Mitochondrial myopathy is a term representing a group of disorders that arise from mutations in both nuclear and mitochondrial DNA. Several distinct syndromes have been described in the literature, the most important examples being progressive external ophthalmoplegia, and mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS) syndrome. The diagnosis mandates a thorough clinical and imaging investigations, but muscle biopsies and genetic studies are required to confirm clinical suspicion and determine the exact type of myopathy.
Signs and symptoms of mitochondrial myopathies stem from defects of mitochondrial function. As these organelles are crucial for the production of energy from the respiratory chain, mutations that affect this step inevitably affect tissues that strongly depend on it - the muscles, the nervous system, the heart, and the endocrine system . As a result, the clinical presentation often encompasses multiple findings     :
- Nervous system - Ataxia, spasticity, migraine headaches, cognitive deficits, and stroke-like episodes are notable signs involving the central nervous system (CNS), whereas hearing loss, poor autonomic function, and polyneuropathy are findings that relate to the peripheral nervous system (PNS) .
- Muscles - Weakness and myopathy of the muscular system is a constitutive feature of a mitochondrial myopathy  . Ocular muscles are most commonly affected, followed by those of the axial skeleton and proximal limbs . Dysphagia can arise due to impaired smooth muscle function .
- Endocrine system - Hypothyroidism, hypoparathyroidism, diabetes mellitus, and growth hormone deficiency may develop in a significant number of cases .
- Gastrointestinal system - Diarrhea, constipation, gastroparesis, and liver insufficiency.
Other important manifestations include defects of the kidneys and the heart (the development of conduction deficits and cardiomyopathies, more commonly of hypertrophic type)  . In some cases, neuropsychiatric symptoms of depression and psychotic-like syndromes are reported  .
In the muscular dystrophies, which tend to manifest in childhood or adolescence, dyspnea, cardiac abnormalities, contractures, scapular winging, calf hypertrophy, and skeletal deformities may be present in addition to slowly progressive weakness. [clevelandclinicmeded.com]
Neck Flexor Muscle Weakness
Out of these 22 patients, dysphagia/dysarthria, neck flexor muscle weakness, dyspnea, cardiomyopathy and exercise induced myalgia were observed in five, two, four, one and four patients, respectively. [ncbi.nlm.nih.gov]
Through a detailed patient history and a thorough physical examination, the physician plays a crucial role in raising clinical suspicion toward a mitochondrial myopathy. Several syndromes present with a distinct combination of demographic and clinical findings. For example, mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS) syndrome should be suspected in individuals younger than 40 years of age who present with stroke-like episodes, seizures, migraine headaches, and has elevated lactate levels in blood  . On the other hand, Kearns-Sayre syndrome (KSS) is the most likely diagnosis with an early onset (< 20 years of age) of extraocular muscle weakness, pigmentary retinopathy, and either cardiac conduction abnormalities, elevated proteins in the cerebrospinal fluid, or ataxia  . For this reason, a meticulous laboratory and imaging assessment should follow clinical workup. A hormonal panel (thyroid stimulating hormone, cortisol, parathyroid hormone), glucose parameters (including hemoglobin A1c), serum electrolytes, and creatine kinase (CK) should be measured, while electrocardiography (ECG), electroencephalography (EEG), nerve conduction studies, magnetic resonance imaging (MRI) of the endocranium, a full ophthalmologic examination, and audiogram are recommended studies in order to evaluate the extent of organ damage and discriminate between different types . To make a definite diagnosis of a mitochondrial myopathy, either a muscle biopsy and/or genetic studies are necessary    . COX-deficient and succinate dehydrogenase (SDH)-positive muscle fibers are the hallmarks of a mitochondrial myopathy, whereas accumulated mitochondria in the subsarcolemmal area manifesting as either "ragged-blue fibers" or "ragged red fibers" (stained by SDH or Gomori trichrome stain, respectively), the pathognomonic features of mitochondrial myopathies .
- Pfeffer G, Chinnery PF. Diagnosis and treatment of mitochondrial myopathies. Ann Med. 2013;45(1):4-16.
- Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF. Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet. 2008;83:254–260.
- Schoser BG, Pongratz D. Extraocular mitochondrial myopathies and their differential diagnoses. Strabismus. 2006;14(2):107-113.
- Berardo A, DiMauro S, Hirano M. A Diagnostic Algorithm for Metabolic Myopathies. Curr Neurol Neurosci Rep. 2010;10(2):118-126.
- Sproule DM, Kaufmann P. Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome. Ann N Y Acad Sci. 2008;1142:133–158.