, is consistent progress even if that rate of progress looks different for each child.

Gilmore: I work really closely with both occupational therapists and speech and language pathologists, and specifically in these two cases, they have been really incremental in their continued gross motor progress. Their receptive and expressive communication has improved greatly…Speech has been really important for them to understand commands, to then progress skills, but also to start to express their own wants and needs.

Gilmore: With occupational therapy, they address body and environmental awareness, sensory input to regulate systems, more specific attention span and fine motor work, work on cognition and multi-tasking. I attempt to strengthen the big muscles while they are working on more of that fine motor work that's still important for a child to color, to do a puzzle, to play with toys, to drop something into a container when needed.

I want to teach them to use their body to run, jump off things, climb on toys and surfaces, but we also have to keep them safe. So, occupational therapy is there to address body awareness, environmental awareness, the cognitive aspects to know how and when to keep themselves safe.

As a team of therapists seeing them on a weekly basis, we can pick up on different behaviors and mannerisms that we're seeing and we're sometimes able to give words to parents who are immersed in it all day long. So, we can then help to brainstorm how to address those certain behaviors.

Gilmore: We have two mental health counselors on staff here and I think that's huge for families as they adjust to a different normal and help to manage some behaviors. It really helps to get parents different coping strategies or play strategies, behavioral management, when the typical time-out, or the typical addressing of behavior doesn't work.

Parents coping with the challenges that a genetic syndrome can bring allows for a changed family unit, a changed family dynamic, hopefully in a positive way, and so we find that having mental health counseling can help the family as a whole, as they learn more and more about how a genetic syndrome can affect their life.

Messerschmidt: Life is really interesting with having children with a rare disease like TANGO2. Our life revolves around it, and the disease symptoms kind of guide us on how we're going to live our life. My husband has been very supportive and hopefully I've been supportive for him as well, but he's really helped me through some really tough times and we have really supportive families.

We have amazing friends that help us through, and even with that, I would say that no one really understands the way that Brad and I understand it. And so, I would say, getting the diagnosis alone was hugely helpful and I was able to join a Facebook group for TANGO2 families. And through that I've been able to connect with other TANGO2 families.

Potential Complications of TANGO2 Disease ( 8)

A metabolic crisis can lead to death if treatment is not administered immediately. TANGO2 can affect the heart, leading to ventricular tachycardia and cardiac arrest.

Arrhythmias degenerate rapidly and any patient with premature ventricular contractions (PVCs) should be immediately transferred to an intensive care unit.

In some cases, hemodialysis to remove fluids and wastes may be necessary if there is severe fluid overload or irregularities with electrolyte balances. Electrolytes are certain salts and minerals in the body and individuals with TANGO2 should be monitored for normal levels of potassium, magnesium, and glucose.

However, hemodialysis does not remove myoglobin and is not an effective therapy for myoglobin accumulation associated with rhabdomyolysis.

The Prognosis of TANGO2 disease

Because it is such a rare and recently discovered condition, the prognosis of TANGO2 disease is difficult to accurately surmise.

However, research on several fronts has started, and many people are hopeful that more effective treatments and a possible cure will be found eventually 9.

“The TANGO2 Research Foundation has its focus to improve the lives of children and young adults, and the foundation has recently funded five research projects. Several of these projects are just focused on understanding the disease mechanism at a cellular level. We hope that efforts like these will help in understanding the disease better,” said Dr. Lalani.

What to do Next: Living with TANGO2 Disease

There are no proven treatments or diet recommendations for TANGO2 disease, but there are recommendations for management. TANGO2 symptoms seem to appear when the body is stressed in any way.

However, sometimes there does not seem to be a direct reason why worsening symptoms are experienced.

For newly diagnosed individuals, it is recommended that they undergo the following initial evaluations:

  • Neurological examination: for gait, weakness, seizures
  • Cardiovascular examination: A baseline ECG and echocardiogram
  • Metabolic examination: Variant of metabolic levels via urine and blood
  • Endocrine examination: Looking at levels indicative of hypothyroidism
  • Gastrointestinal examination: To monitor any difficulty swallowing
  • Neurodevelopmental evaluation: for identification of developmental delays
  • Ophthalmology examination: to evaluate vision
  • Audiologic examination: to evaluate hearing

It is recommended that children with TANGO2 disease 10:

  • Stay hydrated.
  • Eat regular, frequent meals that include carbohydrates and healthy low-fat proteins.
  • Have regular bowel movements. Some families report that their doctors recommend laxatives
  • Exercise frequently without overheating or over exertion
  • Wash hands regularly to prevent illness.
  • Avoid public places when possible during the winter season to prevent illness.
  • Some cardiologists have recommended that patients have a LINQ monitor to notate any
  • irregular heart rates

As part of living with TANGO2 disease, children should also undertake the following 11:

  • Yearly blood draws to check for hypothyroidism.
  • Initial audiology exam is recommended as hearing loss has been seen in some cases. Follow-up exams may be yearly.
  • Initial eye exam completed by a pediatric ophthalmologist is recommended, as some children experience vision loss and eye muscle problems. Follow-up exams may be yearly.
  • Evaluations and treatment by a Physical Therapist, Occupational Therapist, and Speech-Language Pathologist can help manage developmental delay and maximize the child’s ability to participate in activities of daily living.
  • Some children benefit from seeing a dietician, to ensure proper growth and adequate nutrition/hydration.
  • A gastroenterologist is a doctor that can help if your child is experiencing chronic constipation or other digestive problems.

Parents have also seen varying results in health from the “mito cocktail,” consisting of B vitamins, CoQ10, and levocarnitine. Some doctors have recommended the liquid form of CoQ10 stating that it is more effective than the powder 12.

According to Dr. Lalani, research for TANGO2 disease is important and critical to advancing solutions to the condition.

“Our first conference, the Family Conference in 2019, was patient-driven and parents were asked about their priorities regarding research areas, and what they said was, managing and understanding life-threatening symptoms of TANGO2 was the highest priority for them.

“Improving quality of life and independence of children, preventing loss of function, was another matter of importance. Then finding ways how to avoid crisis episodes in rhabdomyolysis, studying cellular response to medications, and determining which treatment has the potential to work.

“We knew that we needed funding to address these research questions, so the TANGO2 Research Foundation applied for the Chan Zuckerberg Initiative, the CZI grant, and fortunately got funded. In 2019 they received $450,000 that could help families realize these goals. And this foundation works so fast, so effectively, it started the research proposal call in October 2019 and has successfully funded multiple projects that are so aligned with families' priorities.

You can see the details of these funded research projects on their website, TANGO2research.org,” added Dr. Lalani.

For More Information

TANGO2 Research Foundation 300 Plaza Middlesex
Middletown, CT 06457 E-mail: info@TANGO2research.org

Genetic and Rare Diseases (GARD) Information Center PO Box 8126 Gaithersburg, MD 20898-8126 Phone: (301) 251-4925 Toll-free: (888) 205-2311 Website: http://rarediseases.info.nih.gov/GARD/

Metabolic Support UK 5 Hilliards Court, Sandpiper Way Chester Business Park Chester, CH4 9QP United Kingdom Phone: 0124420758108452412173 Email: contact@metabolicsupportuk.org Website: https://www.metabolicsupportuk.org/

Referenced Sources

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  2. Dines JN, Golden-Grant K, LaCroix A, Muir AM, Cintrón DL, McWalter K, Cho MT, Sun A, Merritt JL, Thies J, Niyazov D, Burton B, Kim K, Fleming L, Westman R, Karachunski P, Dalton J, Basinger A, Ficicioglu C, Helbig I, Pendziwiat M, Muhle H, Helbig KL, Caliebe A, Santer R, Becker K, Suchy S, Douglas G, Millan F, Begtrup A, Monaghan KG, Mefford HC. TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants. Genet Med. 2019;21:601–7.
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Transcript

Sheena: You're listening to the Rare Disease Connection, a production of Aspect Health and raredisease.com. There are some rare diseases that get talked about so much they start to feel a lot less rare. It's not often that we hear the name of a condition that we've truly encountered before. While it can be fascinating for doctors or genetic counselors to learn about a new condition, we have to realize the families impacted must feel completely lost. Today we're going to talk about one of the rarest of the rare. Not only is this condition rare, it's also only been described in the last several years, so the information out there is very limited. Sheena: The rare disease I'll be introducing you today is called TANGO2. It's our goal to make this episode a first-of-its-kind resource for the TANGO2 community. Rare Disease Connection and our additional resources on raredisease.com and yourdna.com bring together the people whose expertise can explain what you are facing, from diagnosis to prognosis to treatment options all the way to questions like, "Who do I talk to? Where are the people who've been through this before?" You'll find those answers here. From doctors, geneticists, academics, genetic counselors, patient organizations, other patients and their families, all within your reach, we are here to connect you. This is Rare Disease Connection. Sheena: Hey, everyone, this is Sheena, and for this episode I am your guest host of Rare Disease Connection. I'm nearing the end of a summer fellowship with yourdna.com and I'm honored for the opportunity to be involved in this podcast. Today I'm going to bring you conversations with three experts on TANGO2. Before we get started you should know that this podcast is just the beginning. We have taken the information from this podcast and added additional resources, explanations, links and references for you in a downloadable guide. You can get your free copy by going to raredisease.com/tango2. That's raredisease.com/tango2. Sheena: Our first guest today is Dr. Seema Lalani, a clinical geneticist at Texas Children's Hospital, and also a Professor at Baylor College in Medicine. Dr. Lalani was part of a team at Baylor who first characterized TANGO2 in 2016. She's worked directly with patients diagnosed with TANGO2 and continues to focus on research that expands our understanding of the condition. Today Dr. Lalani is on the board of the TANGO2 Research Foundation. Please welcome Dr. Lalani. Sheena: Hi, Dr. Lalani. Thank you for joining us today. Please introduce yourself to our listeners. Dr. Seema Lalani: Hi, Sheena. Thank you so much for this opportunity. My name is Seema Lalani, I'm a clinical geneticist, and I work at Texas Children's Hospital in Houston. I'm a faculty member in the Department of Molecular and Human Genetics at Baylor College of Medicine. As part of my work I routinely see children with rare diseases and TANGO2 is one such rare disease. We have found the cause of TANGO2 disorder in 2016, and it was a collaborative effort at Baylor College of Medicine. There were multiple doctors, scientists involved, and I was fortunate to be part of that effort. Dr. Seema Lalani: So since it was described since 2016, there have been multiple children who now have this diagnosis worldwide. So, how am involved with TANGO2? It is actually on multiple levels, so the first one is, of course, seeing these children in clinic at Texas Children's Hospital. I'm also involved in the research part related to this genetic condition. In addition, I'm also a board member of the TANGO2 Research Foundation, and that foundation was established in 2017 to improve the lives of children with TANGO2 disorder. And my other experience related to TANGO2 is regarding organization of the first family conference in Houston. We did that in summer of 2019, and that was with the support of the PCORI grant, and that first conference was attended by over 100 people from different countries who all came together. Dr. Seema Lalani: Families had the chance to meet each other, doctors had a chance to share what they currently know about this rare disease. There's still a lot we don't know about TANGO2 but we are very committed to working together to find answers for our families. Sheena: Wow, yeah, so you've had a big scope of involvement in TANGO2, and then have really been helping to pioneer some really great research. That's really inspiring to hear about. Dr. Seema Lalani: Thank you. Sheena: So let's start off talking about the clinical aspects of TANGO2. Can you provide our listeners with an overview of how this condition impacts people and what kind of symptoms you see? Dr. Seema Lalani: Yes, of course. This is a rare disease that affects multiple organ systems including brain, heart and skeletal muscles. Children can present with life-threatening episodes of cardiac arrhythmia and muscle breakdown which is called rhabdomyolysis. Children can have acute episodes of crises, and these crises can be described as a state where their blood sugar drops, they have great abnormalities, they have altered mental status, and they end up in the emergency room. Frequently they are in coma when they arrive and often they require intensive care unit admission for managing their cardiac arrhythmia and rhabdomyolysis. And unfortunately some children have passed away during their acute episode. Dr. Seema Lalani: So it is a serious disorder, and children who survive, they continue to have significant health challenges. They can have difficulty walking, slurred speech, they can have seizures, intellectual disability, also hypothyroidism is one medical problem we see with this. And so these children also continue to have this risk of rhabdomyolysis and metabolic and cardiac decompensation which can be life-threatening. Sheena: Do these symptoms change over time, or do they ever go away? Or is it pretty much a life-long condition? Dr. Seema Lalani: It is a life-long condition, and what makes it worse is that you cannot predict if a child will ever develop metabolic crisis or die suddenly from a cardiac cause, so it's really difficult for families. Sheena: I know that this is a rare disorder, but how common is it, or how many cases are there? And do you see it more in certain populations or different areas of the world? Dr. Seema Lalani: As I said earlier, it was such a recently diagnosed condition, so a recent disorder which was... We didn't know anything about it until 2016. So, honestly, we don't know how many families are affected. But through the TANGO2 Research Foundation we are aware of about 100 families worldwide, and some of these families have had multiple children affected. Regarding ethnicity, we've seen that all ethnicities are affected, Europeans and Hispanic populations are more affected because both populations have this common genetic variation that can predispose to TANGO2 disorder. And through the Foundation we are aware of families from Saudi Arabia, Germany, France, Italy, Sweden, Australia, of course USA, Canada, South America, so it affects a lot of children worldwide. Sheena: So let's go a little bit deeper into this. What is actually occurring down at the biological level to cause all of the signs and the symptoms that you see? Dr. Seema Lalani: Good question. So, because it's such a newly-discovered genetic disorder, and like many new conditions, there are several unanswered questions. What causes disease at a cellular level or what treatment would work, how do we prevent the medical concerns. So, we really don't know what causes the life-threatening cardiac arrhythmias and recurrent muscle breakdown in these children, and we don't know how we can prevent them. As of yet there are no established evidence-based studies to propose best medications or supplements or diet that can reduce morbidity in these children. Dr. Seema Lalani: But there is good news. So the TANGO2 Research Foundation has its focus to improve lives of children and young adults, and the foundation has recently funded five research projects, and several of these projects are just focused on understanding the disease mechanism at a cellular level. So we hope that efforts like these will help in understanding the disease better. Sheena: So even though we don't really know what's causing this yet, can you explain what the diagnostic process looks like? How do we know what to test for? And how do we know when a child is affected by this? Dr. Seema Lalani: Many children with TANGO2 disorder were initially identified through exome sequencing. This is a test where approximately 20,000 genes are sequenced in the hope of finding the disease-causing change in the genome. So since its description in 2016 we now know that the disease manifestation can be very specific, and I feel that we have come to a point where we can see a child and just test for TANGO2 as a single gene. For example, if I see a young child in the clinic who has difficulty walking, has slurred speech and has a past history of very high CK level which indicates rhabdomyolysis, and if that child has had cardiac arrhythmia in the past that required hospitalization, I would just test him for a single gene TANGO2. That can be sequencing our Plus deletion testing, and there are commercial labs that can actually do that. Dr. Seema Lalani: And then regarding the diagnosis, there's also one interesting fact about TANGO2 is that the gene is in the critical region of DiGeorge deletion of 22q11 deletion, so children who have DiGeorge already have one copy of TANGO2 missing. So, if the second copy has a mutation in it, then children with the DiGeorge syndrome can also have the manifestation of TANGO2 disorder which would be muscle breakdown, cardiac arrhythmia, that generally are not seen in 22q11 deletion. Sheena: Because we're just learning so much about TANGO2, do you think that there are a lot of undiagnosed cases out there? Dr. Seema Lalani: Yes, definitely. And that's why it's very hard to say how common it is. But we do know that new families are joining the closed Facebook group and contacting the TANGO2 Research Foundation, so, yes, I think, as doctors are more able to recognize TANGO2 I think more children will be getting diagnosed. Sheena: So let's talk a little bit about the research that you've been doing. Can you describe what kind of studies your teams are working on in order to uncover the underlying cause? Dr. Seema Lalani: Yes. I'm very happy to talk about that. Currently we are working with the TANGO2 Research Foundation on TANGO2 natural history study, and what this involves is interviewing and collecting clinical data on a large number of patients to understand the disease better. Which treatment worked in children who had difficulty to control to arrhythmias, for example, what saved their lives? Are there certain supplements that reduced the number of crisis episodes in these children? So natural history study can be a very powerful and guiding treatment because we know so little about the disease mechanism at this point. Dr. Seema Lalani: I work very closely with Christina Miyake who's a cardiologist and she spent countless hours on the natural history study talking with these families, trying to understand the disease better. And we have a research coordinator, Mahshid Azamian, who helps in the recruitment of these families. This work is so important and it would not have been possible without the support of the TANGO2 Research Foundation, and we are very grateful for their effort in making this successful. Sheena: Is there a way for patients and families to get involved in these research efforts? Dr. Seema Lalani: Yes. These families are introduced to the natural history study very early on, as soon as they initiate contact with the foundation, and they have this venue to share stories about their children. Some families, as I said, have unfortunately lost children either from muscle breakdown or from the fatal cardiac arrhythmias or poorly controlled seizures, and these families understand that meaningful data from a large study like natural history study will only come out or be more relevant if the maximum number of children are involved in it, so we are truly grateful to these families for participating in the study. Dr. Seema Lalani: And I mentioned our first conference, Family Conference in 2019, so this conference was patient-driven and parents were asked about their priorities regarding research areas, and what they said was, managing and understanding life-threatening symptoms of TANGO2 was the highest priority for them. Improving quality of life and independence of children, preventing loss of function, was another matter of importance. Then finding ways how to avoid crisis episodes in rhabdomyolysis, studying cellular response to medications, and determining which treatment has the potential to work, These are all important priorities for families. Dr. Seema Lalani: So, after that conference we knew that we needed funding to address these research questions, so the TANGO2 Research Foundation applied for the Chan Zuckerberg Initiative, the CZI grant, and fortunately got funded, so in 2019 they received $450,000 that could help families realize these goals. And this foundation works so fast, so effectively, it started the research proposal call in October 2019 and has successfully funded multiple projects that are so aligned with families' priorities. And you can see the details of these funded research projects on their website, tango2research.org. One funded project, for example, aims to study the pathophysiology of TANGO2 disease in zebrafish model, and there are other studies that are looking for mitochondrial function and disruption of membrane trafficking in mutant cells. Dr. Seema Lalani: There is another project that's looking at metabolomic profile in skin fibroblast of children and it's interesting that these fibroblasts are coming from children who participated in the conference last year and the families opted to get skin biopsy on their children. So, all of this is going to come back to them. Hopefully, we want the awardees to give the data back to these families which hopefully we can do in the next conference. So, yes, I think we are very fortunate to have those, the strong patient-centered community and have prioritized this research that is really important for these families. Sheena: Great, yes. And we will include a link to the TANGO2 Research Foundation in the patient guide that goes along with this episode, so if anybody wants to check it out or get involved, that information will be available there. Dr. Seema Lalani: Great. Sheena: Okay. So, we are getting close to the end of our time but I just wanted to have a closing statement. So, if you could leave our listeners with a final message about TANGO2, what would that be? Dr. Seema Lalani: Oh, yes, definitely. So, rare disease families can move mountains. I have learned so much from these families and I've been very, very fortunate to be involved with them. I've rarely witnessed such a model where patient-selected research goals could be translated so effectively into active projects and this is through collaboration, fund raising, family and community outreach. I feel that there is nothing that these parents cannot do. So, I'm just very grateful to be part of their story. Sheena: Yes, that's really inspiring. So, it's been great having you as a guest today, Dr. Lalani. Thank you so much for speaking with us. Sheena: Our next guest today is a pediatric physical therapist. Jayme Gilmore received her doctorate in Physical Therapy from Eastern Washington University. Throughout her career she's worked with adults and children with a variety of orthopedic, neurological, general surgical and cardiac conditions. Jayme has worked directly with TANGO2 patients and has a wealth of knowledge about the practical aspect of helping these children succeed. Please welcome, Jayme Gilmore. Sheena: Hi, Jayme, thank you for joining us today. Please introduce yourself to our listeners and tell us a little bit about your background. Jayme Gilmore: Hi, yeah, thanks for having me. As you said, my name is Jayme Gilmore. I graduated with my doctorate in Physical Therapy in 2015 from Eastern Washington University in Spokane, Washington. I grew up in a small town in Central Washington, in Yakima. Had a couple of high school injuries which brought me to PT which initially made me consider it a profession. Ended up going to Seattle Pacific University, got my undergraduate degree in Biology with the emphasis on human anatomy, and it wasn't until college that pediatrics came into my passion, I guess you could say. Jayme Gilmore: I went on a physical therapy related mission trip to Costa Rica in Nicaragua, and that solidified my love for pediatrics within this field. We got to work with a ton of just overlooked kids with disabilities that had physical disabilities but had the most beautiful personalities and hearts. Some were abandoned, living in homes of 100 kids, whether they had genetic syndromes, whether they were disabled due to abuse, whether they were in severe accidents and their families couldn't care for them, so I went to PT school after that no longer wanting to be an outpatient therapist for athletes and wanting to more specialize in acute therapy meaning right after an injury in the hospital, and then specifically down the road I knew I would always get into pediatrics. Jayme Gilmore: So I started my career at Sacred Heart Medical Center in Spokane, primarily hired as an adult acute care therapist, but also cross-trained in pediatrics. It was two years after that that I moved over to Stepping Stones and pursued pediatrics full-time. And so, I've been here for three years and it's just a special place to be, part of families as we grow together, develop together and help them to meet some of their milestones that are a little more challenging for kids with disabilities to meet. Sheena: Wow, very interesting background that have led you to where you are today. I love that. Jayme Gilmore: Yeah. Sheena: So, can you tell us a little bit about your first experience with TANGO2? Jayme Gilmore: Yeah. My first experience with TANGO2 was my first week at Stepping Stones. That was July of 2017, where I met my two friends, Danny and McKenna. Danny was a couple of months from turning three-years-old at the time, McKenna was just over 15-months-old. Danny was ambulatory already when I started to work with him. He was struggling with surface changes, stairs, standing on one leg. A year later we were working on jumping, riding a tricycle, ball play, throwing and kicking a ball to enhance family and peer interactions. When I first started working here and first met McKenna, her main means of locomotion were rocking on her knees. She was having a substantial number of drop seizures which were increasing the longer that I worked with her. Jayme Gilmore: So that really eliminated safety, her independence and progression of milestones. We never knew when another drop seizure would come, and therefore interrupt her mobility, interrupt her play, and interrupt her confidence. And so she tolerated very little vestibular and put on swings. She was able to stand independently on her own up to 10 seconds at that point, but we did see a regression in that because the uncontrolled seizures. There is a point when the EEG caught 300 seizures in a 30-minute period, and so she was limited in safety, constantly dropping down when we would work on different skills. Jayme Gilmore: So we used specific tools to help her further progress motor skills but really it was the medication change that helped us. So, neurology and metabolics were going back and forth, whether which medications were appropriate for her. All the ones that they had tried were not working previously. They finally tried a medication that Metabolics was unsure about based on the liver function, but neurology ended up kind of winning out based on her function and how much it was impairing her quality of life and any sort of progression towards walking on her own. So, that new medication was probably like summer of 2018. In November of 2018 she had her first normal EEG for a 45-minute period, and then all of a sudden just took off, which was so cool to witness. Jayme Gilmore: She started ambulating with the use of a grocery cart for 50 feet. She was able to ambulate with just minimal assist from me for up to 15 feet prior to losing her balance. At the end of November, just a month later, she was taking up to 11 steps independently. By December she was ambulating independently, rising to stand in the middle of the floor on her own. Really took off and that just reiterated the importance of the medical team and therapy team communicating together to regulate systems. If we wouldn't have regulated procedures I anticipate we probably would have continued to see regression rather than her great progression as soon as we got the seizures regulated. Jayme Gilmore: And I do understand that not all kids with TANGO2 are able to sit or are able to walk. Danny and McKenna both can, and so now we're working on more higher level balance and coordination skills, but they did have an older brother who has passed. I never got to work with him or meet him. But he was wheelchair dependent, so there are different ranges of skills there and different severities of the illnesses. But Danny and McKenna are my primary resource to TANGO2. Sheena: Wow. It sounds like there's really a lot that goes into treating these patients, it's not just you show up for a physical therapy session and do some exercises and then leave. They really have a lot of planning that goes into this with a solid team of medical professionals. Jayme Gilmore: Right. Yeah. I mean, Danny and McKenna go to Seattle Children's frequently with a huge team over there that really look at whole body care which is so important with a genetic syndrome to make sure that they're getting everything that they need. Sheena: I'm curious. Are these therapy methods and the things that you're doing, are these specific to TANGO2 or do these have a broader application to other types of patients? Jayme Gilmore: I would definitely say they have a broader application. We do use them with TANGO2 and we do use specific pieces of equipment that I can explain that we use for McKenna to progress her specifically, but I mean these have applications for a variety of patients regardless of diagnosis or syndrome. More specifically, for McKenna, she was a little later to weight-bearing through her feet because of all of her seizures, and so there was a part of us that didn't want to train her to weight-bear through her feet because of her constant drop seizures. So we didn't want her to be higher off the ground for safety, so walking on her knees, a drop seizure then, a lower amount of space to cover before she hits the ground. Jayme Gilmore: And so she was later, in weight-bearing through her feet until her seizures were managed, and in order to help her then progress once she did start to learn to stand on her own, we used orthotics. So, specifically for McKenna, we used supramalleolar orthosis. The abbreviation is SMO, S-M-O, and they helped her significantly progress in her weight-bearing activity and independent upright mobility. What they do is really improve the ankle in the foot, or the distal alignment of the lower extremity, to provide a more stable base to rely on for a dynamic movement for that independent ambulation. Jayme Gilmore: We really like to use these with a lot of kids, not just with TANGO2, but both Danny and McKenna tend to demonstrate some midfoot pronation and calcaneal eversion of the foot which then impairs balance and ability to activate their more proximal muscles in their hips, their knees, their core, all because of that distal alignment, what's happening at the foot and the ankle. So the knees tend to bow in a little bit with this posture nearly touching each other in a position we call genu valgum, and that changes the position. You have a femur in the acetabulum and so forth. So we really do like to give them a stable base of their feet so that they can activate more appropriate muscles, approximately, and therefore progress their motor skills. Jayme Gilmore: Another piece of equipment or tool that we use with McKenna because of all of her seizures was the Danmar Soft Shell Protective Helmet. We modified it a little bit for her because she seems to go forward with her drop seizures a lot, so in order to protect her from extreme cervical extension and worry of spinal cord injury after a drop seizure, we did have our local orthotist, Adam, add some things on the helmet in order to protect her from further injury with her drop seizures, but ultimately, our main goal is to protect the head when she is dropping so much. So that's definitely something to look into. McKenna also really [inaudible 00:27:07] from a Rifton gait trainer to help with her independent ambulation prior to having that postural control or stability to do it on her own. So this piece of equipment is a walker but it also has a chest harness and a pelvic harness to help develop that control prior to having it on their own. Jayme Gilmore: We used it a lot in therapy to activate this reflex of stepping pattern or the central pattern generator that we all have in our brains and just a biological neural circuit that produces rhythmic outputs despite the absence of the input there. So when one extremity extends, the brain tells the other one to flex and then opposite happens too when the opposite extremity extends, the one flex. And so she is given the chest support so that she doesn't have to do all of the postural control on her own while her brain is starting to learn what a walking pattern feels like. That was really helpful for McKenna to learn to walk on her own, and also kept her safe when she was having the seizures. Having her chest in a pelvic harness allows her to weight-bear through her feet but also prevent the injury from dropping so close to the ground because those harnesses are helping to hold her upright. Jayme Gilmore: Other pieces of equipment we use, just any sort of equipment or play structures that generally promote more flexor activation rather than extensor activation. So kids all develop their extensor muscles first, but especially when kiddos have feeding difficulties and G-tubes which we often see in kids with TANGO2 based on their energy that's required for digestion. So, then, these extensor motor patterns become dominant and really preferred. They seem to have difficulty activating their flexor muscles, their pectoral muscles for reaching for a toy, their abdominals for a postural control, or rolling or climbing. So any pieces of equipment that allow them to practice climbing with more of a forward lean like a ladder to a slide, any peanut balls to activate their core and to maintain an upright posture with less mass to manage, trampolines to balance out the flexor-extensor muscle imbalances of the lower extremities. Jayme Gilmore: The other thing that I've used on both of them is a Rifton adaptive tricycles. These are super helpful, cool pieces of equipment that help the kiddos to learn reciprocal motion. So, bilateral coordination and the ability for one extremity to affect what the other extremity is doing. It's a wider base tricycle with a pulley system for the feet to make it easier to propel. There are straps to hold the feet on the pedals, so straps on the pedals. Has a lower center of gravity for safety and a low gear ratio to make pedaling easier, so they get to learn that their right leg can affect what their left is doing, that reciprocal motion, bilateral coordination, and it's a social tool. If they can ride a tricycle they can play with other peers in a different way. Jayme Gilmore: So, those are some of the tools that we've used for Danny and McKenna. I know that if a kiddo is not able to ambulate and they're wheelchair dependent, it's really important to get a lightweight wheelchair to make it easier on mom and dad. It's really important to have a good seating system in there to make sure that there is a good cushion for lack of skin breakdown. We don't want any bedsores or anything if they can't stand up or walk on their own, so that's really important. And then, the other thing that we found helpful was the P-Pod seating system that can be helpful to keep kids safe, especially with seizures, while allowing them to sit more upright, more independent, and still be part of their family and community. Jayme Gilmore: So those are all different tools that we've used in TANGO2 and also the different tools that, I mean, really can be used for a variety of diagnoses or syndromes, not necessarily specific to TANGO2 but are definitely helpful in the management and the therapy of this diagnosis. Sheena: Yeah. It's great to know that there are so many tools out there specifically for children that need this kind of assistance to really make it easier to get them to their fullest potential. So, I know that every kid is different, but based on what you've seen and what you know, what kind of improvements do we hope to get to, and what is the ultimate angle? Jayme Gilmore: Yeah, I think that every child is different, the severity of the syndrome definitely matters and definitely impacts the route or the trajectory that we're looking at. We do hope to see continued progression in gross motor skills despite their genetic syndrome. We know that that progression will look different for each kid but we do hope that we always are making improvements for the child for their quality of life, for their mobility, for their independence. We know there will always be a delay. We know that they rely on different motor patterns to accomplish the same motor tasks as some kids, but we do hope to see continued progress and skills, just at a different pace. Jayme Gilmore: Danny and McKenna both walk, they both run. I struggle to catch up with them a lot. They both jump, they kick a ball on command, they throw a ball, intentional release can be somewhat tricky, but they both can throw a ball. Danny has a very fierce throw. McKenna has a little bit harder with that intentional release of a ball. But riding a tricycle, riding a bicycle with training wheels are still difficult for both of them, especially with the added cognitive component of turning and maneuvering around obstacles. But, they're both making consistent progress and that's ideally what we want to see, is consistent progress even if that rate of progress looks different for each child. Sheena: Yeah. You had mentioned medication changes earlier for McKenna that really helped her get through physical therapy in the best way. So I'm curious, are there other types of therapy that you've seen really compliment the work that you're doing? Jayme Gilmore: Yeah. I work really closely with both occupational therapists and speech and language pathologists, and specifically in these two cases, they have been really incremental in their continued gross motor progress. Their receptive and expressive communication has improved greatly. If they can't understand a command to jump or run or pick up a ball, kick a ball, stand on one leg, it's really hard to advance higher level balance and coordination skills more typical of their age. If they can't understand stop when they are continuing on in an activity that may become unsafe because of lack of environmental awareness, we have an issue. So, speech has been really important for them to understand commands, to then progress skills, but also to start to express their own wants and needs. Jayme Gilmore: And then, occupational therapy, they address body and environmental awareness, sensory input to regulate systems, more specific attention span and fine motor work, work on cognition and multi-tasking, and so I attempt to strengthen the big muscles while they are working on more of that fine motor work that's still important for a child to color, to do a puzzle, to play with toys, to drop something into a container when needed. As a PT I want to teach them to use their body to run, jump off things, climb on toys and surfaces, but we also have to keep them safe. So, occupational therapy is there to address body awareness, environmental awareness, the cognitive aspects to know how and when to keep themselves safe. Jayme Gilmore: And so us as a team of therapists seeing them on a weekly basis, we can pick up on different behaviors and mannerisms that we're seeing and we're sometimes able to give words to parents who are immersed in it all day long. So, we can then help to brainstorm how to address those certain behaviors. He may not be running away from parents just because he doesn't know better or hear, but it can be that term, "Come here," that immediately activates into, "Oh, this is now a game." And so, are there different words that we could use in order to keep him safe instead of running out into the street. So just putting different words to behaviors that are unsafe for children. Parents sometimes they're immersed in it all day, every day, and so it's sometimes harder to step back and adjust behaviors or wording to get a specific response. Jayme Gilmore: Which finally brings me to mental health counseling. We have two mental health counselors on staff here and I think that's huge for families as they adjust to a different normal and help to manage some behaviors. It really helps to get parents different coping strategies or play strategies, behavioral management, when the typical time-out, or the typical addressing of behavior doesn't work. Parents coping with the challenges that a genetic syndrome can bring allows for a changed family unit, a changed family dynamic, hopefully in a positive way, and so we find that having mental health counseling can help the family as a whole, as they learn more and more about how a genetic syndrome can affect their life. Sheena: Right. So definitely needing a big team of people to work together is how we're going to be successful. So, kind of reaching the end of our time here, so in closing, Jayme, I'm curious what advice you have for a family who wants to start their children on physical therapy but they don't know to pick a therapist or how to find the right one. What can they do? Jayme Gilmore: Sure. Well, in order to start with physical therapy, we need a referral from a doctor, and so hopefully you have a good relationship with your primary care physician or a specialist physician, and they can start that process for you and lead you in the right direction for picking a clinic and maybe more specifically a therapist. It's usually easiest to pick a clinic closest to your home for proximity and ease knowing that you could be coming multiple times a week for a couple of different therapies, but asking a doctor what they have heard about pediatric clinics in the area can be really helpful. Jayme Gilmore: Usually they can lead you in the right direction to start. Every therapy clinic should also have a website, so looking at their website, looking at the team of professionals can be really helpful, but ultimately I think it's important to know that it's always your choice as a parent to advocate for your child, and if something doesn't seem to be working for one reason or another, it's okay to ask for a different therapist. It's important to have a team of therapists behind you and your children who want the best for them. If you aren't being heard, consulted on your goals for your child, seeing progress, it is okay to attempt to process why and ask for a change. Sometimes a new therapist can be helpful for a new pair of eyes and fresh ideas, even if things are going extremely well. Jayme Gilmore: I think ultimately looking for some guidance from your primary care physician or another physician can be helpful, but then knowing that you have the power of advocacy for your child to fight for them and to continue to promote change for them through their therapy team, so if something doesn't feel right it's always okay to ask. Sheena: Great. Well, thank you so much, Jayme. This has been really fascinating, and it's really such a helpful and practical topic to share with families and parents who are affected. So, we really appreciate your time today. Sheena: Our final guest today is Lindsey Messerschmidt, a licensed speech pathologist. Lindsey is a mom of three children born with TANGO2. She has worked tirelessly to understand and diagnose their conditions and find the best forms of therapy and treatment for them. Lindsey is active in the TANGO2 community and has worked to co-found a Parent Support Committee. Please welcome Lindsey. Sheena: Hi, Lindsey, thank you so much for joining us today. Please introduce yourself to our listeners. Lindsey Messerschmidt: Hi, there. My name is Lindsey Messerschmidt. I live in Spokane, Washington, with my husband, Brad, and our two children, with a very rare disease called TANGO2 disease. Our son Daniel is five and McKenna is four, our daughter, and we also had another son named Jackson who passed away at the age of three in 2015 from TANGO2 disease. I am a licensed speech language pathologist but I'm currently working as a family resource coordinator for families with children with developmental delays. My husband is working as a financial advisor. His job is really flexible so that's really, really nice having medically complex kids. Sheena: Yeah. Can you tell me a little bit more about your children? What are they like, what kind of thing that they do, what are their hobbies? Lindsey Messerschmidt: Sure. So, as I have said, I have three children with TANGO2 disease. All three of my children have been affected differently, yet they do have really similar symptoms, and Jackson was just really severely affected and his disease progressed very quickly. And so, sometimes the way I would describe when I'm talking with someone what TANGO2 is like, is that it's kind of similar to ALS or Lou Gehrig's disease, except for, with ALS there's this very steep slope of disease progression, and in TANGO2 disease I would say the progression is not as steep and that it's more of this kind of gradual up and down trajectory with, of course, this general decline throughout life. Lindsey Messerschmidt: And so what's different about Jackson from my other kids is that his disease progression was just so fast. We don't know why and we may never know why, but he was born healthy, so to speak, and he began with symptoms around two to four months of life, and by the time he was one-years-old he was unable to hold his head up, he was unable to roll over, he was unable to sit, he had catastrophic seizures, he had severe gastroparesis, he had a lot of feeding issues with a feeding tube, and over the course of MRIs you could see substantial cerebral volume loss. Lindsey Messerschmidt: So, there's a million medical terms that I could use to describe him, but he was so much more than that. He had these piercing beautiful blue eyes and quite the presence about him. He loved music. His favorite book was Gertrude McFuzz by Dr. Seuss, and because he couldn't really move well he was confined to wheelchairs and different seating devices, but he loved to be held, he loved to be rocked in a rocking chair. One thing that all people who met him or saw him, one thing they would say is that just how happy he was, and this was really true, but just below this was a little boy who was suffering really severe pain and we couldn't figure out why. Lindsey Messerschmidt: I remember one time a nurse came in, Jackson was in the hospital, and she had to document what number on the pain scale, you know, where did we think he was at? And he had quite a bit of pain meds on board at that time and we couldn't even answer the question. We were trying to console him and she just had to look away because she was starting to cry seeing him in that much pain and not being able to help him. So, by the time he passed away in 2015 at the age of three, we had no diagnosis. Talking about Jackson is so much different than talking about Danny and McKenna. Although Danny and McKenna have similar symptoms, the severity is just not near as much as Jackson experienced. Lindsey Messerschmidt: Danny and McKenna, they both have epilepsy, they both have eating tubes, they both have developmental delays and they really struggle to communicate and talk, but they run, they play, they jump, they climb, and Danny, he's really interested in lawn tools, especially the lawnmower. He wants to mow the lawn every day, all the time, and he's really motivated by that, and he's really kind of funny. McKenna, on the flip side, she's really interested in cleaning everything and she's got a little spray bottle that she carries around with her and a rag and she's scrubbing things all... She's always trying to clean and she really loves taking care of her baby dolls. She's very nurturing. Lindsey Messerschmidt: I would say both of my kids are and they're both just so social, and talking with other TANGO2 families it's kind of a theme among all of the kids is that they're really social, they're very happy, they have a lot of joy. And especially for Danny and McKenna, not so much Jackson, but you might look at them and not really immediately even realize that anything is wrong. And even if you did realize, "Oh, they're developmentally delayed, something's off," you certainly wouldn't realize or be able to see that they're living with this fatal condition called TANGO2. Sheena: So can you tell me a little bit about what the diagnosis process was like? At what point in their lives did you realize that things weren't going quite as planned? I know with Jackson you described how... That was much earlier, but for McKenna and Danny, was it that same time frame, or how did that look? Lindsey Messerschmidt: I would say for all three kids, their first symptoms were overall different in severity, but it really... I think that they were there, just in different degrees around the same time. I think some of that I've realized looking back, but just in my educational background I have some experience in early childhood development. So I always joke with the kids' specialist that I know just enough to really scare myself, something's really wrong. I can spot a symptom and be like, "Huh, that's really a neurological symptom," and be like, "That's really weird." But then it's followed by panic, like, "Well, what does that mean? And why are they doing that?" Lindsey Messerschmidt: With Jackson, I would say, though, that I knew almost right away. I mean, I just knew something's off. Something was just weird. I had that weird gut feeling. I just knew something wasn't right, and if you talk to my husband, at that point was kind of thinking I was crazy, actually, because I just... Like, "Something just doesn't feel right here." Where with my other two children it was a lot more gradual and maybe by the time there was truly obviously something wrong, they were probably closer to one. So, there was like three different symptoms that I really noticed, and it was right around, I would say, two to five months of age. Lindsey Messerschmidt: There was, in all of the kids, kind of this sudden onset, gastrointestinal symptoms. It was like sudden onset acid reflux, and right about that time they also started having trouble feeding. It was like they would be drinking fine and then all of a sudden they would fatigue and just stop, but they weren't satisfied. So, that really concerned me, but acid reflux is a super common symptom in infants, so we take our kids to the pediatrician and switch bottles, formulas, try medications. But it was like nothing worked and if anything it just seemed like they were getting worse. So that's kind of that first symptom. And I would say the second early symptom that I really noticed was that their muscles... It was with their muscles and coordination. Lindsey Messerschmidt: So, sometimes around six to 12 months it was... became apparent. Some days they would appear really coordinated, they'd be holding their heads up, rolling over, moving normally, as I would describe it. And this would be followed by days on end where we wouldn't see them roll over, we wouldn't notice that they were looking around as much, their head control just wasn't as good as it had been days prior. And so, that was really difficult for us to document as parents, and it was difficult for us to communicate it with pediatricians because the symptoms were so fleeting. We would rush them to the pediatrician, we'd be like, "Oh, they're not really... Something's wrong. They're not holding their head up." And it would just vanish. They'd be back to baseline. Lindsey Messerschmidt: And so pediatricians would just really be like, "You know, it could just be really you're worried, first time parents. Maybe..." They weren't as concerned, but of course as they got older it just became more and more apparent. I would say the third thing that we noticed was just weird neurological abnormalities. Sometimes they would experience nystagmus. Out of nowhere their eyes would kind of look like they were dancing. And you can imagine a parent taking their kid to the pediatrician. Like I had enough background knowledge to... I've heard the word nystagmus, but to see it in my own kid, I'm telling them like, "Oh, their eyes are dancing." And by the time they look, the nystagmus has essentially resolved, so looking at me, and they're like, "Oh, we don't really see..." Lindsey Messerschmidt: So it was just like really little odd things, and the other neurological thing that Danny, McKenna and Jackson all experienced a seizure by the time they were 15 months of age. Very different epilepsy types, very different levels of severity, but they all had a seizure by the time they were 15 months of age. Sheena: Now at what point in time did the TANGO2 name get introduced to you, and when did that get attached to your children? Lindsey Messerschmidt: We started the whole quest for a diagnosis in early 2012 when Jackson started showing symptoms. We did various panels based on his symptoms which eventually led us to whole exome sequencing, and I believe the first time that was completed was in 2012. But in 2012 TANGO2 disease wasn't even recognized as a disease yet, so nothing popped up on any of the whole exome sequencing that was completed. Lindsey Messerschmidt: We had it done, whole exome sequencing completed done, I think we had it done four times, and the fourth time happened to be in 2016. And luckily we had started the process just after... I mean, like two months after TANGO2 disease was recognized. So, thankfully, in 2016 we did get our answer in September, that all three kids have this rare disease called TANGO2 disease. Sheena: I'm curious, in your second pregnancy and your third pregnancy, were you expecting that your children would be born with the same type of condition as the previous ones? Or were you given any risk information from your doctors? Lindsey Messerschmidt: It really varied. In Jackson, the tricky part about us was Jackson, and he was this medical mystery. And so there were doctors that were like, "This is one in a million. We've never seen anything like this. I don't think this is going to happen again." And they were more encouraging just because all of the genetic testing had been coming back normal. But then, there was one doctor in particular who is the kids' neurologist today, and he was like, "This just looks like a mitochondrial disease. This looks recessive. I worry that there's a 25% chance that this could happen again." Lindsey Messerschmidt: And so, it was kind of a crazy time because we had decided to have another child, so we had Daniel, and we had Jackson, and then Jackson passed away. Danny was four months of age at that time, and he was nearing one years of age and I had taken Danny to Jackson's neurologist, and I was like, "Look at him. What do you think? Is he... What would you say on this? We're thinking about having another child, but what do you think about Danny?" And at that time, from a neurological perspective, Danny passed. He looks very typical. I mean, at this stage, Jackson was much more severe. "He looks really healthy, just hopefully I'll never see you again, but check back in six months if you have concerns." Lindsey Messerschmidt: So we decided, "Okay, let's have one more kid and be done with it." And literally I was eight weeks pregnant with McKenna and Danny had his first seizure. And so we were like, "Oh, no." It was just a tough situation, and it's hard to grasp that it can happen again, as a parent, and even if you logically know that, if you're not given a definitive diagnosis, it makes it really hard to start family planning. Sheena: Yeah. So, Lindsey, I mean, this sounds like this has really been difficult on you and your husband and your family. And so, I'm wondering, where do you turn for support? How did you manage all of this for you, specifically? Lindsey Messerschmidt: Yeah. Life is really interesting with having children with a rare disease like TANGO2. Our life revolves around it, and the disease symptoms kind of guide us on how we're going to live our life. So, my husband has been very supportive and hopefully I've been supportive for him as well, but he's really helped me through some really tough times and we have really supportive families. We have amazing friends that help us through, and even with that, I would say that no one really understands the way that Brad and I understand it. And so, I would say, getting the diagnosis alone was hugely helpful and I was able to join a Facebook group for TANGO2 families. And through that I've been able to connect with other TANGO2 families. Lindsey Messerschmidt: They're experiencing the exact same things I am. It was like joining a new family. My husband and I, we feel like we belong now and being truly related, it feels like a true family. So, yeah, we ask questions, we get support from these families, and we don't really have to explain ourselves, they just get it. They just understand what that's like. Sheena: It's my understanding that you've been able to do a lot of community involvement and advocacy work with the TANGO2 community. Can you tell me a little bit about what type of work you do, and then also, how you got involved with that? Lindsey Messerschmidt: Yeah. The TANGO2 community is really amazing. I mean, for a disease that was just found in 2016, a lot came from a simple Facebook group, and my good friend, Veronica, she's a TANGO2 parent, she started this Facebook group and there was like nine families in it to begin with. Eventually, one day, a couple joined and their son had just been diagnosed. They're from Connecticut, their names are Mike and Kasha Morris. They have a son named Ryan, and they connected with several parents within this TANGO2 Facebook group, and we rallied together and we were interested in serving on a board of directors if they were going to start a nonprofit foundation. Lindsey Messerschmidt: And so, in 2018, after a lot of hard work on their part, the TANGO2 Research Foundation was officially born. Another key part to the story of the TANGO2 community and the TANGO2 Research Foundation is amazing doctors from around the world who really care deeply about helping TANGO2 children and adults. Two doctors stick out in my mind. Dr. Seema Lalani and Dr. Christina Miyake, and these are doctors... Dr. Seema Lalani is a geneticist and Dr. Christina Miyake is a cardiologist. They work at Baylor College of Medicine, and Dr. Seema Lalani actually found the disease. Dr. Miyake is a cardiologist who has... She works tirelessly to help TANGO2 families. Lindsey Messerschmidt: And Seema's also at every single board meeting, which is amazing. It just really speaks to these doctors' dedication and involvement to the cause. We wouldn't be able to accomplish what we have without them. So, where I kind of fit into this, I was a really passionate parent and I knew that I wanted to help but it was hard for me to figure out where I fit in, and a couple... I think it was almost two years ago now, myself and a few other TANGO2 moms got together and we formed a Family Support Committee for the foundation. It's just helpful for us to be able to... We had each other. When we first got our diagnosis we connected fairly quickly and we want to replicate that and we want other TANGO2 families to feel like they have somewhere to go, and we want them to feel like there's some resources out there that can help them. We just want them to not feel alone. Sheena: Yeah. That's really impressive work. So, in our last couple of minutes here, I just have one final closing thought that I'd like to get from you. If you could go back in time, what is something that you wish you knew about TANGO2 that would have been helpful for you and your family, back in the beginning? Lindsey Messerschmidt: Yeah. I would say that a really helpful piece of information we received through getting a TANGO2 diagnosis is that the kids can't fast, especially during illness, and fasting during illness has been linked with hypoglycemia, metabolic cirrhosis, life-threatening cardiac arrhythmias, so thankfully my children, they haven't had this problem yet, but with this diagnosis it's always going to be a risk. And with this little simple piece of information we can... It might not work every time, but we know, if they're sick and they're not eating and they're not drinking, they need to go to the hospital. They can get simple IV fluids with dextrose. They can be monitored closely, and once they're able to either tolerate their tube feeds or eat and drink some, we can leave the hospital, hopefully, having prevented any major crisis. Sheena: Yeah, yeah, it sounds like really important information to know how to manage them properly to avoid any of those more severe symptoms coming up. That's great advice. Lindsey, your story is really powerful and I am so thankful that you were able to share this with us today. So, thank you again for your time. It's been really great talking with you. Sheena: I know our guests were so honored to be able to share information about TANGO2 with all of you. We were fortunate to talk to three experts today in TANGO2, but this is just the beginning. We have taken all of today's information and included it in a free downloadable guide. You can get your free copy by going to raredisease.com/tango2. We would love to connect with you. Sheena: If you need to talk to someone, we are standing by. Go to raredisease.com/help. We are waiting for you. Rare Disease Connection is a production of Aspect Health and raredisease.com. Thanks for joining us.

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