TANGO2 Deficiency Disorder and Constipation/Ileus

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Robin and Bob Mitchell

INTRODUCTION

Our daughter Hanna was diagnosed with TDD in 2022 via whole genome sequencing (WGS) when she was 27 years old. The diagnosis occurred when she experienced a life-threatening metabolic crisis that was provoked in part by severe constipation and an ileus (i.e., when the intestines cannot push out waste).

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Hanna’s 27-year diagnostic journey started at age two when she began to experience a variety of “unexplained” challenges including:

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• Developmental delay, cognitive impairment, speech and language impairment
• Episodes of ataxia, drooling, slurred speech
• Amblyopia (lazy eye)
• Hypothyroidism
• Tonic-clonic seizures

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MAINTENANCE

Over the past two years since the metabolic crisis and TDD diagnosis, Hanna has been spell-free, we think contributing factors are:

• Avoiding constipation - in addition to the Miralax and Senokot, Hanna is careful to always get good daily hydration, eats fiber-rich foods and gets daily exercise (walking).
• B Vitamins and mitochondrial cocktail - Hanna has been taking a twice daily dose of a mitochondrial cocktail that includes Vitamin B1, B2, B5, and B9, Ubiquinol, Vitamin E and Creatine.

The metabolic crisis that led to her TDD diagnosis, was the unfortunate culmination of two months of poor health characterized primarily by the reappearance of spells of ataxia, episodic muscle weakness, drooling and garbled speech after many years of being “spell-free”.

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In addition to the reappearance of the “spells,” she was experiencing a non-specific feeling of being uncomfortable, sick and very unhappy. We now realize that her discomfort was related to symptoms of severe constipation (and possibly an ileus) she had probably been experiencing for months: fullness in her stomach that led to eating only bites of her meals, extreme discomfort, backache, and nausea.

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INTERVENTION

QUALITY OF LIFE

Hanna has a joyful quality of life! She enjoys her family, Special Olympics, Therapeutic Recreation, volunteering with her vocational day program staff, and her job selling concessions at a local park. She is a sister, cousin, granddaughter, and niece.

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We are grateful to the TANGO2 Research Foundation for helping guide us through our TANGO2 journey!

Finally, after two months of episodic spells and severe constipation, she experienced a metabolic crisis that resulted in 11 days in the neurology Intensive Care Unit (ICU) and a total of 56 days in the hospital. Ultimately the constipation and an ileus were confirmed and addressed. Whole Exome Genome Sequencing confirmed a TANGO2 diagnosis.

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Her providers recommended daily use of Miralax (polyethylene glycol) and Senokot (docusate sodium). Both are laxatives and stool softeners, which help to prevent constipation.

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My Victory: The Long, Hard Road to a Diploma

Jamie and Oliver Angus

My educational journey included a total of 9 public & private schools in 3 School Districts in Los Angeles & New York.

BACKGROUND

Oliver has endured, persevered, and ultimately found success throughout his winding educational road as a Tango2 child. The constant search for the right educational and social “fit” has been exhausting and rewarding. With each move and transition, we wondered if the next school or program would provide opportunities or challenges. As a medically fragile student, schools have not always understood how to support him, and Oliver wasn’t diagnosed with Tango2 until middle school. Throughout his journey, he has had to shorten his school days or miss them altogether due to fatigue or sickness.

His resilience is a story of hope!

INTERVENTION

MAINTENANCE

QUALITY OF LIFE

CONCLUSIONS

PHOTOS

SCHOOLS

When Oliver was 3 years old, he experienced a 6-month energy crisis. During this time, a mitochondrial geneticist suggested that we try the mitochondrial cocktail (CoQ10 and Carnitine). Fortunately for Oliver, the brand of liquid carnitine we bought also contained B5 (Pantothenic Acid), which people with Tango2 cannot produce on their own. We believe the cocktail and B5 have had positive effects on his cognition and health, but even with it there have been academic struggles.

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Oliver has always been classified as a special education student, receiving additional support at school, but many times it wasn't enough. He also needed outside speech, occupational, and vision therapy interventions for several years after school hours. Ironically, our special needs son with energy deficits attended a full day of school and up to 5 hours a week for speech, OT and vision therapy sessions. We do think they made a difference.

Navigating the challenges of school and puberty have been tough as we tried to maintain Oliver's energy, especially during the middle and high school years. Maintaining supplements or increasing them as needed have been critical as well as maintaining friendships and social supports when his energy has flagged. 

It has been a struggle to maintain quality of life during different phases of Oliver’s educational journey. During the early years and in middle school, Oliver could only attend school for ½ days, which is typical for students with mitochondrial dysfunction. As the academic and social demands increased in high school, he had difficulty keeping up. The physical demands of navigating the campus and the pressure to perform academically at a level with typical peers weighed on Oliver. During his Senior year, he moved to a private school with a smaller environment. He has thrived there, and he now remembers that learning can be fun, positive, and challenging.

Having completed this hard, long educational and winding road, he did it! We couldn’t be prouder of our son for graduating and receiving his high school diploma in June 2024.

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Preschools:

• Private Preschool Los Angeles – Experienced anxiety and instant-onset fatigue. Several visits to ER. Initiated IEP with large school district. Only attended for a few months due to the identification of Oliver’s special needs.
• Public Special Ed Pre-School – 2-hour program from Monday-Friday – Experienced fatigue & would fall into my arms at conclusion of the program. A stroller was used for drop-offs and pick-ups to conserve his energy and prevent cramps.

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Elementary Schools:

• Private General Ed Pre-K Program in Los Angeles – Attended for ½ days initially and built-up stamina to full days. Had a 1:1 support staff to provide academic & social support and report medical issues.
• Private Special Education School in New York – Small therapeutic school, providing academics, speech, OT and social skills for a full day of school. Partially funded by NY State Ed Department.
• Private Special Education School in Los Angeles – Small therapeutic school which provided speech, OT therapies and academic interventions during the day. This environment was beneficial for therapies, but light on academics.
• Public Elementary School – Small elementary school environment with one Special Day class with specialized academic instruction– Intensive (SAI-Intensive). Special education with general education inclusion for part of the day.

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Middle School:

• Large Public Middle School (1,200 students) – Attended SAI-Intensive, Specialized Academic Instruction (special ed teacher) and general ed classes. During puberty, had several months of extreme fatigue & attended only ½ days.

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High Schools:

• Large Public High School (2,800 students) – . Due to Covid, the end of 8^th grade & 9^th were completely online. Attended SAI Intensive (diploma track), collaborative classes with both general education and a special education teacher & general education classes. An extreme fatigue episode in Junior year led to a 5-week absence.
• Small alternative campus for Fall Semester (Senior Year) – Attended a small campus, but lost special education support, peers, electives. Oliver expected to self-teach via an online program and no direct academic teaching occurred.
• Small Private School (125 students) for Spring Semester – Attended in the spring semester to finish the last few requirements at a school with a low teacher to student ratio with typical and special education peers. Oliver thrived here.

LESSONS LEARNED

• A smaller environment has tended to have more positive effects.
• Typical peer modeling has been very beneficial.
• The path is not always straight.
• One year the school or program can be great and the next very difficult. Stay flexible.
• Advocate for your child for supports, emergency care plans and the right ”fit”.

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Empowering TANGO2 Deficiency Disorder Stakeholders: A Digital Framework for Patient Engagement & Education in Rare Disease Research

Deena Chisholm, MPH, CHES¹; Ann Geffen, JD, MA¹; Seema Lalani, MD²; Annalyse Kofoed, Kasha Morris^{1 1}TANGO2 Research Foundation, Hadlyme, CT, USA, ²Baylor College of Medicine, Houston TX, USA

References & Funding Acknowledgement

1. Lalani SR, Liu P, Rosenfeld JA, et al. (2016). Recurrent muscle weakness with rhabdomyolysis, metabolic crises, and cardiac arrhythmia due to bi-allelic TANGO2 mutations. Am J Hum Genet, 98(2), 347–357. https://doi.org/10.1016/j.ajhg.2015.12.003
2. Lalani SR, Burrage LC. (2022). TANGO2-related metabolic encephalopathy and arrhythmias. In: Adam MP, Mirzaa GM, Amemiya A, et al. (Eds.), GeneReviews®. University of Washington, Seattle. https://www.ncbi.nlm.nih.gov/books/NBK476443/

This project was funded through a Patient-Centered Outcomes Research Institute® (PCORI®) Eugene Washington PCORI Engagement Award (EASO 30416). The statements presented in this poster are solely the responsibility of TANGO2 Research Foundation and do not necessarily represent the views of PCORI®.

TANGO2 Deficiency Disorder (TDD) is an ultra-rare autosomal recessive genetic disorder often characterized by intellectual disability, seizures, hypothyroidism, and recurrent episodes of rhabdomyolysis with metabolic and cardiac crises. This disorder affects over 8,000 individuals worldwide, with a carrier frequency of ~1/500. There are limited clinical care guidelines, no treatments and/or cure.

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Engaging all stakeholders (patient families, clinicians and researchers) in research design and education is critical but underdeveloped, presenting an opportunity to advance patient-centered comparative effectiveness research (CER) and community driven clinical care.

Background

Key Results Included:

• TDD RLN quarterly engagement from over 90 global stakeholders with over 295 forum threads and 68 discussion topics.
• Development of a research engagement roadmap that directly guided multiple externally funded and TANGO2 Research Foundation funded proposals.
• Educational events that informed revisions in clinical study design.
• Advocacy campaigns that boosted the TDD RLN membership and global awareness by 17% over one year.

Purpose

To bring together patient families, healthcare professionals, and researchers, July 2023 through June 2024, the TANGO2 Research Foundation developed a free, customized open-source online discussion platform using Discourse. This platform fosters open communication, strengthens collaboration, and helps break down barriers that often limit progress in rare disease research and care.

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We implemented four key engagement strategies:

1. Digital Learning Workshops & “Ask a Stakeholder” Forum: Quarterly educational modules with real-time Q&A and a moderated discussion forum to facilitate two-way learning and insight sharing. Forum contributions were summarized and escalated to guide the foundation’s strategic research directions.
2. Community-Informed Research Engagement Roadmap: Input From 90+ stakeholders across 10 countries was collected through the TDD RLN workshops. The feedback informed key priorities such as early and accurate diagnosis, metabolic monitoring, and nutritional interventions and guided the development of a roadmap to align future collaborative research studies with community needs.

Methods and Materials

The TDD RLN’s structured, technology enhanced model supports patient-centered education, integrates caregiver perspective into study design, and strengthens advocacy. This scalable framework aligns with NORDS criteria for Patient Engagement and Education in Rare Diseases and offers a replicable model for other rare conditions seeking to inclusively involve patient families in research and rare disease education.

Conclusions

To present how the TANGO2 Research Foundation’s TDD Research Learning Network (RLN) uses innovative digital methods and stakeholder co-creation to educate patient families, clinicians and researchers, integrate caregiver input into research processes, and elevate advocacy for TDD through technology-driven communication.

Results

Figure 1. TDD RLN Highlights

Figure 2. TDD RLN Facts and Figures

Methods and Materials

3. Multimedia Outreach: Patient-centered blogs, newsletters, social media campaigns and fundraising events amplify lived experiences, driving advocacy and increasing stakeholder engagement growth by 20%.
4. Live Stakeholder Heatmap: A dynamic tool that maps active TDD RLN participants globally, fostering peer connection and enabling clinicians and researchers to identify geographic representation and outreach gaps.

Table 1. TDD RLN Community Demographics

Missing: Gender n=80; Role n=1; T2RF Regional Coordinator n=21

*Additional category "Organizational Administrative Staff (n=5). Percentages in table reflect only the categories listed

Insights From the Natural History Study of an International TANGO2 Deficiency Cohort

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Conclusions

Background

Results

Purpose

Results

• This large international TANGO2 disorder natural history study delineates early signs of the disease which can help with timely diagnosis and improving health outcomes
• A subset of patients with 22q11 deletion syndrome also have TANGO2 deficiency and may remain undiagnosed until their first metabolic/arrhythmia crisis.
• Vitamin B complex can prevent life-threatening metabolic crisis in the affected individuals.
• Future studies are warranted including prospective natural history study to understand the role of B-vitamin supplementation on disease modulation.

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Methods

• A retrospective natural history study of 73 patients with molecular confirmation of TANGO2 deficiency was conducted, using in-depth interviews and medical record evaluations. International families were interviewed using a standardized set of questions, and responses were imported into a REDCap database that was used for analysis.

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• Children have normal development until about 6 months of age with first symptoms manifesting as developmental milestone delay.
• Episodic neurologic symptoms (TANGO2 spells) with ataxia, dysarthria and lethargy are early signs of this disease.
• Nearly all patients have developmental and intellectual delay with dysarthria. Seizures and hypothyroidism affect half of patients.
• Illness, fever, and poor oral intake can result in metabolic crises that are life-threatening and are the leading cause of mortality.
• Patients supplemented with B vitamins experienced no metabolic/cardiac crises!

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References/Funding

1. Lalani et al., AJHG 2016, “Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-Allelic TANGO2 Mutations.”

2. Lalani SR, Burrage L, et al. TANGO2-Related Metabolic Encephalopathy and Arrhythmias. In: GeneReviews®, 2022, University of Washington, Seattle, Seattle (WA).

The research is supported by the TANGO2 Research Foundation and by CZI grant DAF2020-211954 and grant DOI https://doi.org/10.37921/829804vjpejy from the Chan Zuckerberg Initiative DAF, an advised fund of Silicon Valley Community Foundation (funder DOI 10.13039/100014989).

Saad Ehsan¹, Erica J. Lay, MD², Claudia Soler-Alfonso, MD², Kevin Glinton, MD², Kimberly Houck, MD³, Mustafa Tosur, MD⁴, Mahshid S Azamian, MD², Seema R. Lalani², MD, Christina Y. Miyake, MD^5,6

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¹Baylor College School of Medicine, Houston, TX USA, ²Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA, ³Department of Pediatrics, Division of Neurology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA, ⁴Department of Pediatrics, Division of Endocrinology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA, ⁵Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA, ⁶Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX USA

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Absence of metabolic crises in patients taking vitamin B complex

Life-threatening complications: metabolic crises and cardiac arrhythmias in the cohort