From Saddle to Steps: Equine Therapy Enabling Independent Walking in a Child with TANGO2 Deficiency Disorder
Cameron, K.1,2
1Canadian TANGO2 Rare Disease Foundation, Nova Scotia, Canada, 2TANGO2 Research Foundation, Hadlyme, Connecticut, USA
Background: TANGO2 Deficiency Disorder (TDD) is an ultra-rare metabolic and genetic condition characterized by developmental delay, metabolic crises, muscle weakness, and neurological impairment. Many affected children experience significant challenges with mobility, coordination, and core stability despite extensive therapies. Families often pursue multiple interventions, including physical, occupational, and speech therapy to support independence. Yet, evidence for alternative approaches in TDD remains limited. Equine-assisted therapy (hippotherapy) has shown benefits in other neuromuscular and developmental disorders by promoting balance, core strength, sensory integration, motor planning, and confidence. This abstract describes the experience of a TDD child who achieved independent walking following the introduction of therapeutic horseback riding after years of limited progress with conventional therapies.
Intervention: At age three, our daughter began structured equine therapy guided by trained instructors. Sessions incorporated dynamic postural engagement, repetitive balance adjustments, task-oriented activities, and pattern recognition through riding sequences and obstacle navigation. The rhythmic movement simulated natural walking, promoting neuromotor engagement not achievable in traditional therapy. After the third session, she took her first independent steps.
Maintenance: Ongoing weekly sessions reinforce gains, integrating movement patterns into daily mobility, core strength, and posture.
Therapeutic Mechanisms - Pelvic Motion Simulation: The horse’s gait generates three-dimensional pelvic movement (rotational, anterior-posterior, lateral) that closely resembles human walking.
Core Activation: Maintaining posture on a moving horse engages abdominal, spinal, and hip stabilizers, strengthening core and improving balance.
Balance & Neuromuscular Training: Continuous micro-adjustments during riding enhance neuromotor coordination; 3,000–5,000 strides per 45-minute session provide high-intensity neuromuscular training.
Sensory Integration: Vestibular stimulation from movement and proprioceptive input through pelvis and legs promote neuromuscular pathways.
Spasticity Reduction: Rhythmic, repetitive movement and warmth help reduce muscle spasms, particularly in thigh adductors.
Quality of Life: Our daughter experienced independent walking, improved core stability and balance. Additionally, she has shown increased confidence and willingness to attempt new tasks as well as the ability to follow multi-step instructions and attend to structured activities. She also has enhanced emotional, social, and overall quality of life. This family experience suggests equine-assisted therapy may be a valuable complementary intervention for children with TDD, particularly when traditional therapies have not produced desired mobility outcomes.
Dietary Supplementation is the Primary Contributor to Vitamins B5 and B9 Intake in a Population of Patients with TANGO2 Deficiency Disorder
Hsu, Z.1, von Thun, Nancy L.1, Zolnierczyck, N.1, Witherspoon, A.1, Bihuniak, J.1, Kerrihard, A.1, Lalani, S.2, Miyake, C.Y.2,3, Espinosa Alvarez, S.A.2, Castro Lorenzo, J.2, Bose, M.1
1Montclair State University, Montclair, New Jersey, USA, 2Baylor College of Medicine, Houston, Texas, USA, 3Texas Children’s Hospital, Houston, Texas, USA
Background: TANGO2 deficiency disorder (TDD) is a rare genetic disease which can result in a range of symptoms. Recent research has suggested that supplementation of B-vitamins can reduce TDD symptoms in patients. Patients with TDD are presently recommended to take a daily multivitamin or B-complex supplement that fulfills individual Dietary Reference Intakes (DRI) for vitamins B5 and B9. This study aims to determine the daily energy and nutrient intake in patients with TDD.
Methods: Family caregivers of patients with TDD participated in a 24-hour dietary recall interview on behalf of their child. Individual energy, macronutrient, micronutrient intake and Healthy Eating Index scores (measure of diet quality) from diet and supplements were determined using Nutrition Data System for Research (NDSR) software. Descriptive data included individual and mean results. Pearson’s correlation coefficient was used to compare variables.
Results: Twenty patients with TDD were represented in this study. Mean nutrient intake for patients either met or exceeded DRIs. Mean daily intake of vitamin B5 (351.1±275.0 mg per day) was 86 times over the DRI, and vitamin B9 (8483.1±5443.1 mcg per day) was 48 times over the DRI. The majority of vitamins B5 and B9 intake in patients were mainly attributable to supplements (accounting for 90.4±24.5% and 60.0±31.1% of intake, respectively). Vitamins B5 and B9 intake were not significantly correlated with energy intake, protein intake, or Healthy Eating Index score.
We observed that patients with TDD met or exceeded age- and sex-appropriate DRIs for vitamins B5 and B9 intake, with individual vitamin B5 intake up to 150 times its DRI in patients. Vitamins B5 and B9 intake were primarily attributable to supplement intake, and did not significantly correlate with overall dietary intake or quality. In light of recent studies that support supplementation of B5 and B9 at minimum 10 times the DRI for symptom management of TDD, our data supports the recommendation that all patients with TDD will likely need to augment their diet with additional vitamin B5 and B9 supplementation to meet these goals.
Conclusion: This is the first study to assess the dietary intake and dietary quality of patients with TDD, supporting the recommendation that patients with TDD should be taking a daily B-vitamin supplement that includes vitamins B5 and B9 to manage symptoms of TDD. Our study is an important first step in the development of well-designed clinical trials studying nutrient interventions and symptom management in TDD.
TANGO2 PubNav - Building Exploration, Understanding and Community Around TDD Published Literature
Morris, M.1
1TANGO2 Research Foundation, Hadlyme, Connecticut, USA
Background: The body of published research around TANGO2 Deficiency Disorder (TDD) is relatively small but rapidly evolving. For clinicians, researchers, and patient families, accessing and synthesizing this literature can be difficult. Articles are dispersed across journals, often highly technical, and not easily navigable by non-specialists. To address this challenge, we developed TANGO2 PubNav, an AI-assisted literature exploration platform designed to make the published TDD research corpus more accessible, searchable, and interpretable.
The goal of TANGO2 PubNav is to accelerate understanding of TDD by creating a centralized, interactive environment where users can explore the published literature, identify key findings, and generate insights that support research, clinical awareness, and patient education.
Methods: TANGO2 PubNav aggregates peer-reviewed publications related to TANGO2 Deficiency Disorder into a structured knowledge base enriched with article metadata and semantic embeddings. Using modern large language model (LLM) techniques and vector-based retrieval, the platform allows users to query across the literature in natural language and receive contextualized answers grounded in specific publications. Users can navigate directly from responses to the relevant sections of the underlying papers, preserving transparency and enabling deeper review. The system is designed to support multiple audiences, including researchers, clinicians, and patient families.
Results: TANGO2 PubNav enables users to:
Explore the TDD literature through natural language queries
Rapidly identify themes, findings, and relationships across journal articles
Trace responses back to specific publications and passages
Discover emerging research directions and knowledge gaps
Engage with complex literature without requiring specialized technical expertise
By lowering the barrier to accessing complex biomedical research, the platform helps transform static publications into an interactive knowledge resource.
Conclusion: TANGO2 PubNav demonstrates how AI-enabled literature navigation tools can support rare disease communities by improving access to scientific knowledge. Beyond TDD, this approach may serve as a model for other rare disease ecosystems seeking to connect researchers, clinicians, and patient communities through shared understanding of the scientific literature.
Mitochondrial Drug Assay on C. elegans Model of TANGO2 Deficiency Disorder
Zimmerman, M.1, Sandkuhler, S.E.1, Mackenzie, S.J.1
1University of Rochester Medical Center, Rochester, New York, USA
Background: TANGO2 deficiency disorder (TDD) is an autosomal recessive neurometabolic disorder characterized by developmental delay, learning disabilities, seizures, and episodic metabolic crises, which can lead to cardiac arrhythmias, rhabdomyolysis, and death. In animal models and human cell lines, mutations in TANGO2 or its homologs are associated with mitochondrial fragmentation and impaired cellular metabolism. Vitamin B5 supplementation may be effective at ameliorating these crises and other symptoms of TDD, but the underlying mechanism remains unclear.
Purpose: Given the known relationship between TANGO2 deficiency and mitochondrial dysfunction, we investigated a series of mitochondrial targeted drugs in both wild type (N2) and double knockout (DKO) C. elegans worms to garner a better understanding of the mitochondrial functions of TANGO2 and potential additional therapeutic avenues for those with TDD.
Methods: A C. elegans model of TDD generated by CRISPR knockout of TANGO2 homologs, hrg-9 and hrg-10, was used. Using the Mitochondria-Targeted Compound Library from MedChem Express, we tested 958 drugs on their survival effects in N2 and DKO worms after exposure to oxidative stress. L1 worms were exposed to 25 µM paraquat, a potent generator of superoxide, to induce oxidative stress. Concomitantly, worms were treated with either 10 or 100 µM of each drug. A live-dead assay using Sytox Blue to stain dead worms was performed 24 hours after exposure. Drugs were then rated based on improved survival in DKOs and neutral effects in N2s.
Results: Preliminary data shows that 17 drugs stood out as strongly effective in reducing paraquat-induced death in C. elegans at both 10 µM and 100 µM doses. Another 27 were effective in reducing death in one dose. These effective drugs had a range of classifications including monoamine oxidases and the Bcl–2 family, though no pattern could be identified amongst their classifications or mechanisms of action. Likewise, drugs that severely impeded survival rate came from varied drug classifications. Ongoing work includes replicating the assay on key ameliorative or detrimental drugs to ensure the accuracy of our initial findings. Effective drugs will then be tested on other behavioral phenotypes to assess therapeutic benefit in other domains.
Conclusions: A first pass screen through this drug library has identified several compounds with therapeutic effect on worm survival. Additional work is needed to uncover possible benefits to other disease phenotypes and to identify potential mechanisms underlying this effect in the setting of TANGO2 deficiency.
How T2RF’s Clinical Consult Hotline and the TANGO2 Community Saved My Son’s Life: Connor’s Journey with TANGO2 Deficiency Disorder
Guillet, C.1
1TANGO2 Research Foundation, Hadlyme, Connecticut, USA
Background: While 22q11.2 Deletion Syndrome can explain many medical challenges, some individuals may experience symptoms that do not fully fit the typical pattern. In rare cases, likely affecting fewer than 1% of individuals, there may be an additional underlying condition, such as TANGO2 Deficiency Disorder (TDD). This may be considered when symptoms like metabolic crises, muscle breakdown, seizures, or heart rhythm changes occur and are not commonly associated with 22q11.2 alone.
Despite receiving a diagnosis of 22q11.2 Deletion Syndrome at birth, Connor experienced 15 years of recurrent, unexplained episodes consistent with TANGO2-related events, including “spells”, seizures, ataxia, and profound lethargy. In June 2025, following multiple generalized (grand mal) seizures, he did not recover as expected and progressed into a severe TANGO2 metabolic crisis, requiring a 40-day hospitalization.
Intervention: Connor was admitted to the pediatric Intensive Care Unit (ICU). As his health deteriorated, he experienced rhabdomyolysis, life-threatening ventricular fibrillation, prolonged QTc intervals, and creatine kinase (CK) levels exceeding 300,000 U/L.
Fortunately, a prior TANGO2 Research Foundation (T2RF) Family Conference established a vital connection between clinician researchers at Nemours Children’s Hospital in Florida and Texas Children’s Hospital/Baylor College of Medicine in Texas. Dr. Tisma-Dupanovic consulted with Dr. Miyake and her team via T2RF’s 24/7 TDD Clinical Consult Hotline. Following consultation, a “banana bag” IV and supplemental folic acid, pantothenic acid, and multivitamins were initiated immediately. This rapid intervention stabilized Connor and saved his life. Just three short weeks after being completely bed-bound with paralysis, he was eating, drinking, walking, and even using his wheelchair to push adults across the hospital room.
Maintenance: Connor now maintains a steady regimen of B vitamin supplements and multivitamins, closely monitored by the TDD Baylor College of Medicine/Texas Children’s Hospital team and his providers at Nemours Children’s Hospital.
The family remains deeply engaged with the TANGO2 community through T2RF’s social media platforms, conferences, and educational initiatives, receiving vital updates and supporting other families.
Quality of Life: “This event took Connor completely and totally out and he came back stronger. He overcame battles a lot of adults would’ve given up on. Only we know how incredible his recovery was, and it was INCREDIBLE!” While the medical journey continues, the partnership with Drs. Miyake and Tisma-Dupanovic, and the T2RF has ensured Connor the best possible quality of life.”
There is a critical need to increase provider awareness and consider universal TANGO2 Deficiency Disorder testing in the 22q11.2 population, ideally at birth, to prevent life-threatening metabolic crises.
We acknowledge “Connor’s Angels,” Drs. Tisma, Miyake, and Lalani, along with Julissa Castro and Ann Geffen for their contributions to care, advocacy, and support. This case highlights the life-saving impact of coordinated, patient-centered care, research and advocacy. The T2RF’s mission extends beyond funding research to saving lives.
Investigating Heme Trafficking in a C. elegans Model of TANGO2 Deficiency Disorder
Gottipalli, O.1, Sandkuhler, S.E.2,Mackenzie, S.J.2
1College of Arts and Sciences, Emory University, Atlanta, Georgia, USA, 2University of Rochester Medical Center, Rochester, New York, USA
Background: Prior studies have proposed that TANGO2 functions in intracellular heme trafficking. However, observations in patients and several models of TDD instead support an as yet undefined role for TANGO2 in cellular metabolism. As such, the “heme hypothesis” represents a shift from the current scientific consensus regarding TANGO2 function. We sought to determine whether previously reported defects in heme trafficking are central to the pathophysiology of TDD or instead represent downstream effects of cellular dysfunction.
Methods: To investigate the role of TANGO2, we performed experiments using a C. elegans model harboring homozygous deletions in two TANGO2 homologs, hrg-9 and hrg-10 (double knockout; DKO). Wild-type (N2) worms were exposed to several stress conditions (heat, starvation, and paraquat) followed by RNA extraction and cDNA synthesis for real-time qPCR analysis to assess changes in hrg-9 expression. In parallel, NGM plates seeded with OP50 were supplemented with increasing concentrations of gallium protoporphyrin IX (GaPP), a toxic heme analog. Survival of offspring laid on GaPP plates was quantified and compared between DKO and N2 worms along with a third strain known to exhibit defective feeding (eat-2 mutant). Finally, to directly test the heme trafficking hypothesis, bleach-synchronized DKO and N2 eggs were hatched to L1 larvae and cultured in axenic media containing either low (4 μM) or standard (20 μM) heme concentrations. Larvae were then exposed to 40 μM zinc mesoporphyrin (ZnMP), a fluorescent heme analog, for 16 hours. Worms were imaged by fluorescence microscopy, and ZnMP fluorescence intensity in the proximal intestine was quantified using ImageJ as a measure of heme uptake.
Results: Exposure to paraquat induced increased hrg-9 expression in N2 worms (Figure 1), suggesting that this gene may be broadly responsive to oxidative stress. DKO worms raised on GaPP plates exhibited a modest survival advantage compared to N2 worms (Figure 2), although this effect was smaller than previously reported and less robust than that observed in eat-2 mutants. Phenotypic observations also revealed reduced pharyngeal pumping and increased lawn-avoidance behavior in DKO worms. Under standard heme conditions, both DKO and N2 worms developed normally to the L4 stage, and no significant differences in ZnMP fluorescence intensity were detected between groups (Figure 3).
Conclusions: These findings do not provide strong support for the hypothesis that TANGO2 primarily functions as a heme chaperone. Observed phenotypes in response to heme analog exposure may instead reflect secondary physiological or behavioral differences rather than a primary defect in intracellular heme trafficking.*
*Results from this study were recently published in eLife (Sandkuhler et al., 2026; DOI: 10.7554/eLife.105418).
Benefits of Vitamin B5 Increase in a TANGO2 Warrior After a Chest Infection
Yakoub, S.1
TANGO2 Research Foundation, Hadlyme, Connecticut, USA
Background: TANGO2 Deficiency Disorder (TDD) complications are often worsened by illness and infection. In 2025–2026, a 20 year-old individual with TDD developed a chest infection lasting nearly two weeks, accompanied by increased dystonic seizures.
Intervention: A general practitioner prescribed a 7-day course of antibiotics. On day 5, the individual experienced low oxygen levels, requiring evaluation in the emergency department, where they received monitoring, antibiotics, and intravenous (IV) fluids. After discharge, the antibiotic course was completed; however, the individual did not return to their baseline respiratory status. Breathing improved temporarily with repeated use of continuous positive airway pressure (CPAP).
Following consultation with the TANGO2 family community on social media, pantothenic acid (vitamin B5) supplementation was increased by 200 mg (in addition to a baseline of 500 mg three times daily). Noticeable improvement, including increased energy and more typical behavior, was observed after two doses.
Maintenance: The increased vitamin B5 dose was continued until daytime CPAP was no longer needed. One week later, supplementation returned to baseline levels, with CPAP used only overnight. Oxygen levels stabilized, and the individual became more alert, vocal, and clinically stable.
Quality of Life: After recovery, the individual resumed attending a specialist college and participating in daily activities. This case suggests that increasing vitamin B5 (pantothenic acid) supplementation, alongside standard medical care, may support recovery during infection in individuals with TDD. Early supportive interventions may help improve outcomes and reduce respiratory complications.
Idiopathic Intracranial Hypertension (IIH) - A Family Perspective of Sebby’s Journey with this Diagnosis
Hull, A.1,2
1Tango2UK, Warwickshire, England, 2TANGO2 Research Foundation, Hadlyme, Connecticut, USA
Background: Routine eye examinations are critical for individuals with TANGO2 Deficiency Disorder (TDD), as eye and neurologic complications such as strabismus and idiopathic intracranial hypertension (IIH), are increasingly recognized. TDD natural history study data suggests exotropia (a form of strabismus) occurs in roughly 70% of individuals with TDD, often worsening with fatigue or metabolic stress, highlighting the high prevalence of ocular involvement.
IIH is characterized by elevated intracranial pressure without an identifiable cause. Symptoms can include swollen optic discs (papilledema), headaches, visual changes, nausea and vomiting, as well as cranial nerve dysfunction. Papilledema is particularly concerning, as prolonged swelling can result in permanent vision loss. Routine eye exams that evaluate the optic nerve and screen for strabismus or disc swelling are essential for early detection, especially since symptoms can be subtle and overlap with other neurologic features.
Our 11 year-old son Sebby, with TDD was diagnosed with IIH in 2022 following an eye exam that revealed grade 3+ optic disc swelling. Symptoms had been present for at least three years prior to diagnosis, and clinicians warned that ongoing swelling could compromise vision.
Intervention: Our son underwent a spinal infusion procedure in 2024 to reduce intracranial pressure, followed by initiation of a targeted medication regimen and ongoing monitoring.
Maintenance: Since diagnosis and intervention, symptoms, including nausea, cyclical vomiting, migraine, balance issues, fatigue, and general lethargy have resolved. Sebby’s condition is approaching remission, with continued monitoring and medication as needed.
Quality of Life: Health and wellbeing have significantly improved. Prior to the IIH diagnosis, symptoms had been attributed to abdominal migraine, for which only symptom management was provided. Identification and treatment of IIH have clarified the cause, resolved chronic symptoms, and dramatically improved quality of life for our son with TDD.
Remote Video Assessment of Early Movement Abnormalities in TANGO2 Deficiency Disorder
Myers, S. P.1, Sandkuhler, S. E.2, Hewitt, A. L.1, Hull, M.3, Mink, J. W.4, Kwok, C.5, Ladha, F. A.6, Azamian, M. S.7, Miyake, C. Y.8, Lalani, S.6, Vermilion, J.1, Mackenzie, S. J.1,9
1Division of Child Neurology, Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA, 2Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA, 3Section of Child Neurology and Neurodevelopmental Disabilities, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA, 4Dystonia Medical Research Foundation, Chicago, IL, USA, 5Department of Physical Medicine and Rehabilitation, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA, 6Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA, 7Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA, 8Division of Cardiology, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA, 9Division of Neuromuscular Disease, Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA
Background: Movement abnormalities, including episodes of transient weakness and fatigue, have been reported in TANGO2 deficiency disorder (TDD) but have not been systematically characterized. Limited evidence suggests vitamin B-complex supplementation, inclusive of pantothenic acid, may reduce symptom burden.
Methods: Individuals with genetically confirmed TDD were recruited as part of the ongoing TANGO2 Natural History Study. Caregivers submitted videos of abnormal movements and completed structured interviews detailing symptom onset, progression, and response to interventions, including pantothenic acid. A subset of participants underwent in-person assessment that included evaluation of baseline dystonia and spasticity.
Results: We analyzed home videos from 26 participants; interviews were completed for 23 (12 male, 11 female; median age 9.5 years [range 4 - 29], including one deceased), and nine underwent in-person evaluation. Dystonia (19/23, 83%) and ataxia (9/23, 39%) were the most common movement disorders. Participants also experienced transient fatigue and weakness ("TANGO2 spells"; 14/23, 61%) which did not meet criteria for a canonical movement disorder subtype in isolation. More than one identifiable movement disorder occurred in 15/23 (65%). Movement symptoms presented at a median age of 1.5 years (range 0.5 - 6). Among those with a history of metabolic crisis, movement symptoms preceded crisis in 8/14 (57%). Pantothenic acid supplementation was associated with partial or full cessation of movement symptoms in 15/20 (75%; OR 3.0, 95% CI 1.04 - 10.55; p=0.041).
Conclusions: Dystonia, ataxia, and TANGO2 spells are common, early manifestations of TDD. Recognition of these symptoms may facilitate diagnosis before metabolic crises occur. B-complex supplementation, inclusive of high-dose pantothenic acid, appears beneficial based on retrospective caregiver report, supporting its use as an early intervention; however optimal dosing requires further study.
Why Community Matters: Reflections One Year After National Charity Recognition
Driffill, H.1,2, Driffill, T.1,2
1Tango2UK, Warwickshire, England, 2TANGO2 Research Foundation, Hadlyme, Connecticut, USA
Background: TANGO2 deficiency disorder is an ultra-rare, genetic metabolic disorder characterized by life-threatening metabolic crises and neurologic complications, with only a handful of United Kingdom (UK) families formally diagnosed despite potentially many more being affected worldwide. While the TANGO2 Research Foundation (T2RF) has played a vital role in advancing global research, connecting families worldwide, and driving scientific progress in TDD, many families in the UK still face challenges accessing tailored support and clinical resources within their own health systems due to the rarity of the condition.
Intervention: Since its foundation in March 2024, Tango2UK has looked to support and build up the UK based TANGO2 community. Aiming to better represent its affected patient group and build community, promoting clinical awareness and working with connected clinicians to be in a better position to support international and locally based TDD research. We have worked closely with UK families to highlight our achievements and identify lessons learned from establishing the charity, providing insights that can guide future efforts in rare disease support.
The most valued method for fostering community connection among affected families was WhatsApp, identified as an immediate, accessible, and low-resource platform for peer support. In contrast, more resource-intensive tools, such as websites, were primarily used by clinicians at the point of diagnosis and less frequently by families for ongoing engagement.
Families diagnosed prior to the establishment of Tango2UK reported limited early support and greater feelings of isolation. Engagement with the Tango2UK community was associated with increased support and a reduced sense of isolation.
Direct interaction with the charity, through patient events, community gatherings, and personal outreach, was identified as the primary benefit, underscoring the importance of community-building in rare disease support organizations. However, awareness of the charity’s broader activities, including contributions to clinical discussions, research, and education, was comparatively lower.
Maintenance: Future priorities varied among families and included advancing research, strengthening community engagement, and increasing awareness. These differences reflect the diverse needs and experiences within the TDD community and highlight the importance of a balanced, multi-faceted approach to support and development.
Quality of Life: Tango2UK has increased visibility for affected families and established connections that enhance clinical understanding and research participation. In this report we include our achievements but also future aspirations for Tango2UK. This charity establishment highlights the value of local support when linked to international connections. Together, proving the value of both international and nationally based communities and the symbiotic and synergistic effect of their collaborations, providing a replicable model for other countries.
Cerebellar Mechanisms Underlying Movement Dysfunction in TANGO2 Deficiency Disorder
Peacoe, L.1, Sillitoe, R.1
1Baylor College of Medicine, Houston, Texas, USA
Background: TANGO2 Deficiency Disorder (TDD) commonly causes individuals to develop dystonia (uncontrolled muscle contractions), ataxia (difficulty with balance and coordination), and tremor (shaking). These movement challenges can greatly affect daily life, but we still do not understand how loss of TANGO2 disrupts brain function to cause them. The cerebellum, a region of the brain that plays a key role in coordinating movement and maintaining balance, is a strong candidate. The cerebellum has a repeating circuit architecture, and dysfunction in this circuit is a well-established driver of movement disorders, including dystonia, ataxia, and tremor. We hypothesize that the loss of TANGO2 affects cerebellar neuron firing patterns, leading to abnormal circuit output and motor impairment in TDD.
Methods: We use a mouse model that lacks the Tango2 gene (Tango2-/-mice) to examine cerebellar circuit functioning. A precise metal electrode is used to record single neuron activity from Purkinje cells and cerebellar nuclei neurons, two critical cell types, from awake and behaving mice. Custom code in MATLAB is used to quantify spike timing and variability in different neuron types. In Tango2-/- and wild-type control mice, we analyzed firing rate, coefficient of variation (CV), and CV2.
Results: Behavioral observation reveals that mice display episodic movement abnormalities similar to those seen in TDD warriors, including ataxia, dystonia, and tremor that worsen with exercise. Preliminary recordings reveal changes in cerebellar spike variability between wild-type and Tango2-/- mice. Purkinje cell simple spikes trend toward reduced irregularity, with CV2 significantly decreased. In contrast, Purkinje cell complex spikes exhibit significantly increased CV and CV2, indicating greater variability in this type of signal. Cerebellar nuclei neurons display polarized abnormalities, with subsets showing either unusually regular or unusually irregular firing compared to wild-type. Mean firing rates do not differ. These data suggest that altered spike timing and variability, rather than firing rate, may drive cerebellar circuit dysfunction in Tango2-/- mice and contribute to movement dysfunction.
Conclusions: These findings provide the first evidence that TANGO2 loss disrupts cerebellar circuit dynamics. If confirmed with increased sample size, the data support a novel mechanism in which abnormal spike patterning within the cerebellum underlies motor dysfunction in TDD. Defining this circuit mechanism will establish a neural framework for understanding motor symptoms, guiding therapeutic testing. Ongoing studies will expand electrophysiological power, evaluate deep brain stimulation of the cerebellar output as a circuit-based intervention, and determine whether vitamin B5 supplementation engages cerebellar mechanisms to restore brain activity.
Modeling TANGO2 Deficiency Disorder Using Patient-derived iPSCs Models: Insights Into Neuronal Dysfunction, Phenotypic Variability, and Rescue by Vitamin B5
Carestiato, S.1, Vulic, K.1, Amos, G.1,Sterlini, B.2, Servetti, M.2, Puliti, A.3,Scudieri, P.3, Baldassarri, S.3, Zara, F.3,
1ETH Zurich, Institute for Biomedical Engineering, Laboratory of Biosensors and Bioelectronics, Zurich, Switzerland, 2University of Genoa, Department of Experimental Medicine, Genoa, Italy; Medicine, Genoa, Italy, 3IRCCS Giannina Gaslini Institute, Medical Genetics Unit, Genoa, Italy
Background: TANGO2 disorder is a rare inherited metabolic disease characterized by developmental delay, seizures, and recurrent metabolic crises resembling fatty acid β-oxidation defects, often accompanied by rhabdomyolysis, hypoglycemia, cardiac arrhythmias, encephalopathy, and coma. Despite being caused by loss-of-function variants in the TANGO2 gene, patients carrying identical mutations can display markedly different clinical phenotypes. This variability is exemplified in our cohort of two siblings with the same genetic variants, one asymptomatic and the other severely affected by developmental delay and recurrent metabolic decompensations.TANGO2 has been implicated in lipid metabolism and mitochondrial function, both essential for cellular energy homeostasis, but its precise role, especially in neuronal development, remains poorly understood. Vitamin B5 (pantothenic acid), a precursor of coenzyme A, has been suggested as a potential therapeutic strategy, although the mechanisms underlying its beneficial effects are still unclear.
Methods: To investigate the role of TANGO2 during human neurodevelopment, we used neural stem cells and mature neurons derived from our patient-specific human induced pluripotent stem cells (hiPSCs). Cellular and functional analyses were performed to assess neurogenesis, progenitor migration, oxidative stress, synaptic activity, glutamate release, and mitochondrial quality-control mechanisms. In addition, the potential therapeutic effect of vitamin B5 was evaluated in patient-derived cells.
Results: The absence of TANGO2 in the symptomatic patient led to several alterations during neurogenesis, including reduced neural rosette size and organization, impaired migration of neural progenitor cells, and increased neuronal cell death associated with oxidative stress. In contrast, cells derived from the asymptomatic sibling did not show significant structural or developmental abnormalities. Functionally, neurons from the symptomatic patient displayed impaired neuronal network activity and reduced glutamate release, indicating altered synaptic communication. Conversely, neurons from the asymptomatic sibling maintained normal electrophysiological activity but exhibited increased mitophagy, suggesting the presence of compensatory mitochondrial quality-control mechanisms. Notably, vitamin B5 treatment partially rescued several defects in symptomatic patient-derived cells, improving rosette morphology, progenitor migration, and neuronal activity.
Conclusion: TANGO2 plays a key role in neuronal development and function. Its deficiency disrupts neurogenesis, cell migration, and synaptic activity, contributing to the neurological features of TANGO2 Deficiency Disorder (TDD). The increased mitophagy observed in the asymptomatic sibling suggests compensatory mechanisms that may reduce disease severity. Importantly, the partial rescue obtained with vitamin B5 supports the potential of metabolic interventions to ameliorate neuronal dysfunction in TDD. Overall, our results provide new insights into the neuronal role of TANGO2, supporting the potential of metabolic interventions to mitigate neuronal dysfunction.
The Importance of Fundraising and Its Impact on the TANGO2 Community
Jones, V.1
1TANGO2 Research Foundation, Hadlyme, Connecticut, USA
Background: For families affected by TANGO2 Deficiency Disorder (TDD), a rare genetic condition, the diagnosis can feel overwhelming and isolating. Loved ones often want to help but may be unsure how. Community-based fundraising offers a meaningful way for families and friends to come together with a shared purpose. These efforts not only provide emotional support but also generate critical funding for patient advocacy organizations and research initiatives. Because rare disease research often receives limited traditional funding, grassroots fundraising plays an essential role in advancing scientific understanding of TANGO2 and supporting life-saving research. Family-led events can empower communities to contribute in meaningful ways while also increasing awareness of this rare disorder.
Intervention: To support the TANGO2 Research Foundation, our family organized a community Casino Night fundraiser. The event brings together friends and family for an evening of games, food, and philanthropy. A local casino company provides gaming tables and instruction so that guests can learn and enjoy casino-style games in a welcoming environment. Attendees purchase tickets that include dinner, drinks, and gaming chips. Additional fundraising activities include themed raffle baskets and a 50/50 raffle. Many raffle baskets are created by friends who contribute items related to their personal interests or talents, such as handmade ceramics, a curated book basket, a beach-themed basket, and a succulent arrangement. Guests may also donate additional funds if they run out of gaming chips, allowing them to continue playing while supporting the cause. The event combines entertainment, education, and philanthropy while creating an engaging way for the community to contribute to research.
Maintenance: To build consistency and sustainability, the fundraiser is held annually each May so the community can anticipate and plan for it. Over time, the event has become more organized and efficient. We continue to partner with the same casino company, bartender, and event structure, which simplifies planning and ensures a smooth experience. Detailed planning notes help streamline logistics each year, and friends and family contribute by preparing raffle baskets throughout the year, making the event a collaborative effort.
Quality of Life /Impact of Research Funding: Funds raised support research to better understand the biological function of the TANGO2 gene, improve diagnostic and clinical care guidelines, explore potential treatments, and promote collaboration among researchers and clinicians studying TDD. For families, fundraising provides hope, strengthens community connections, and offers loved ones a meaningful way to support affected individuals.
Fundraising can feel daunting at first, but it can become a powerful and rewarding experience. What began as small raffles gradually evolved into a larger community event. The Casino Night fundraiser has become a meaningful annual tradition that raises funds for critical research while creating lasting memories and strengthening the TANGO2 community.
Acute Management of TANGO2 Deficiency Disorder: Clinical Consensus Guidelines from a Modified Delphi Study
Ariola, A.1, Scaccia, J.7., Chisholm, D.L.3,Sen, K.4, Ghaloul-Gonzalez, L.5, Meisner, J.K.6, Mackenzie, S.J.2 on behalf of the TANGO2 Acute Care Guidelines Neurology, Cardiology, and Genetics, Intensive Care & Nutrition (GIN) Working Groups
1SUNY Upstate Medical University, Syracuse, New York, USA, 2Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA, 3TANGO2 Research Foundation, Hadlyme, Connecticut, USA, 4Division of Neurogenetics and Neurodevelopmental Pediatrics, Children’s National Hospital, Washington DC, USA, 5Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, 6Division of Pediatric Cardiology, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA, 7Dawn Chorus Group, Lancaster, Pennsylvania, USA
Background: TANGO2 deficiency disorder (TDD) is a rare, life-threatening metabolic disorder that, when untreated, is associated with movement disorders, seizures, and recurrent acute metabolic crises that involve rhabdomyolysis, encephalopathy, and life-threatening cardiac arrhythmias. Despite growing recognition of TDD, standardized, evidence-informed guidance for acute management remains limited.
Methods: We conducted a comprehensive literature review of published cases, cohort studies, mechanistic investigations, and existing expert recommendations related to TDD. Three multidisciplinary working groups (Neurology, Cardiology, and Genetics/ICU/Nutrition) that included clinical experts and caregivers of individuals with TDD were convened to draft domain-specific clinical statements. Draft statements were discussed during an in-person consensus meeting in Houston, Texas in December 2025. Areas of overlap were identified to ensure consistency across disciplines, and statements were refined for clarity and scope. A modified Delphi process was used to formalize consensus. All participants were asked to rate each statement on agreement, strength of recommendation, and clarity, and to provide structured comments.
Results: The initial voting phase is currently underway. Feedback from this round will inform iterative revisions, a second voting phase, and the finalization of recommendations.
This work will address the acute management of TDD, including management of paroxysmal neurological symptoms, crisis recognition, cardiac monitoring strategies, metabolic stabilization, and ICU-level interventions.
Conclusions: By integrating the available evidence with structured expert consensus, this effort aims to standardize acute care, reduce preventable complications, and improve outcomes for individuals with TDD.
Seeking the ‘Just Right’ Dose: A Review of Vitamin B5 (Pantothenic Acid) Dosage and Outcomes in TANGO2 Deficiency Disorder
Morris, K1.
1TANGO2 Research Foundation, Hadlyme, Connecticut, USA
Background: Families managing TANGO2 Deficiency Disorder (TDD) face a constant search for stability amidst life-threatening metabolic crises, cardiac events, and daily challenges with motor skills and speech. While there is no universal cure, growing evidence from both research publications and family-reported data suggests that Vitamin B5 (pantothenic acid) may be a transformative supportive therapy. However, a significant hurdle remains: we do not yet know the appropriate or “ideal” dosage of B5 for individuals with TDD. This review examines the relationship between specific B5 dosages and reported outcomes.
Intervention: Research literature shows a wide range of effective doses, from 100 mg/day in acute crisis settings to 500 mg/day for long-term functional improvement in older patients. Notably, a 7-year-old child showed significant cognitive and motor improvements on a 200 mg/day monotherapy. Family-reported data offers deeper insight into the necessity of dose titration. Often, lower dosages are insufficient to fully alleviate symptoms. For example, one 19-year-old experienced frequent “spells” of weakness and garbled speech at 100 mg/day; it was not until the dose reached 800 mg/day that the spells stopped and the patient achieved a faster return to baseline energy after illness. Similarly, a 15-year-old reported persistent “spells of low energy” at 500 mg, which were only resolved after increasing to 1,000 mg, a dose the family noted “brought him back to life”. In younger patients, we see similar trends, such as a child moving from daily spells to infrequent episodes of ataxia by increasing from 100 mg to 200 mg daily.
Maintenance: The goal of sharing this data is to shed light on what a therapeutic dose of vitamin B5 might look like.
Quality of Life: By highlighting these “just right” moments where symptoms were finally alleviated, we hope to encourage clinicians to move beyond standard Recommended Dietary Allowances (RDAs) and investigate a standardized, weight-based B5 protocol. For the TANGO2 community, finding the right dose isn't just about vitamins; it’s about reclaiming daily life.
Investigating the Role of TANGO2 Protein in Yeast: A Gateway to Understanding TANGO2
Naaz, A1, Sacher, M1.
1Department of Biology, Concordia University, Montreal, Canada
Background: TANGO2 Deficiency Disorder (TDD) is a rare genetic condition that can cause recurrent metabolic crises, muscle breakdown (rhabdomyolysis), cardiac arrhythmias, and neurological symptoms. Although mutations in the TANGO2 gene are known to cause the disease, the precise cellular function of the TANGO2 protein remains unclear. Understanding what this protein does inside cells is an important step toward identifying the metabolic pathways disrupted in TDD.
Methods: To investigate TANGO2 function, we use the yeast Saccharomyces cerevisiae as a model system. Yeast encodes a conserved ortholog of TANGO2, Tng2p (YGR127W), enabling genetic and cell biological analyses. Subcellular localization was assessed using fluorescence microscopy. Growth assays under metabolic stress conditions (fatty acid-containing media and low glucose) were used to evaluate functional phenotypes. Humanized yeast strains expressing human TANGO2 were generated to assess functional conservation. Selected disease-associated variants were tested for their ability to complement the tng2Δ phenotype. A genetic suppressor screen using the MoBY-ORF library was performed to identify potential compensatory pathways.
Results: Fluorescence microscopy suggests that Tng2p localizes to peroxisomes, consistent with the presence of a noncanonical C-terminal FKL motif and a potential dependence on the peroxisomal receptor Pex9. Deletion of TNG2 is associated with growth defects under metabolic stress conditions, particularly during growth on fatty acids and low-glucose media. Expression of human TANGO2 in yeast partially rescues the growth defect of the tng2Δ strain, indicating functional conservation. In contrast, some disease-associated TANGO2 variants show reduced ability to rescue this phenotype. The genetic suppressor screen identified one candidate gene that partially restores growth in the tng2Δ background, suggesting the involvement of a compensatory pathway.
Conclusions: Ongoing work focuses on validating this suppressor and determining how it functionally compensates for the loss of TNG2. Together, these findings establish yeast as a powerful system for studying the cellular role of TANGO2 and provide insights that may help clarify the metabolic mechanisms underlying TANGO2 Deficiency Disorder.
Finding Our Voice: Improving Speech and Quality of Life in TANGO2 Deficiency Disorder
Clay, A1.
1TANGO2 Research Foundation, Hadlyme, Connecticut, USA
Background: Velopharyngeal insufficiency (VPI) occurs when the soft palate does not fully close during speech, leading to a nasal tone and difficulty being understood. In individuals with TANGO2 Deficiency Disorder (TDD), speech challenges can become more pronounced following metabolic crises. This case describes our daughter with TDD whose speech declined over time, making communication increasingly difficult for both her and our family.
Intervention: Concerns raised at school led to a referral to an ear, nose, and throat specialist. Testing (nasoendoscopy) confirmed VPI. After careful evaluation by a multidisciplinary team, including cardiac assessment and a sleep study, our daughter underwent pharyngeal flap surgery in 2019. The care team worked closely with the family to ensure the safest possible approach, given the complexities of TDD.
Maintenance: After surgery, our daughter followed a modified diet and continued speech therapy to strengthen communication skills. Recovery was smooth, with minimal pain, and ongoing care, including metabolic support, remains in place.
Quality of Life: This case highlights how timely evaluation and coordinated care can make a meaningful difference for individuals with TDD. Addressing speech challenges like VPI can significantly improve communication and overall quality of life. Collaboration between families and care teams is essential to achieving the best outcomes.
Hybrid Mathematical Framework for Early TANGO2 Diagnosis: Prediction from Baseline Symptoms and PDE Based Crisis Forecasting
Tippimath, A.1, Lalani, S.2
1McNeil High School, Austin, Texas, USA, 2Baylor College of Medicine, Houston, Texas, USA
Background: TANGO2 deficiency disorder is a rare genetic condition characterized by unpredictable life-threatening metabolic crises, neurological decline, and cardiac complications. Current diagnostic approaches rely on recognizing acute crisis events, resulting in average diagnostic delays of years during which patients receive improper treatments. Additionally, families face constant uncertainty regarding crisis timing with no ability to prepare for emergencies. My research develops a hybrid mathematical framework combining machine learning classification and partial differential equation modeling to identify TANGO2 patients from baseline neurological symptoms appearing years before crises and to predict patient-specific crisis timing, transforming reactive emergency care into proactive risk management.
Methods: I analyzed over 200 patients including 90 confirmed TANGO2 cases and 141 similar non-TANGO2 patients provided by Baylor College of Medicine. For diagnosis, I trained a Random Forest classifier on 1,249 baseline clinical features excluding all post-crisis markers. For prediction, I developed a custom reaction-diffusion partial differential equation ∂r/∂t = D(∂²r/∂x²) + α·r·(1-r) + β·S(x) that combines three mathematical components: the diffusion term D(∂²r/∂x²) models metabolic risk spreading across organ systems, the logistic growth term α·r·(1-r) captures risk amplification with physiological limits, and the patient-specific source term β·S(x) represents each patient's severity. I solved this equation numerically using an IMEX finite difference method with 260 spatial grid points and half-day time steps over 900-day forecasts, detecting predicted crises at specific key timings.
Results: The classifier achieved 95.5% accuracy, revealing three dominant predictors forming a neurological signature: dysarthria in 90% of TANGO2 patients versus 3.5% non-TANGO2, gait disturbance in 88% versus 2.8%, and intellectual disability in 88% versus 7.1%. Two symptoms showed TANGO2-specific association: paroxysmal lethargy in 82% versus 0% and compensatory head posture in 70% versus 0%. The partial differential equation generated individualized crisis forecasts by calibrating the patient-specific parameter β from each patient's baseline symptom severity, where high-severity patients showed six predicted crises at 150-day intervals, moderate-severity patients showed four predicted crises at 225-day intervals, and mild-severity patients remained sub-threshold with zero predicted crises. Sensitivity analysis validated biological validity.
Conclusions: My hybrid mathematical framework represents a transformative approach to TANGO2 management, offering the ability to identify patients with 95.5% accuracy from baseline neurological symptoms and predict metabolic crises 150 to 225 days in advance using partial differential equations. My methodology enables early diagnosis years before the first crisis occurs and transforms unpredictable emergencies into expected high-risk windows that allow for proactive medical care. Clinical implementation of my framework could reduce diagnostic delay from years to months, decrease emergency hospitalizations by 30 to 40 percent, and improve overall patient outcomes through predictive rather than reactive care. Further research is needed to validate my predictions in newly diagnosed patients and to integrate my framework into clinical decision systems for widespread pediatric use.
Sammy Lopez - From First Case Description to a Growing Movement: The Origins of the TANGO2 Community
Lopez, M.1, Geffen, A.1
1TANGO2 Research Foundation, Hadlyme, Connecticut, USA
Background: TANGO2 deficiency disorder (TDD) is a rare condition in which early case recognition and family-driven advocacy have been central to scientific progress. The TANGO2 community’s collective story is closely linked to one of the first individuals with TDD described in the medical literature, Sammy Lopez.
Intervention: After 15 years of extensive evaluations by multiple physicians and specialists, Sammy received a diagnosis of TANGO2 Deficiency Disorder on January 26, 2016. This diagnosis was made through participation in a study on recurrent muscle weakness, rhabdomyolysis, metabolic crises, and cardiac arrhythmias associated with bi-allelic TANGO2 mutations, led by clinician researchers at Baylor College of Medicine. Sammy’s diagnosis marked a pivotal moment that advanced recognition of the condition and catalyzed the formation of a broader patient and research community.
Maintenance: Sammy’s case brought broader attention to TDD and helped catalyze a coordinated vision for research, emerging therapies, and the establishment of the TANGO2 Research Foundation by the Morris family. His impact extends beyond an individual story, contributing to growing research momentum and evolving care strategies informed by early discoveries.
Over time, observed clinical and community outcomes have included expanded identification of affected individuals and improved pathways to diagnosis & support; increased optimism for symptom management & supportive care; and reports of meaningful developmental & functional gains, such as standing, walking, and running, associated with B-vitamin–based therapeutic approaches informed by TDD.
Quality of Life: Sammy passed away from a seizure in his sleep on October 23, 2018. We carry forward both his words and his legacy. He often said, “God has a plan for us; God has a plan for everyone.” We believe his life served as a catalyst for the discovery and recognition of this rare disease, and the community’s continued progress stands as both a tribute and a responsibility as we advance research in pursuit of a cure.
While honoring Sammy’s story, we also recognize the broader community of TANGO2 angels, individuals whose lives were cut short and whose memory continues to drive urgency and purpose in our work.
The Lopez family, particularly Marcie, remains deeply engaged in strengthening the TANGO2 community through fundraising, volunteerism, event participation, and ongoing awareness efforts. Their advocacy continues to inspire families to engage in research, support one another, and share their stories. Sammy’s journey brought global attention to TDD and helped catalyze a movement toward research, treatment, and community-building. His legacy endures through continued scientific progress and the Lopez family’s leadership. Sammy’s story will forever be a guiding light, inspiring progress, new treatments, and hope for a cure!
Empowering TANGO2 Deficiency Disorder Stakeholders: A Digital Framework for Patient Engagement and Education in Rare Disease Research
Chisholm, D.L.1
1TANGO2 Research Foundation, Hadlyme, Connecticut, USA
Background: TDD is an ultra-rare metabolic–neurological disorder with frequent life-threatening metabolic crises and limited clinical care guidelines. 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 and community-driven clinical care.
The TANGO2 Research Foundation’s Research Learning Network (RLN) uses innovative digital methods and stakeholder co-creation to educate patient families, clinicians & researchers, integrate caregiver input into research processes, and elevate advocacy for ultra-rare TANGO2 Deficiency Disorder (TDD) through technology-driven communication.
Methods: We implemented four key 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 are summarized and utilized to guide the foundation’s strategic research directions.
2. Community-Informed Research Engagement Roadmap: Input from 90+ stakeholders across 10 countries was collected through RLN workshops. Feedback informed priorities, including early diagnosis, metabolic monitoring, and nutritional interventions and produced a roadmap to align future collaborative research studies with community needs.
3. Multimedia Outreach: Patient-centered blogs, newsletters, social media campaigns and fundraising events (e.g., “Shine a Light”) amplify lived experiences, driving advocacy and increasing stakeholder engagement growth by 20%.
4. Live Stakeholder Heatmap: A dynamic tool that maps active RLN participants globally, fostering peer connection and enabling clinicians & researchers to identify geographic representation and outreach gaps.
Results:
Quarterly engagement from 90+ global stakeholders with over 295 forum threads and 68 discussion topics.
Research Engagement roadmap directly guided multiple externally funded and foundation funded proposals.
Educational events informed revisions in clinical study design.
Advocacy campaigns boosted RLN membership and global awareness by 17% over 1 year.
Conclusions: The TANGO2 RLN’s structured, technology-enhanced model supports patient-centered education, integrates caregiver perspectives into study design, and strengthens advocacy. This scalable framework aligns with many national organization’s criteria for patient engagement and education in rare diseases and offers a replicable model for other rare conditions.
TANGO2 Protein Expression in Mouse and Human Tissues: A Survey of Tissue and Sex Variability
Garretson, P.1, Powers, A.1, Ghaloul-Gonzalez, L.1
1Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Background: TANGO2 Deficiency Disorder (TDD) is an autosomal recessive disorder caused by mutations in TANGO2. It is a multi-system disorder characterized by seizures, episodic rhabdomyolysis, metabolic crisis, global developmental delay, and cardiomyopathy/arrhythmias. The function of TANGO2 and the pathophysiology of TDD remain poorly understood. Abnormalities in mitochondrial function, fatty acid oxidation, ER-Golgi trafficking and lipid homeostasis have been observed in TDD-derived cells. This study aims to examine TANGO2 protein expression across human and mouse tissues to identify potential tissue-specific and sex-based differences, and to better understand the complex phenotype of TDD and inform potential therapeutic targets.
Methods: Tissue expression analysis was performed on both human and mouse tissues. Human tissue samples were obtained from the Cooperative Human Tissue Network (CHTN) and age and sex matched wild-type C57BL/6J mice from The Jackson Laboratory (n=3 males, n= 3 females). Eight tissue types were obtained: brain, skeletal muscle, heart, liver, kidney, lung, small intestine, and spleen. Age- and sex-matched human tissues were obtained from three male and three female donors spanning three age categories: birth to 30 years, 30 to 60 years, and 60 to 90 years. Tissues were homogenized manually using mortar and pestle over dry ice and mixed with a protease inhibitor cocktail. TANGO2 protein levels were assessed via western blotting, with purified TANGO2 protein used as a positive control.
Results: TANGO2 was expressed in all mouse and human tissues analyzed. The highest expression levels were observed in the heart, kidney, and brain across both species. There was no sex-dependent expression identified in either species.
Conclusion: The widespread expression of TANGO2 aligns with the multisystem clinical presentation of TDD. High expression in the heart and brain supports the severe cardiac and neurological phenotypes observed in affected individuals. Unexpectedly high expression in the kidney, despite the absence of reported renal dysfunction in TDD to our knowledge, raises questions about potential late-onset kidney involvement. These findings support ongoing surveillance of renal function in individuals with TDD and highlight the need for further research into tissue-specific roles of TANGO2.
Thyroid Nodules in TANGO2 Deficiency Disorder: A Case Series Suggesting a Potential Novel Association
Castro Lorenzo, J.1,2, Espinosa Alvarez, S.A.1,2, Lalani, S.1,2, Miyake C.Y.1,2, Hoyos-Martinez, A.1,2, TANGO2 Research Foundation.3,BCM TANGO2 Team.1,2
1Baylor College of Medicine, Houston, Texas, USA, 2Texas Children’s Hospital, Houston, Texas, USA, 3TANGO2 Research Foundation, Hadlyme, Connecticut, USA
Purpose: To describe thyroid nodules identified in patients with TANGO2 Deficiency Disorder (TDD) and highlight a potential association with this disorder.
Background: From the TANGO2 deficiency disorder Natural History Study (NHS), initiated in 2018, among 136 participants, hypothyroidism was a common finding, affecting 45% of patients. All patients require treatment. Primary hypothyroidism in the general population is predominantly autoimmune in origin, but can result from other inflammatory, acquired, or genetic causes. In TDD, the etiology of hypothyroidism remains elusive and does not appear to be secondary to autoimmune thyroiditis. The prevalence of thyroid nodules in children is 1-2% but may be as high as 25% in at-risk populations, like those with autoimmune thyroid disease or certain genetic syndromes (i.e., PTEN hamartoma syndrome). These nodules carry a significantly higher risk of malignancy when compared to adults (~25% vs 5%).
We describe three TDD patients presenting with thyroid nodules, suggesting a potential previously unrecognized endocrine association.
Method: Data was obtained from the ongoing TDD NHS, which includes 136 participants from 105 families across 22 countries. Information was collected through parent interviews conducted via phone or video, annual follow-up assessments, and review of available medical records. The three cases included in this series were identified within this cohort and reviewed by physicians at Texas Children’s Hospital. All patients had genetically confirmed TDD.
Results: Three patients with TDD were identified with thyroid nodules. Ages ranged from 13–22 years at the time of diagnosis. Thyroid nodules were detected via palpation or ultrasound during evaluation for endocrine related concerns.
Case 1: An 18-year-old male with a homozygous exon 3–9 deletion in TANGO2 presented with a bilateral multinodular goiter. Fine-needle aspiration (FNA) was consistent with follicular neoplasm. He underwent a total thyroidectomy. Final pathology confirmed a follicular adenoma (benign) with an NRAS mutation. He had normal thyroid function and absence of thyroid autoimmunity. No prior thyroid disease or family history was reported.
Case 2: A 22-year-old female with a homozygous exon 3–9 deletion in TANGO2 and a family history of hypothyroidism was found to have non-malignant thyroid nodules on routine evaluation. She underwent a total thyroidectomy and was started on levothyroxine.
Case 3: A 13-year-old female with a TANGO2 missense mutation (c.460G>A; p.Gly154Arg) and an intronic variant (c.605+1G>A) presented with goiter and subclinical hypothyroidism, in the absence of autoimmune thyroid disease. No family history of thyroid disease was reported. Ultrasound identified multiple, bilateral nodules. FNA was suspicious for malignancy. She underwent a total thyroidectomy with central neck dissection. Pathology confirmed a follicular variant in the left lobe, with three more follicular adenomas bilaterally without metastasis.
Conclusion: This case series raises the possibility of an association between TDD and thyroid neoplasms, in patients without autoimmune thyroiditis, irrespective of their thyroid function. This may represent an underrecognized risk for thyroid neoplasms in this population.
Although larger studies are needed to clarify this potential association, the identification of thyroid nodules in three TDD patients (2.2%) suggests the need for routine screening, in addition to the previously recognized thyroid function. These findings support increased clinical awareness and further investigation into thyroid abnormalities in patients with TANGO2 deficiency.
Acknowledgement
This study was funded by the TANGO2 Research Foundation and NHLBI K23HL136932.
We’d like to acknowledge the Texas Children’s Hospital/Baylor TANGO2 Clinical Team
Developing Therapeutics for TDD Using a Zebrafish Model of TANGO2 Deficiency
Tate, G.R.1, Zhang, A.2, Gupta, V.A.1
1Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA, 2Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, Massachusetts, USA
Background: TANGO2 deficiency disorder (TDD) is a rare, multisystem metabolic disease characterized by recurrent episodes of rhabdomyolysis, cardiac arrhythmias, and metabolic crises that can be life-threatening. Rhabdomyolysis in TDD leads to rapid skeletal muscle breakdown and release of intracellular contents such as myoglobin, often resulting in acute kidney injury and systemic complications. These episodes are frequently triggered by metabolic stressors, including illness, fasting, or exertion. Despite its severity, there are currently no effective targeted therapies for preventing or treating TDD-associated rhabdomyolysis.
Methods: To address this unmet need, we developed a zebrafish model that recapitulates key features of TDD, including muscle pathology and susceptibility to metabolic and exertional stress. Using this in vivo system, we performed a small-molecule screen to identify compounds that prevent or delay onset of rhabdomyolysis under fasting and overexertion conditions.
Results: Several candidate compounds emerged that prevented onset of rhabdomyolysis and increased survival under stressor conditions. Together, these findings establish a robust platform for therapeutic discovery in TDD and highlight candidate compounds with potential translational relevance.
Conclusions: This work provides a foundation for developing targeted therapies to mitigate rhabdomyolysis and improve outcomes in patients with TDD.
