Patients’ lived experience of thymidine kinase 2 deficiency: the online survey-based assessment of TK2d patient perspectives study

Abstract

Background:

Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial disease characterized by progressive myopathy.

Objectives:

To understand patient experiences and the impact of TK2d on patient quality of life (QoL), and to explore support needs.

Design:

A cross-sectional international online survey.

Methods:

The survey for the Assessment of TK2d Patient Perspectives (ATP) study, co-created with patient advocates, included multiple-choice questions, verbal rating scales, and open free-text questions. Patients of all ages with a self-reported genetic diagnosis of TK2d were eligible to participate, either directly or through a caregiver proxy. The patient, caregiver proxy, or bereaved caregiver proxy answered questions on demographics, signs/symptoms, impacts on health-related QoL (HRQoL), support needs, healthcare resource use, and overall experience of living with TK2d. Quantitative data were summarized with descriptive statistics. Qualitative data were analyzed using inductive thematic analysis.

Results:

Responses for 32 patients (24 patient and 8 caregiver proxy responses) were collected between September 2023 and February 2024. All patients experienced myopathic symptoms. The most frequently reported impact of TK2d was on patients’ ability to perform basic activities of daily living (26/32), including difficulties in walking (22/32), eating/swallowing (19/32), and breathing (25/32). The proportions of patients reporting a moderate or severe impact of breathing and walking difficulties on HRQoL, and the proportions requiring medical devices, were higher for those with an earlier age of TK2d symptom onset (⩽2, vs >2 to ⩽12, or >12 years). For most patients, TK2d also had a negative impact on mood, social and leisure activities, and employment/education. Progressive loss of abilities, increasing dependency on others, and medical equipment use contributed to mental and emotional burdens.

Conclusion:

These quantitative and qualitative analyses of patients’ lived experiences highlight the substantial, progressive, and wide-ranging burden of TK2d.

Plain language summary

People living with thymidine kinase 2 deficiency experience a range of symptoms that are associated with substantial disease burden, which affect daily living and get worse over time

What is thymidine kinase 2 deficiency (TK2d)?

TK2d is a very rare, life-threatening, genetic disease that causes progressive muscle weakness. People with TK2d often lose the ability to walk, eat, or breathe without assistance.

Why was the study done?

Due to its rarity, medical knowledge about TK2d is limited. However, there is even less understanding about the symptoms and the day-to-day experiences of people with TK2d.

What did the researchers do?

The research team, which included specialists who treat the disease and groups that support patients with TK2d, created a survey with a series of open-text and close-ended questions about living with this disease. Responses were self-reported for patients aged 18 years or older, or provided by a caregiver for patients of any age.

What did the researchers find?

All 32 patients reported muscle-related symptoms, including loss of muscle strength in different parts of the body, leading to difficulties with walking, breathing, and eating/swallowing food and drinks. Other major problems were related to the nervous system, psychological issues, and a variety of conditions affecting the stomach/gut. Most patients reported a negative impact on their emotional state and their ability to join social and leisure activities, as well as employment or education. As patients got older, they often experienced an increase in loss of abilities, dependence on carers/family and need for medical equipment. Participants in the study described their frustration and anger at being unable to do ordinary things or needing help with everyday tasks. They often described feeling overwhelmed and isolated and were worried about the disease getting worse.

What do the findings mean?

This study shows that people with TK2d face a broad range of symptoms which are associated with a substantial impact on their day-to-day living, which gets worse over time and leads to greater and more diverse care needs.

Introduction

Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial disease caused by pathogenic variants in the thymidine kinase 2 gene and subsequent disruption to the synthesis of mitochondrial DNA (mtDNA).^{1 –4} TK2d reflects a spectrum of clinical manifestations but is typically classified into three main subtypes based on age of TK2d symptom onset and rate of progression: onset at ⩽2 years of age, characterized by severe myopathy, frequent neurological involvement, and rapid progression to early death, with a reported median post-onset survival of 1 year; onset at >2 to ⩽12 years, in which generalized proximal weakness occurs, often progressing to loss of ambulation within 10 years and the need for ventilator support, with a median post-onset survival of ⩾13 years; and onset at >12 years, which is characterized by facial and limb weakness and slow progression to respiratory insufficiency, with a median post-onset survival of 23 years.^2,5,6 The age-of-onset thresholds for these subtypes vary in the literature and atypical cases have also been described.^{2,5 –9}

It is challenging to accurately estimate the prevalence of ultra-rare diseases and TK2d is likely underdiagnosed ¹⁰ ; however, current estimates suggest a prevalence of 1.64 per million people worldwide (first and third quartiles [Q1, Q3]: 0.5, 3.1 per million), giving an estimated 1080 patients across the USA, France, Germany, Spain, Italy, and the UK. ¹¹

Doxecitine and doxribtimine is an oral pyrimidine nucleoside therapy that targets the underlying pathophysiology of TK2d by supporting mtDNA replication. ¹² As of November 2025 and March 2026, respectively, it became the first FDA- and EMA-approved treatment for TK2d for pediatric and adult patients with age of symptom onset ⩽12 years.^{12 –14} Patients who accessed treatment before this did so via compassionate use programs. Previously, without a disease-specific treatment, management of the condition relied on supportive care, preventing secondary complications and improving quality of life (QoL), which required a multidisciplinary healthcare team.^2,15 Many patients progressed to become dependent on caregivers and devices for assistance with activities of daily living (ADLs) such as wheelchairs, feeding support devices, and ventilators (invasive and non-invasive).^5,16

To date, reports on TK2d have predominantly focused on the presentation and progression of clinical outcomes; data on patient experience of symptoms and the impact on their daily lives and QoL are limited. The importance of capturing the broader impact of health conditions on physical health and abilities to perform ADLs, psychosocial functioning, and overall QoL is well recognized.^{17 –19} Data from a 2023 study of 25 patients with TK2d, collected using interviews and patient-reported outcome (PRO) tools, indicated that TK2d has a significant impact on PRO scores measuring physical and mental health, physical function, pain, fatigue, anxiety, and social function in adults, and on mobility and pain in children. ⁹ In a 2022 FDA patient listening session, patients and caregivers of patients with TK2d described the devastating impact of progressive symptoms, particularly those related to breathing, eating, and mobility, and the psychosocial consequences, and detailed the broad range of healthcare services used. ²⁰

The Assessment of TK2d Patient Perspectives (ATP) study aimed to collect a comprehensive set of quantitative and qualitative evidence of the lived experiences and burden of TK2d on both patients and caregivers, and identify potential unmet needs and priorities for improvements in care. Results on caregiver burden will be published separately.

The present analysis focuses on the patient experience and specifically aims to gain insights on their experiences of TK2d symptoms and impact on daily living, to assess the dependence of patients on caregivers, on medical devices, and on healthcare providers, and to explore the impacts of TK2d on previously identified physical and psychosocial domains of health-related QoL (HRQoL). ²¹

Methods

Survey design

This cross-sectional, mixed-methods, international online survey was designed to characterize the lived experiences of patients with TK2d and their caregivers.

The survey was co-created and pilot-tested by the study investigators with the support of international patient advisors. At the start of the survey, participants provided written informed consent electronically and answered screening questions to confirm eligibility. Patients, caregivers, and bereaved caregivers were directed to the questions relevant for them. Questions included quantitative multiple-choice questions and verbal rating scales, and qualitative open free-text questions designed to explore both the breadth and depth of patient experience. The three known major impacts of TK2d on breathing, walking, and the ability to eat and swallow were explored in depth.

The survey was hosted on the online Qualtrics^XM platform and was open from September 2023 to February 2024.

Patient recruitment and eligibility

Due to the rarity of TK2d, opportunity sampling was employed but participation was encouraged from a broad demographic by providing the survey in seven languages and giving special consideration in the survey design for patients using reading/writing aids and allowing completion in more than one sitting.

Patient organizations and clinicians across North America, Europe, South America, and Asia shared survey invitations with potential participants. Patients of all ages with a self-reported genetic diagnosis of TK2d were eligible to participate, either directly or through a caregiver proxy. This included patients aged ⩾18 years and caregivers of children (aged <18 years), or individuals who were unable to respond on their own – caregiver proxies. Patients who had received pyrimidine nucleos(t)ide therapy as part of a clinical trial were excluded but those who had received pyrimidine nucleos(t)ide therapy via a compassionate-use program (or by another means, such as self-pay or other access with non-pharmaceutical-grade nucleoside therapy) were eligible to participate. Patients actively enrolled in clinical trials were excluded to avoid any potential interference with trial procedures and regulatory endpoints. Patients receiving pyrimidine nucleos(t)ide therapy via compassionate-use programs were eligible because these programs provide treatment access outside a controlled clinical trial and did not pose the same risk to trial integrity.

Descriptive analysis

All survey responses were screened against the eligibility criteria and then tested for authenticity to ensure only genuine caregivers of patients with TK2d were included. The test for authenticity comprised a three-stage process involving: a predefined system that allocated points for fraud indicators; reviews by two independent researchers; and then reviews by members of the study steering committee.

Quantitative survey data were summarized with descriptive statistics. For analyses, patients were stratified by self-reported age of onset (⩽2 years; >2 to ⩽12 years, and >12 years) and patient age at the time of the survey grouped as follows: infants (⩽2 years); children (3–15 years); young adults (16–34 years); and adults (⩾35 years). Qualitative data were analyzed using inductive thematic analysis, with the analysis grounded to the data, following the Reflexive Thematic Analysis Reporting Guidelines, ²² with two researchers manually conducting the coding using NVivo. ²³

Given the ultra-rare nature of TK2d and the primarily descriptive aims of the study, no formal power-based sample size calculation was performed. Approximately 100 survey responses (50 patient responses and 50 caregiver responses) representing up to 50 individual patients (which would represent approximately one-third of patients known to the international TK2d community) were targeted.

Ethical considerations

This study was conducted in accordance with a predefined study protocol and relevant guidance, codes of conduct, and data protection acts. In line with the European Pharmaceutical Marketing Research Association code of conduct, this research study did not require approval by an ethics committee. In the USA, the study protocol was submitted to an Independent Review (WCG™) and an exemption was obtained. Data confidentiality was protected in accordance with Health Insurance Portability and Accountability Act of 1996 and General Data Protection Regulation and Data Protection Act 2018. All participants provided written informed consent electronically prior to completing the survey.

This manuscript was prepared in consultation with the Standards for Reporting Qualitative Research guidelines (Supplemental Table 1). ²⁴

Results

Responses

In total, 24 patients and eight caregiver proxies completed the survey. Participants were from 12 countries/territories in North America, Europe, South America, and Asia (Table 1).

Table 1.

Patient demographics and clinical characteristics.

Characteristic	All patients (N = 32)	Age of onset group
		⩽2 years (n = 12)	>2 to ⩽12 years (n = 10)	>12 years (n = 10)
Sex, female, n (%)	18 (56)	6 (50)	3 (30)	9 (90)
Age, median (range), years	30.5 (1–54)	23.5 (1–45)	28.5 (12–48)	39.0 (20–54)
Age category, a n
Infants (⩽2 years)	2	2	0	0
Children (3–15 years)	4	3	1	0
Young adults (16–34 years)	15	5	6	4
Adults (⩾35 years)	11	2	3	6
Geographic region, n
North America	15	3	4	8
Europe	11	5	4	2
South America or Asia	6	4	2	0
Age at diagnosis, median (range), years	25.0 (1–46)	11.0 (1–38)	22.5 (10–46)	37.0 (16–46)
Time from onset to diagnosis, median (range), years	10 (0–39)	9 (0–38)	13 (2–39)	3 (0–25)
Duration of TK2d, b median (range), years	18 (1–45)	22 (1–45)	18.5 (4–41)	14 (3–26)
Education/employment, n/N c
Children in education (mainstream or homeschooled)	3/3	3/3	–	–
Young adults not well enough for education/work	5/15	2/5	3/6	0/4
Adults not well enough for education/work	2/11	0/2	1/3	1/6
Employment in young adults	6/15	1/5	2/6	3/4
Employment in adults	4/11	1/2	2/3	1/6
Living situation, n
Live alone in own house	5	0	2	3
Live in household with other people	25	11	7	7
Live in facility such as nursing home which provides meals and 24-hour nursing care	2	1	1	0
Functional status, n
Able to complete all normal activities	3	1	1	1
Need some/significant modifications to normal life or some/significant support from another person	16	2	6	8
Need full-time support (from another person, at home, or at school and/or medical equipment at home/school)	9	5	3	1
Need full-time medical support (e.g. in hospital, medical home, hospice)	4	4	0	0
Treatment with nucleoside therapy, n
Currently receiving treatment via a compassionate-use program	6	5	1	0
Deceased but had been treated	1	0	1	0
Received treatment in the past	1	1	0	0

^aAge at time of survey completion.

^bCalculated as years from self-reported onset.

^cThe question on education/employment was asked for living patients (N = 30).

TK2d, thymidine kinase 2 deficiency.

Patient characteristics

Patient characteristics are described in Table 1. Of the 32 patients, 18 were female. The median age of living patients (30/32) was 31 years (range 2–54 years); two deceased patients were aged ⩽2 and 3–15 years. There were similar numbers of patients across the three age-of-onset categories. Overall, the median (range) age of onset was 25.0 (1–46) years and the median (range) number of years from self-reported onset to diagnosis was 10.0 (0–39) years. Overall, 8/32 patients had received treatment with pyrimidine nucleos(t)ide therapy via an expanded access or compassionate-use program (Table 1; the survey did not collect information comparing pre-and post-treatment experiences in any patient).

Symptoms and impacts

Symptoms were categorized according to the body system from which patients perceived them. While all patients experienced muscular/myopathy symptoms (proximal muscle weakness and fatigue, bulbar and facial, respiratory, ocular), neurological (poor coordination or balance, seizures, heat intolerance, pain or discomfort), psychological (anxiety, depression, mood swings, irritability), gastrointestinal (frequent sickness, nausea or vomiting, frequent constipation, frequent diarrhea), and musculoskeletal (joint stiffness, frequent bone fractures) symptoms were also prevalent (Figure 1).

Figure 1.

Categories of reported signs/symptoms by age of onset and age group.^a

^aDefinitions of age groups: infants, ⩽2 years; children, 3–15 years; young adults, 16–34 years; and adults, ⩾35 years.

Signs and symptoms included in each category:

^bMuscular/myopathy: proximal muscle weakness and fatigue, bulbar and facial, respiratory, ocular.

^cNeurological: poor coordination or balance, seizures, heat intolerance, pain or discomfort.

^dPsychological: anxiety, depression, mood swings, irritability.

^eGastrointestinal: frequent sickness, nausea or vomiting, frequent constipation, frequent diarrhea.

^fMusculoskeletal: joint stiffness, frequent bone fractures.

The most frequently reported muscular/myopathy symptoms were fatigue (29/32), upper body muscle weakness (27/32), lower body muscle weakness (25/32), ptosis (18/32), and difficulties swallowing (16/32). Most (29/32) patients had neurological symptoms, with pain or discomfort (20/32) and poor coordination or balance issues (18/32) most frequently reported. Psychological symptoms were experienced by 25/32 patients, with anxiety being the most common (19/32) and depression affecting 13/32 patients. Gastrointestinal symptoms affected over half of patients (17/32), most commonly frequent diarrhea (10/32). Approximately one-third of patients (11/32) had musculoskeletal symptoms, with joint stiffness described by eight patients, all aged ⩾18 years, and frequent bone fractures reported for one child and two young adults (Supplemental Table 2).

The types of symptoms experienced were generally similar irrespective of the age of onset, with few differences noted (Figure 1).

Impacts of TK2d

The most frequently reported impact of TK2d was on patients’ ability to perform basic ADLs (26/32), including difficulties walking and eating/swallowing, in addition to difficulties breathing (25/32; Figure 2; Supplemental Table 2). Muscle weakness was the most frequently reported cause of walking difficulties (22/22) and swallowing difficulties (16/19). A lack of energy/fatigue was also commonly reported as a reason for walking difficulties (13/22).

Figure 2.

Impact categories by age of onset and age group.^a

^aDefinitions of age groups: infants, ⩽2 years; children, 3–15 years; young adults, 16–34 years; and adults, ⩾35 years. Impacts are grouped by World Health Organization International Classification of Functioning, Disability and Health components – impairment, activity, and participation.

^bBasic ADLs include difficulties walking and eating/swallowing, issues with control of urine, and issues with bowel control.

^cDevelopment includes developmental delays and loss of normal milestones and/or functions.

^dPhysical development includes failure to thrive, losing weight, or unable to maintain weight, and malnutrition.

^eCommunication includes communication challenges, problems with non-verbal communication (e.g., nodding), and speech problems.

ADLs, activities of daily living.

Impact of breathing, walking, and eating and swallowing difficulties on HRQoL

On a rating scale from 0 (no impact) to 4 (extreme impact), a score of 3 or 4 for the impact of breathing difficulties (11/25), walking difficulties (15/22), and eating and swallowing difficulties (8/19) on HRQoL were frequently reported (Supplemental Figure 1). In particular, patients with an age of onset ⩽2 years reported high HRQoL impact scores, with a median score of 4 for the impact of breathing difficulties and walking difficulties (Supplemental Table 3).

Impact of TK2d on other HRQoL domains

When participants were asked to rate the impact of TK2d on mood, relationships with family, relationships with friends, social and leisure activities, employment or education, and finances, “extremely negatively” or “somewhat negatively” were the most frequent responses across all domains (Figure 3; Supplemental Table 4). The frequency of “negative” responses was highest for the impacts on social and leisure activities (27/32), mood (25/32), and employment and education (23/32).

Figure 3.

Impact of TK2d on HRQoL domains.^a

^aThe impact of TK2d on all aspects of HRQoL affects all age groups irrespective of age of onset. HRQoL, health-related quality of life; TK2d, thymidine kinase 2 deficiency.

Lived experience

One-third of young adults (5/15) and 2/11 adults were not well enough to attend education or work (Table 1). Results of the qualitative analysis are given in Supplemental Table 5 and summarized here. Frustration and anger at not being able to do things or needing help with everyday tasks, the fear of disease progression and becoming dependent on others, and feelings of being overwhelmed and isolated were commonly expressed.

For me it [the most challenging aspect of living with TK2d] would be the ever-growing weight of knowing the progression in muscle loss and increase in dependence on medical equipment and caretakers. It feels like an approaching storm you have no hope of outrunning. It comes with little reminders, an infection here, a new muscle group being lost to time. That creates a lot of stress, self hate, and anger at the world around you. Knowing I won’t be able to live the life I would rather have hurts.

Young adult, age of onset >2 to ⩽12 years (self-report)

Life was difficult and challenging, and described as exhausting and overwhelming. The combination of muscle weakness and fatigue limited patients’ activity, meaning their days had to be carefully planned to conserve energy and an increasing dependence on others. Once they became reliant on supportive equipment, their activities were further restricted, and it became much more difficult to leave home. Having TK2d meant that you would not have the life you had hoped for.

Living with TK2d isn’t easy. It’s daily survival and coping with extreme tiredness, difficulty breathing, swallowing and speaking, depending on other people, depending on a non-invasive respirator, routine daily care and home care, coping with emotions day to day, all the while being hopeful of better days ahead.

Adult, age of onset >12 years (self-report)

Being born with TK2d is like being born with a defective battery. It works well at first but in a few months, it starts to malfunction, and your energy is depleted more rapidly. Your body doesn’t perform as it should and gets worse over time until one day the battery stops working completely.

Young adult, age of onset ⩽2 years (self-report)

Disease progression

Breathing, walking, and eating and swallowing difficulties had progressed for most patients experiencing these impacts of TK2d, with a trend toward earlier progression to ventilation, wheelchair use/immobility, and tube feeding with younger age of onset (Supplemental Table 6).

Breathing difficulties

Patients described how their breathing had become more difficult and more tiring over time, with many progressing to reliance on assistive devices (Supplemental Table 7).

I led a relatively normal life until adolescence, when I started feeling breathless when talking or singing. At school, I started getting low grades for work where I had to present because I talked really quietly.

Young adult, age of onset ⩽2 years (self-report)

[Breathing difficulties] have become worse over the years because I can no longer be off of the ventilator for more than 30 seconds to 1 minute. Coming off of the ventilator for even a short time brings on a slight headache and the feeling of my lungs or chest deflating.

Adult, age of onset >12 years (self-report)

Breathlessness limited patients’ physical activity and made it difficult to participate in social activities. Reliance on breathing devices exacerbated these issues, further restricting patients’ daily lives and ability to do anything both at home and outside of the home (Supplemental Table 7).

Daily life attached to a breathing ventilator makes showering, using the bathroom and eating difficult. My life has become sedentary due to the use of the breathing ventilator.

Adult, age of onset >12 years (self-report)

Patients’ sleep was affected by their breathing difficulties and use of breathing devices. Breathing difficulties could also have an impact on speech, reduce patients’ independence, and cause distress when experiencing or anticipating breathlessness and fear of device failure.

Walking difficulties

Some infants and children with an age of onset ⩽2 and >2 to ⩽12 years were never able to walk or lost the ability early in childhood. Adults described their progressive loss of abilities (Supplemental Table 7).

[Child’s name] never had enough strength to walk, I never saw him stand, his muscles were too weak as a result of TK2d.

Infant, age of onset ⩽2 years (bereaved caregiver)

I lost the ability to run a long time ago. However, over time, I also lost the ability to squat. Lots of difficulty to rise from floor position, to walk for long periods of time and it’s extremely tiring and difficult to simply climb stairs. Now I avoid any activities or positions that’d be lower than sitting on a chair, to ensure I can get up.

Adult, age of onset >2 to ⩽12 years (self-report)

Among those who were ambulatory, walking difficulties made everyday activities such as self-care, household chores, working, and socializing a challenge. The distance walked was limited by fatigue, stairs had to be avoided, and the fear of falls meant that some would only go out when accompanied. Those in wheelchairs faced accessibility issues, and some were dependent on carers to operate their wheelchairs (Supplemental Table 8).

Wanting to walk like I used to and not being able to as I tire really quickly. It makes my legs really hurt to the point I have to sit down because I feel so weak, not being able to do lots of things at home and needing to ask for help, not being able to climb the stairs.

Adult, age of onset >12 years (self-report)

Eating and swallowing difficulties

As muscle weakness progressed, chewing and swallowing became more difficult, the types of food that could be eaten had to be adjusted, and mealtimes became exhausting (Supplemental Table 7).

I have to cut food into smaller pieces and chew food longer. I also use a straw with liquids because drinking/gulping sometimes causes me to choke. Certain foods like peanuts feel like the tiny pieces get stuck and have to drink a lot of liquid to feel it cleared.

Young adult, age of onset >2 to ⩽12 years (self-report)

Tube feeding was necessary when there was a risk of choking or aspiration, or difficulties in obtaining optimal nutrition. Mealtimes required planning and additional preparation of food, more time, chewing thoroughly, supervision, and dependence on devices, such as modified utensils or feeding tubes. These modifications introduced practical and logistical issues for patients and resulted in a loss of enjoyment of food and eating, making eating a stressful and tiring event. This reduced their ability to participate in social events centered around meals, leading to feelings of isolation and disconnection from others (Supplemental Table 8).

I have to really pay attention as I can choke on food easily. As such, I pay attention on what I can and cannot eat, and make sure I’m not putting myself in danger/alone when eating.

Adult, age of onset >2 to ⩽12 years (self-report)

End-of-life experience

Two caregivers completed the survey for deceased patients, including one infant and one child. Both patients had required full-time medical support, with breathing and eating difficulties necessitating ventilation and nasogastric tube feeding. Their combined symptoms and impacts of TK2d experienced included: upper and lower body muscle weakness; fatigue; pain or discomfort; frequent sickness; nausea or vomiting; frequent bone fractures; failure to thrive; malnutrition; developmental delays; loss of normal milestones and functional abilities; walking, breathing, and eating/swallowing difficulties; problems with non-verbal communication; irritability; and feelings of isolation. The causes of death were heart and respiratory failure.

His brain was completely unaffected but his muscles were failing so at times he would be frustrated that he could not throw the ball or speak anymore. He went from a normal happy 11-month-old baby to not being able to lift head, crawl, sit, speak. Over a period of 8 months the decline in skills lost was rapid.

Infant, age of onset ⩽2 years (bereaved caregiver)

Most challenging aspects of living with TK2d

Common themes expressed were often the combination of muscle weakness and fatigue that lead to difficulties in performing ADLs and subsequent loss of independence when support becomes necessary. These factors, alongside the progressive nature of TK2d and lack of treatments, contributed to an emotional burden that included fear, isolation, and depression (Supplemental Table 9).

For me it would be the ever-growing weight of knowing the progression in muscle loss and increase in dependence on medical equipment and caretakers. It feels like an approaching storm you have no hope of outrunning. It comes with little reminders, an infection here, a new muscle group being lost to time. That creates a lot of stress, self hate, and anger at the world around you. Knowing I won’t be able to live the life I would rather have hurts.

Young adult, age of onset >2 to ⩽12 years (self-report)

Positive aspects

Positive aspects of living with TK2d were reported by 21/32 patients including: learning resilience; growing in confidence; feeling more grateful; becoming more compassionate; experiencing personal growth; connecting with a supportive community; and feeling hopeful for potential treatments (Supplemental Table 9).

It grows you as a person. You learn resilience, trust, patience, bravery, and stamina, in both physical and mental health aspects.

Young adult, age of onset >2 to ⩽12 years (self-report)

Support needs

Support with daily living

Most patients (25/32) lived with other people, some (5/32) lived alone, and two lived in a specialized facility (e.g. a nursing home). Only 3/32 were able to complete normal activities without support, 16/32 required some/significant modifications to normal life or some/significant support from another person, and 13 required full-time support (Table 1).

Most patients (29/32) received support from another person to manage their daily life. Family or friends were the sole support for 19/32 patients, with parents being the primary caregivers in most cases. Professional care, with or without additional care from family/friends, was reported for 7/32 patients (Table 2).

Table 2.

Medical device use, support needs, and healthcare resource use by age of onset.

Measured parameter	All patients (N = 32)	Age of onset group
		⩽2 years (n = 12)	>2 to ⩽12 years (n = 10)	>12 years (n = 10)
Use of medical devices, n
For breathing, walking, and/or eating	22	9	7	6
Breathing equipment	20	9	6	5
Walking aids or wheelchairs	10	5	3	2
Nasogastric tubes or gastrostomy for feeding	8	5	3	0
Support, n
Requirement for support from another person to manage their daily life	29	12	9	8
Reliance solely on family or friends for support	19	8	6	5
Professional care (with or without additional care from family/friends)	7	3	1	3
Healthcare resource use in the last 12 months, a n
⩾1 day in hospital	19	6	6	7
⩾20 days in hospital	5	2	2	1
⩾10 healthcare appointments	20	8	5	7
⩾30 healthcare appointments	8	4	2	2

^aOr 12 months prior to death for deceased patients (data on the reason for or the type of these medical appointments [e.g., emergency visits, scheduled follow-ups, urgent care, specialist consultations] were not collected).

All but one patient aged ⩾18 years (25/26) required support with household tasks inside the home, 24/26 needed help with household tasks outside the home, and 20/26 required assistance with transport/travel outside the home; 14/26 reported needing help with self-care.

Medical needs

Medical devices for breathing, walking, and/or eating were required by 22/32 patients (Table 2). The majority of patients (20/32) used breathing equipment, with the proportion being higher in patients with a younger age of onset. The most frequently used pieces of breathing equipment were bilevel positive airway pressure and continuous positive airway pressure machines. The use of walking aids or wheelchairs was reported for 10/32 patients, and the requirement for nasogastric tubes or gastrostomy tubes for feeding was recorded for 8/32 patients. The frequency of use of these devices was again higher in patients with a younger age of onset. Two patients, both with an age of onset ⩽2 years, were immobile.

Healthcare resource use

In the last 12 months (or final 12 months for deceased patients), 19/32 patients had spent ⩾1 day in hospital and 5/32 patients had spent ⩾20 days in hospital (Table 2). Over the same 12-month period, 20/32 patients had ⩾10 healthcare appointments, and 8/32 had attended ⩾30 healthcare appointments. Among patients aged ⩾18 years, 14/26 spent ⩾5 h per month coordinating care and 4/26 spent ⩾20 hours per month coordinating their care.

Discussion

The quantitative and qualitative data on the experiences of 32 patients with TK2d from across North America, Europe, South America, and Asia reported here provide a comprehensive picture of the broad range of symptoms and HRQoL impacts of TK2d across age of onset, and the extensive support required from both caregivers and healthcare services. These findings provide a valuable addition to current knowledge and understanding of the patient experience of TK2d.

Previous studies have generally focused on the clinical manifestations of TK2d, detailing the wide spectrum of clinical phenotypes, and the most common symptoms, such as progressive muscle weakness in the limbs, face, neck, oropharynx, and respiratory muscles, as well as ptosis and ophthalmoparesis in the late-onset form.^{2,4 –6,25 –27} The present study confirms and extends the impact of TK2d by showing the high prevalence of neurological, psychological, and gastrointestinal symptoms in addition to the universal myopathy symptoms. These findings complement existing natural history studies by providing patient-reported perspectives on daily-life impacts that clinical reports do not typically capture. They also highlight gaps in scientific knowledge, particularly around the psychosocial burden associated with this progressive disease. In relation to previously published QoL work, our results are broadly consistent with Amtmann et al. (2023), ⁹ which also reported substantial limitations in physical functioning, fatigue, and social participation. The present study provides evidence based on robust mixed-methods research based on a larger cohort of patients for understanding the depth of experience, emotions, and personal perspectives (such as fear of progression, isolation, and emotional strain), which quantitative measures alone, like standard PRO instruments, are unable to express, and provides qualitative insights into how patients feel, think, and navigate the realities of living with TK2d.

Myopathy symptoms, most commonly fatigue and upper and lower body muscle weakness, as the core cause of the challenges of living with TK2d were clearly represented throughout the narratives of patients and caregivers. Their impact on breathing, walking, eating, and functional ability underpinned patients’ increasing dependency on others and medical devices, and the associated worsening of emotional and mental health. The progressive course of disease is characterized by an increasing physical, mental, and psychosocial burden experienced by patients over time, with a constant need to adapt to new limitations and loss of independence; indeed, in a recent study, the impact on ADLs and need to adapt to preserve independence and QoL were identified as central themes of patient experience of mitochondrial myopathy. ²⁸

As patients became more reliant on medical devices, their ability to perform ADLs, leave the home, or participate in social activities was further reduced, and anxiety and fear of equipment failure added to the psychosocial burden. Breathing equipment interfered with sleep, which may have affected the fatigue already experienced by patients with TK2d. These findings are confirmed by previous reports of the psychosocial impacts on patients receiving long-term home ventilation and tube feeding, including fear and acceptance of being dependent, anxiety, inability to perform ADLs, limits to mobility and travel, and interference with family life, intimate relationships, professional and social activities, and hobbies.^{29 –31}

Patients with an age of onset ⩽2 years generally had the highest level of HRQoL impact related to breathing, walking, and eating and swallowing difficulties, and reported the greatest need for and progression to the use of supportive medical equipment (walking aids, wheelchairs, breathing equipment, feeding tubes). These results are in line with the established clinical phenotypes for these age-of-onset subgroups.^2,5,6 Nonetheless, the symptoms and impacts experienced were similar across all phenotypes and the HRQoL of patients of all ages was impaired.

More than half of patients with an age of onset ⩽2 years were aged ⩾16 years at time of completing the survey, so it is likely that the most serious cases of TK2d were underrepresented. Patients with an age of onset ⩽2 years are known to experience rapid progression and early death (reported median post-onset survival of 1 year), and therefore our sample was almost exclusively a “survivor” population.^2,5 The association between age of onset and survival is also documented in other mitochondrial diseases (e.g., mitochondrial cardiomyopathy, chronic progressive external ophthalmoplegia plus and sensory ataxic neuropathy, dysarthria, and ophthalmoparesis). ³² Given the potential greater disease burden among patients with age of onset ⩽2 years, the severity and impact of those symptoms, as well as their association with age of onset, may be underestimated in the present study. As such, further research may be required to fully explore and understand the patient experience in the most severe and rapidly progressive cases of TK2d that represent the most common outcome for those with age of onset ⩽2 years.

The proportion of patients requiring support with ADLs was also greater in patients with a younger age of onset, but the current age of the patients was likely a contributing factor because some patients in the age of onset ⩽2 years subgroup were infants. Overall, there was a high need for modifications or support reported for patients of all ages. For healthcare resource use, associations with age of onset were less clear.

The considerable negative impact of TK2d across multiple HRQoL domains is consistent with reports on other rare diseases such as mucopolysaccharidosis and spinal muscular atrophy, which have detailed a wide range of impacts on patient HRQoL, including physical, social, mental, and emotional functioning.^{33 –36} The described challenges with healthcare, such as low levels of awareness and understanding among some healthcare professionals, are also common to other rare diseases. ³⁴

Limitations

It is important to consider the limitations of this study when interpreting the results. Although the total number of patients (N = 32) included is relatively high in the context of TK2d as an ultra-rare disease, the sample size precluded inferential analysis of differences between the patient subgroups. Additionally, given the ultra-rare nature of TK2d, the quantitative component used opportunity sampling with a recruitment target rather than a power-based sample size calculation. Therefore, quantitative findings, particularly subgroup patterns, should be interpreted cautiously; however, some trends were observed that may support associations with age of onset, disease severity, and rate of progression.

As for all surveys, people who can participate may not be fully representative of a patient population, but steps were taken to minimize this bias by ensuring that the survey was accessible for those using assistive technologies, allowing caregivers to answer on behalf of patients and including bereaved caregivers. Nonetheless, only two bereaved caregivers participated, limiting the ability to explore rapidly progressive and end-stage disease more fully. Medical confirmation of age of onset was not requested, and it is possible that medical opinion may differ from the patient or caregiver perspective on the early symptoms of disease, and in part, account for the large proportion of age of onset ⩽2 years “survivors” in the study. More broadly, because all information in this study was self‑reported, the accuracy of symptom prevalence and some patient‑described disease impacts may be influenced by recall or reporting bias. This should be taken into account when interpreting the descriptive patterns presented.

Despite these limitations, our study remains the largest qualitative study of patient experience in TK2d to date and adds considerable depth to the understanding of its impact on the lives of those affected. Comprehensive information on all aspects of the patient experience of TK2d can help to improve education and awareness of the disease and facilitate optimization of management, while also informing the design of future studies on the disease and emerging treatments, to ensure that new developments best serve patients’ needs.

Conclusion

This study, the largest of its type describing the lived experiences shared by patients of all ages and phenotypic subtypes, illustrates that TK2d imposes a substantial and progressive health burden on patients. This is marked by debilitating physical impacts and severe psychological strain, which profoundly affect daily functioning and overall well-being/HRQoL, particularly difficulties in breathing, eating/swallowing, and walking. As a result, patients require considerable support from caregivers and healthcare services.