Navigating Life With Primary Mitochondrial Myopathies: The Importance of the Patient Voice and Implications for Clinical Practice

Abstract

Primary mitochondrial myopathies (PMM) are rare disorders with diverse and progressive symptom presentations that cause a substantial, detrimental impact on the quality of life of patients and their caregivers. The burden of symptoms is compounded by their visibility and their unpredictable, progressive nature, leading to a sense of social stigmatization, limited autonomy, social isolation, and grief. There is also a lack of awareness and expertise in the medical community, which presents huge obstacles to diagnosis and provision of coordinated multidisciplinary care for these patients, along with a lack of disease-modifying treatments. The present commentary serves to raise awareness of the challenges faced by patients with PMM and their caregivers in their own words, including diagnostic delays, the burden of disease, and the need for further trials to develop disease-modifying treatments and improved understanding of the disease course. We also provide commentary on considerations for clinical practice, including the need for holistic care and multidisciplinary care teams, details of common ‘red flag’ symptoms, proposed diagnostic approaches, and suggested descriptions of multisystemic symptoms for physician-patient dialogue. In addition, we highlight the role patient advocacy and support groups play in supporting patients and providing access to reliable, up-to-date information and educational resources on these rare diseases.

Introduction

Primary mitochondrial myopathies (PMM) are rare disorders within the group of primary mitochondrial disorders (PMD) that are caused by genetic mutations in mitochondrial or nuclear DNA and predominantly, though not exclusively, affect skeletal muscle.^{1 -3} Mitochondrial disorders are estimated to affect ~1:4300 to 1:5000 people, although determining the true prevalence of PMM is difficult and there are limited epidemiological studies.^3,4 PMM can affect both men and women, and present at any age across individuals of all ethnic and racial groups.^3,4 Given the genetic involvement of mitochondrial disorders, family members are commonly affected, although the specific inheritance pattern varies according to the type of mutation and may even present sporadically. ⁵

Although symptom presentation of PMM is diverse, patients with PMM commonly present with ocular myopathy (chronic progressive external ophthalmoplegia, CPEO). ² In addition, mitochondrial myopathies may involve multiple organ systems, such as in patients with Kearns-Sayre syndrome (KSS), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and myoclonus epilepsy with ragged-red fibers (MERRF).^2,5 Symptoms are generally progressive ⁶ and cause a substantial detrimental impact on the quality of life, with lifelong and far-reaching physical, emotional, social, and financial implications for patients and their caregivers.^{7 -9}

The lack of awareness and expertise in the medical community present huge obstacles to diagnosis ¹⁰ and to the provision of coordinated multidisciplinary care needed to support patients and their families.^2,8,9 Furthermore, patients are also faced with a lack of disease-modifying treatments, with most care being centered around symptom management. ²

The aim of this article is to raise awareness of PMM, outline the challenges faced by patients and their caregivers, and to share the experience and guidance developed by the Mitochondrial Medicines Society (MMS) and the United Mitochondrial Disease Foundation (UMDF) on the diagnosis and effective management of PMM.^11,12 The commentary includes perspectives from 4 adult patients with PMM and 2 caregivers, who were identified through the UMDF, and their testimonials were obtained via semi-structured interviews. These testimonials have been included in this commentary to discuss how they may inform clinical practice. Informed consent was gathered from all patients and caregivers to publish their testimonies.

Challenges in Diagnosis

It is estimated that patients may see an average of 8 clinicians before being diagnosed, and diverse symptom presentation can contribute to delays in diagnosis. ¹⁰ In our conversations with the PMM community, diverse and multisystemic symptom presentation was also identified, with commonly reported symptoms including fatigue, exercise intolerance, weakness and pain, stroke-like symptoms, vision problems, and slurred speech or general cognitive difficulty. Additionally, patients and caregivers often expressed their frustrations with the lengthy diagnosis process, indicating that PMM was often mistaken for conditions such as multiple sclerosis, muscular dystrophy, and rheumatoid arthritis. Similar to experiences of patients reported in the published literature, ⁹ we have found that it is common for patients to report feelings of frustration, loneliness, and desperation during their path to diagnosis. Indeed, patients felt they needed to facilitate their diagnosis through a combination of self-advocacy, independent research, and access to the right specialist.

Illustrative quotes

“I started having trouble with difficulty breathing, swallowing, speaking, holding my eyes open, which led to one doctor after another, after another. . . A lot of doctors try to say it’s psychological.” (Patient)

Considerations

There is a clear need for prompt and accurate diagnosis for patients with PMM. Patients may present with “red-flag” symptoms (see Box 1), or multi-organ involvement. ¹³ Patients with mitochondrial disorders may also have genetic mutations that make them susceptible to diabetes ¹⁴ and, in our experience, the combination of either diabetes and hearing loss or unexplained ptosis and eye movement problems are particularly important red flags for further evaluation for mitochondrial disease. However, it is important that patients who present with more unusual symptoms are not overlooked. Specialists such as neurologists and clinical geneticists also play an important role in facilitating more rapid diagnosis, ¹⁰ and advances in genomics using “massive parallel sequencing” or next-generation sequencing have been pivotal in improving diagnosis for patients with PMM. ¹¹ In 2015, the MMS published the Diagnosis and Management Consensus Statement on the steps for genetic testing of patients with suspected mitochondrial disorders. ¹¹ A proposed diagnostic approach, based on these recommendations, and those of Watson et al, ¹⁵ is shown in Figure 1.

Box 1.

Red-Flag Symptoms for PMM.

Adapted with permissions from Haas et al 13 Pediatrics Neurological  • Cerebral, stroke-like lesions in a non-vascular pattern (brain lesions that do not appear like a regular stroke on imaging) 16  • Basal ganglia disease (physical dysfunction such as would occur with Parkinson’s disease) 16  • Encephalopathy, recurrent, or with low/moderate dosing of valproate  • Neurodegeneration  • Epilepsia partialis continua (recurrent epileptic seizures that affect specific areas and recur every few seconds or minutes for extended periods) 16  • Myoclonus (jerky contraction of groups of muscles) 16  • Ataxia  • Magnetic resonance imaging (MRI) findings consistent with Leigh’s disease (focal, bilaterally symmetric lesions in the basal ganglia, thalamus, substantia nigra, and the brainstem) 17  • Characteristics MRI spectrum peaks:    ○ Lactate (1.3 ppm), time to echo at 35 and 135    ○ Succinate (2.4 ppm) Cardiovascular  • Hypertrophic cardiomyopathy with rhythm disturbance (think heart muscle that can lead to irregular heartbeat) 16  • Unexplained heart block in a child  • Cardiomyopathy with lactic acidosis (>5 nM)  • Dilated cardiomyopathy with muscle weakness  • Wolff-Parkinson-White arrhythmia (a disorder of the heart’s electrical system that can cause fast heartbeat, palpitations, shortness of breath, and fainting) 16 Ophthalmological  • Retinal degeneration with signs of night blindness, color-vision deficits, decreased visual acuity, or pigmentary retinopathy  • Ophthalmoplegia/paresis  • Fluctuating, deconjugate eye movements  • Ptosis  • Sudden- or insidious-onset optic neuropathy/atrophy Gastroenterological  • Unexplained or valproate-induced liver failure  • Severe dysmotility  • Pseudo-obstructive episodes Other  • A newborn, infant, or young child with unexplained hypotonia, weakness, failure to thrive, and a metabolic acidosis (particularly lactic acidosis)  • Exercise intolerance that is not in proportion to weakness  • Hypersensitivity to general anesthesia  • Episodes of acute rhabdomyolysis (death of muscle fibers which are then released into the blood stream) 16

Figure 1.

Proposed diagnostic approach based on Parikh et al ¹¹ and Watson et al ¹⁵ .

Abbreviations: 3MG, 3-methylglutaric; COX, cytochrome c oxidase; CSF, cerebrospinal fluid; CT, computed tomography; H&E, hematoxylin and eosin; MRI, magnetic resonance imaging; mtDNA, mitochondrial DNA; NGS, next-generation sequencing; NADH-TR, nicotinamide adenine dinucleotide-tetrazolium reductase; PMM, primary mitochondrial myopathy; SDH, succinate dehydrogenase.

The Mitochondrial Care Network (MCN) https://www.mitonetwork.org/

The MCN represents a collaboration of physicians with expertise in mitochondrial disease and provides a valuable role in helping clinicians connect with specialist centers as well as providing useful guidance on diagnosis and care.

The MCN was created to improve the quality of care for patients with mitochondrial disorders and to implement best practices and standards of care in mitochondrial medicine.

Following a diagnosis of PMM, patients should be encouraged to engage with the MCN to facilitate the next steps in their multidisciplinary care needs. The MCN serves to provide support and information for patients, including:

• The Guide for Newly Diagnosed Patients, available at: https://www.mitonetwork.org/patient-guide

• The MCN Telehealth Network (https://www.mitonetwork.org/telehealth), where patients can connect virtually to mitochondrial specialists in their state across the US

Living Eith PMM

Physical Symptom Burden

In our conversations with patients and caregivers, they detailed the burden of symptoms, which included frequent debilitating fatigue, a commonly reported symptom of PMM. ² Commonly reported symptoms are shown in Box 2. Symptoms are often progressive, ⁶ and patients described feeling as if their bodies were shutting down.

Box 2.

Discussing Mitochondrial Disease Symptoms With Patients.^18,19

The unpredictability of symptoms makes planning and participation in daily life difficult for patients. Many spoke of the need to make adaptations to their lifestyles and living situations due to PMM; insights that align with those of other patients with PMD. ⁹

Illustrative quotes

“The left-sided stroke-like symptoms are my worst and the scariest because they can go on for a day or for 2–3 months. . .” (Patient)

“[Eye spasms are] the worst – it’s when I can’t control my eyes. When they’re spasming [non-stop] for hours and hours. I have to go to bed. There is no way I can function at all.” (Patient)

“If she can’t get on top of a headache, she will start drooling and slurring her speech. It’s almost like she’s having an actual stroke.” (Caregiver)

“I have swallowing problems. It’s the scariest thing in the world.” (Patient)

“She’s not getting better. She’s getting worse. . .” (Caregiver)

Emotional and Psychological Burden

Patients and caregivers expressed despair and a sense of grief and loss due to their worsening symptoms, which was also reflected in a previous study, where a direct correlation between disease progression scores and impact on quality of life was reported in patients with mitochondrial disorders. ⁷

Illustrative quotes

“I think the hardest part of it all was you mourn the self you could have been. I had found [a career] that I was good at, and I loved. . . and that was taken from me. The fact that I can’t have kids, I always thought I was going to be a mom. . .That’s the life that I didn’t get to have. . .” (Patient)

Impact on Social and Professional Life

The burden of symptoms is compounded by their visibility, for example, eye spasms and drooping eyes, twitching and jerking, and slurred speech, which makes patients feel vulnerable to discrimination and socially excluded because of a lack of recognition of the disease by peers, family, friends, and employers.

Although some patients can adapt their lifestyle to help manage their condition, the increased financial burden of managing their symptoms and their impact on their daily life in the absence of effective treatments is substantial. As their PMM progresses, patients feel more vulnerable and increasingly reliant on caregivers due to the physical weaknesses experienced, leading to a loss of independence. Many patients also described being unable to work because of their symptoms. Furthermore, the unpredictability of their symptoms makes patients anxious and causes difficulties in planning an active life. Consequently, patients experience shrinking social worlds, leading to a sense of isolation.

Illustrative quotes

“I want to work. But there’s nothing I can do. . .” (Patient)

“Mito can be very isolating. Finding the right support network, where you’re not a burden. . . is really tricky. I’m [training] a service dog because I’m trying to gain little aspects of my independence back.” (Patient)

Lack of Disease Awareness and Disease Narrative

In our experience, patients and caregivers appeared to lack clear mental models about how mitochondrial diseases work and what is going on in their bodies. Consistent with a previous report in patients with mitochondrial disorders, ⁸ patients we spoke with struggled to describe their condition accurately to their healthcare teams, which they felt was compounded by the general lack of awareness of PMM in the medical community. To explain their condition to others, they may refer more often to their comorbidities, for which they have clearer mental models.

Illustrative quotes

“When I say I have ‘mitochondrial disease’ there’s no recognition whatsoever. The closest thing I can say to them is it’s similar to MS. . . It’s really challenging to try to explain it to anyone else. . .” (Patient)

Medical Homelessness

Once their PMM is diagnosed, patients can feel validated but ultimately helpless, given how little is known about PMM and the lack of treatments available. Patients and caregivers often expressed a general feeling of medical homelessness—being marginalized from the mainstream healthcare system, which they felt was not able to support them. A lack of PMM specialists was commonly noted, with some adult patients having follow-up appointments with pediatric neurologists. There was also a sense of diagnostic demotion for those who were previously misdiagnosed with more well-recognized conditions.

Illustrative quotes

“[Most of us with mitochondrial disease] feel that we’re alone and that there is no care. . .” (Patient)

Lack of Disease-Modifying Treatments and Scavenging for Relief

Currently, there is a lack of disease-modifying treatment options for PMM, with most care centered around symptom management and involving exercise therapy, speech therapy, and mixtures of various dietary supplements and mitochondrial co-factors, often termed “mito-cocktails.”^2,20 In our conversations with patients and caregivers, they expressed how helpless this made them feel, with many stressing the financial burden of out-of-pocket expenses for “mito-cocktails” and adaptations to their living arrangements.

Considerations

Specialist centers in mitochondrial disease care have formed to support the diagnosis and multidisciplinary care of patients and provide patients with the opportunity to participate in clinical trials for mitochondrial disease.

The MMS Patient Care Standards Consensus Statement ¹² provides guidance on the complex, multidisciplinary care requirements of patients. The MCN ²¹ also serves to guide clinicians in the provision of clinical care for patients living with PMM and helps clinicians connect with mitochondrial disorder specialists.

Patient advocacy organizations can play a critical role in supporting and connecting patients with others with similar experiences as well as providing information and educational resources.^22,23 Previous research suggests that patients with mitochondrial disease find such groups beneficial. ¹⁰ Patients in the US can connect with other patients and gain access to valuable educational materials through the following institutions.

• The United Mitochondrial Disease Foundation (UMDF) https://www.umdf.org/

The UMDF is a network of top clinicians, hospitals, and researchers, as well as US-wide ambassadors, focused on promoting research and education for the diagnosis, treatment, and cure of mitochondrial disorders, and providing support to affected individuals and their families. The UMDF provides a wealth of educational resources for patients, in addition to facilitating connections to other patients or UMDF ambassadors, and links to clinical trials that are actively recruiting.

• MitoAction https://www.mitoaction.org/

MitoAction is a patient advocacy organization founded by patients, parents, and hospital healthcare leaders to improve the quality of life for patients with mitochondrial disorders. MitoAction provides various ongoing education and support programs and helps connect patients and their families with others who understand the challenges and journeys these individuals face.

An important observation from our discussion with patients is the need to develop a shared vocabulary for common PMM symptoms and patients’ experiences to facilitate discussion between patients and healthcare professionals. To facilitate physician-patient dialogue, the descriptions of commonly-occurring multisystemic symptoms of PMM are shown in Box 2.

Clinical Trials

Clinical trials exploring potential disease-modifying therapies for mitochondrial disorders targeting various underlying mechanisms within the broad spectrum of mitochondrial disorders are underway. ²⁴ Previous reports show patients with mitochondrial disorders are keen to take part in research and clinical trials. ⁸ Indeed, patients and caregivers we spoke with mirrored these feelings, but were frustrated by the limited number of studies and at often being excluded from such trials.

Designing clinical trials for patients with PMD is challenging given their rarity and heterogeneity, the lack of knowledge on the natural history of the disease course, the lack of validated biomarkers and outcome measures for clinical assessments, and the variable and unpredictable nature of the disease. ²⁴ Consequently, clinical trials to date have typically targeted specific types of PMD, reflecting the targeted mechanism of action of these new therapies. ²⁴

Considerations

There is a clear need for further research into PMM. Further clinical trials into novel therapeutics for PMM are required, and these trials would require broad inclusion criteria. Diverse populations of patients with PMM should be included from a range of socioeconomic and cultural backgrounds, and representative of different PMM subtypes. Given the heterogeneity and rarity of mitochondrial diseases, such trials would need multicenter collaboration and detailed phenotypic subgroup analysis, as suggested by other researchers. ²⁵ Multi-site national disease registries could also facilitate the development of multicenter trial networks ²⁶ and help to improve the understanding of the natural progression of PMM.

Summary

Patient and caregiver insights into lived experiences of PMM highlight the many challenges faced by these patients.^8,9 Aside from diagnostic challenges, the lives of patients with PMM are impacted by the lack of awareness of these conditions. The burden of symptoms is compounded by their visibility and their unpredictable and progressive nature, leading to a sense of social stigmatization, limited autonomy, social isolation, and grief. These insights from people living with PMM and their caregivers highlight a clear unmet need for improved disease awareness of PMM within the medical community to support the coordinated multidisciplinary care needs of people living with PMM. In the absence of disease-modifying therapies, holistic care is of great importance. Evolving clinical guidance and the work of specialist centers supported by multidisciplinary teams play an important role in supporting patients living with PMM and their caregivers. In conjunction, patient advocacy and support groups also play a critical role by providing a channel for exchanging experiences, forming connections, and providing links to reliable and up-to-date information and educational resources.