Clinical Presentation of Primary Mitochondrial Myopathy

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Salman Feroz Bhai	--	1222	2023-02-27 08:41:42	\|
2	format correct	Conner Chen	+ 15 word(s)	1237	2023-02-27 09:33:11	\|

This entry is adapted from the peer-reviewed paper 10.3390/muscles2010007

The diagnosis of primary mitochondrial myopathy is often delayed by years due to non-specific clinical symptoms as well as variable testing of mitochondrial disorders. Although a range of symptoms within a clinical presentation may exist in primary mitochondrial myopathy (PMM), there are prominent features to consider when evaluating patients for mitochondrial myopathy. Additionally, PMM is a progressive disease, with symptoms worsening over time, and with the possibility of newer symptoms developing as the disease progresses.

mitochondrial myopathy genetics myopathy

1. Clinical Presentation

Primary mitochondrial myopathy (PMM) is a progressive disease that is both genetically and phenotypically variable and can manifest in a variety of ways. Although originally thought to be extremely rare, mitochondrial DNA (mtDNA) disorders currently affect approximately 1 in 4300 of the population ^[1]. Today, mutations in over 350 genes in both mitochondrial and nuclear genomes affecting multiple aspects of mitochondrial dynamics have been identified as causing PMM ^[2]^[3], along with a wide range of overlapping clinical phenotypes ^[4]. Table 1 below offers some examples of genes causing mitochondrial disorders.

Table 1. Features of select mitochondrial disorders.

Disease	Genes	Mutation Mechanism	Clinical Features	Inheritance
CPEO ^[5]	POLG1, 2, ANT1, OPA1, MPV17, TK2	mtDNA replication maintenance and transcription	Ptosis, myopathy, bilateral ophthalmoparesis	Autosomal dominant, recessive, sporadic, or maternal
MELAS ^[6]	MT-TL1, MT-ND1, 5	mt tRNA and OXPHOS CI subunit	Stroke-like episodes, myopathy, encephalopathy, seizures	Maternal
KSS/PS	Can be anywhere in the mitochondrial genome	mtDNA single or large-scale deletions (~2–10 kb of mtDNA)	CPEO, myopathy, onset before 20 years, cardiomyopathy	Maternal, sporadic
MERRF ^[7]	MT-TK	mt tRNA	Generalized epilepsy, ataxia, myopathy, ragged red fibers	Maternal, sporadic
CoQ10 deficiency ^[8]	COQ2, 4, 6, 7, 8A, 8B, 9, PDSS1, 2	OXPHOS electron transporter	Early infantile onset encephalopathy	Autosomal recessive
TK2 deficiency ^[9]	TK2	Mitochondrial maintenance defect; nucleotide pool maintenance	Infantile onset myopathy, proximal weakness	Autosomal recessive
LHON ^[10]	MT-ND1, 4, 4L, 6	OXPHOS CI subunit mutation	Optic atrophy, possible multisystem involvement, cardiomyopathy	Maternal
LS ^[11]	SURF1, MRPS34, MT-ND3, MT-ATP6	OXPHOS CI and CV subunits, mt ribosomes, and CIV assembly	Developmental delay, regression, ataxia, respiratory abnormalities	Autosomal recessive

Examples of genes leading to mitochondrial disorders (adapted from ^[4]^[12]). This list is not exhaustive. These disorders result in various degrees of oxidative phosphorylation (OXPHOS) dysfunction depending on the mutation. For a more comprehensive list please visit MITOMAP. CPEO: chronic progressive external ophthalmoplegia (OMIM ID: #157640), MELAS: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (OMIM ID: #540000), KSS/PS: Kearns-Sayre syndrome/Pearson syndrome (OMIM ID: #530000), MERRF: myoclonus epilepsy and ragged red fibers (OMIM ID: #545000), LS: Leigh Syndrome (OMIM ID #256000), LHON: Leber’s hereditary optic neuropathy (OMIM ID: #308905), TK2: Thymidine Kinase 2 (OMIM ID *188250), CoQ10: Coenzyme Q10 (OMIM ID: #607426).

PMM is a highly variable disorder that exists on a spectrum, ranging from adult-onset single-organ system involvement to infantile-onset multisystem dysfunction and lethal disease ^[13]. Although named or multisystem disorders (i.e., mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), or Kearns-Sayre/Pearson syndrome: OMIM ID #530000, etc.) ^[14]^[15]^[16] may include myopathy, this clinical feature is often overshadowed by other symptoms.

Although a range of symptoms within a clinical presentation may exist in PMM, there are prominent features to consider when evaluating patients for mitochondrial myopathy. Additionally, PMM is a progressive disease, with symptoms worsening over time, and with the possibility of newer symptoms developing as the disease progresses ^[17].

2. Exercise Intolerance

Most individuals with PMM will have limited exercise capacity due to a low VO₂max (maximal amount of oxygen consumption during exercise) ^[13]^[18]. However, this decreased ability to utilize oxygen extends beyond their exercise performance and into their activities of daily living, such as walking, cooking, cleaning, and grocery shopping ^[13]. This typically presents as premature physical fatigability, which is often disproportional to the degree of muscle weakness ^[16].

This physical fatigue can be defined as the inability to sustain muscle contraction or exertion during aerobic exercise ^[13], which varies from patient to patient and depends on mutation load. On a single-limb scale, fatigue may be induced by restricted adenosine triphosphate (ATP) production, depletion of phosphocreatine (PC) and glycogen stores, as well as increased lactate production; on a whole-body scale, fatigue may be due to factors such as impaired oxygen uptake, increased carbon dioxide levels, and increased lactate production ^[13].

Additionally, patients with severe levels of mtDNA mutations will display exercise intolerance due to the muscle’s inability to increase oxygen utilization in relation to physiological responses that increase oxygen delivery. Also, patients with PMM had significantly lower peak-work capacities and oxygen uptake when compared to healthy controls ^[13].

They also discovered an inverse relationship between the mutation load in skeletal muscle and peak extraction of oxygen during exercise, indicating that the degree of exercise intolerance correlates largely with the severity of impaired oxidative phosphorylation due to the muscle’s impaired ability to extract and utilize oxygen ^[19].

In healthy individuals, the decreased ability to produce additional force at maximal exercise capacity is recognized as a safety mechanism to avoid tissue damage ^[13]; however, in patients with PMM, this subjective sense of fatigue occurs before most patients begin to approach maximal capacity. While data on exercise recovery is unclear, patients with PMM appear to have prolonged recovery periods in the clinical setting, though evidence is needed to support this. Other symptoms of exercise intolerance include elevated baseline cardiac output (Q_c) and dyspnea (shortness of breath) ^[14]. Such symptoms may even be exacerbated during periods of stress, such as injury, infection, fasting, or long-duration exercise ^[14]^[18].

3. Proximal and/or Axial Weakness

Proximal weakness is a common feature in patients with mitochondrial disorder. The degree of weakness is variable and can extend to other muscles in the face, neck, arms, and/or legs. Additionally, in some cases, muscles of the diaphragm or respiratory system can be affected, potentially requiring the need for ventilator support ^[20]^[21].

4. Exercise-Induced Muscle Pain and Rhabdomyolysis

In conjunction with exercise intolerance and muscle weakness, exercise-induced muscle pain (myalgias) is another common feature reported by those affected with PMM ^[19]. This is often reported as burning or leg heaviness during long-duration exercise or even with simple activities. True muscle cramps are not often developed in individuals with PMM ^[14]. Rhabdomyolysis can occur, although it is not common, and can be triggered by exercise or illness.

5. Ocular Abnormalities

Weakness often begins with the muscles of the eyes and eyelids, leading to chronic progressive external ophthalmoplegia (CPEO). Ophthalmoplegia, and/or ptosis, can be one of the first symptoms of PMM ^[20] and is characterized by symmetric, progressive, bilateral paresis of extrinsic ophthalmic muscle. There is often a compensatory contraction of the frontalis muscle, with a head tilt and the need to turn to see ^[22]. Patients initially may complain of blurry vision, and close examination will reveal limited extraocular movements.

CPEO can occur as an isolated symptom or part of multisystem dysfunction, such as in Kearns–Sayre syndrome (KSS) and Pearson syndrome (PS), which are part of a spectrum of disorders with CPEO being the mildest, and PS being the most severe ^[22]. These disorders typically are a result of a large-scale mtDNA deletion, which can be related to nuclear DNA (nDNA) mutations (e.g., TK2 and POLG) ^[2]. In CPEO, proximal myopathy is not necessary, and patients may simply have extraocular movement abnormalities or ptosis.

Although these are common features of PMM, it is important to recognize that fatigue, exercise intolerance, generalized weakness, and muscle pain are all nonspecific symptoms that can be a result of many other disorders other than PMM, such as cardiopulmonary disease, medication use, deconditioning, or psychological disorders. Thus, a careful and thorough workup of the patient history is necessary to increase suspicion of PMM and evaluate for other disorders that may explain the symptoms.

References

Abouhajar, A.; Alcock, L.; Bigirumurame, T.; Bradley, P.; Brown, L.; Campbell, I.; Del Din, S.; Faitg, J.; Falkous, G.; Gorman, G.S.; et al. Acipimox in Mitochondrial Myopathy (AIMM): Study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy. Trials 2022, 23, 789.
Arena, I.G.; Pugliese, A.; Volta, S.; Toscano, A.; Musumeci, O. Molecular Genetics Overview of Primary Mitochondrial Myopathies. J. Clin. Med. 2022, 11, 632.
Pfeffer, G.; Chinnery, P.F. Diagnosis and treatment of mitochondrial myopathies. Ann. Med. 2011, 45, 4–16.
McCormick, E.M.; Zolkipli-Cunningham, Z.; Falk, M.J. Mitochondrial disease genetics update. Curr. Opin. Pediatr. 2018, 30, 714–724.
Seah AB, H.; Newman, N.J. Chronic progressive external ophthalmoplegia (CPEO). Encycl. Neurol. Sci. 2014, 799–800.
El-Hattab, A.W.; Adesina, A.M.; Jones, J.; Scaglia, F. MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options. Mol. Genet. Metab. 2015, 116, 4–12.
Finsterer, J.; Zarrouk-Mahjoub, S.; Shoffner, J.M. MERRF Classification: Implications for Diagnosis and Clinical Trials. Pediatr. Neurol. 2018, 80, 8–23.
Quinzii, C.M.; Hirano, M.; DiMauro, S. CoQ10 deficiency diseases in adults. Mitochondrion 2007, 7, S122–S126.
Jou, C.; Nascimento, A.; Codina, A.; Montoya, J.; López-Gallardo, E.; Emperador, S.; Ruiz-Pesini, E.; Montero, R.; Benito, D.N.-D.; Ortez, C.I.; et al. Pathological Features in Paediatric Patients with TK2 Deficiency. Int. J. Mol. Sci. 2022, 23, 11002.
Bahr, T.; Welburn, K.; Donnelly, J.; Bai, Y. Emerging model systems and treatment approaches for Leber’s hereditary optic neuropathy: Challenges and opportunities. Biochim. Biophys. Acta BBA Mol. Basis Dis. 2020, 1866, 165743.
Gerards, M.; Sallevelt, S.C.; Smeets, H.J. Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options. Mol. Genet. Metab. 2016, 117, 300–312.
Schon, E.A.; DiMauro, S.; Hirano, M. Human mitochondrial DNA: Roles of inherited and somatic mutations. Nat. Rev. Genet. 2012, 13, 878–890.
Jeppesen, T.; Madsen, K.; Poulsen, N.; Løkken, N.; Vissing, J. Exercise Testing, Physical Training and Fatigue in Patients with Mitochondrial Myopathy Related to mtDNA Mutations. J. Clin. Med. 2021, 10, 1796.
Bhai, S. Neuromuscular Notes: Diagnosing Metabolic Myopathies. Pract. Neurol. 2021, 57–63.
Vincent, A.E.; Ng, Y.S.; White, K.; Davey, T.; Mannella, C.; Falkous, G.; Feeney, C.; Schaefer, A.M.; McFarland, R.; Gorman, G.S.; et al. The Spectrum of Mitochondrial Ultrastructural Defects in Mitochondrial Myopathy. Sci. Rep. 2016, 6, 30610.
Finsterer, J. Update Review about Metabolic Myopathies. Life 2020, 10, 43.
Cohen, B.H. Mitochondrial and Metabolic Myopathies. CONTINUUM Contin. Lifelong Learn. Neurol. 2019, 25, 1732–1766.
Tarnopolsky, M.A.; Raha, S. Mitochondrial Myopathies: Diagnosis, Exercise Intolerance, and Treatment Options. Med. Sci. Sports Exerc. 2005, 37, 2086–2093.
Taivassalo, T.; Jensen, T.D.; Kennaway, N.; DiMauro, S.; Vissing, J.; Haller, R.G. The spectrum of exercise tolerance in mitochondrial myopathies: A study of 40 patients. Brain 2003, 126, 413–423.
Ahuja, A.S. Understanding mitochondrial myopathies: A review. Peerj 2018, 6, e4790.
Ahmed, S.T.; Craven, L.; Russell, O.M.; Turnbull, D.M.; Vincent, A.E. Diagnosis and Treatment of Mitochondrial Myopathies. Neurotherapeutics 2018, 15, 943–953.
de Barcelos, I.P.; Emmanuele, V.; Hirano, M. Advances in primary mitochondrial myopathies. Curr. Opin. Neurol. 2019, 32, 715–721.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Pathology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Jose C. Hinojosa

Salman Bhai

View Times: 475

Update Date: 27 Feb 2023

Table of Contents

Video Upload Options

Confirm