Diagnosis Of Mitochondrial Myopathy Research Articles

Reversible cardiac function and left ventricular hypertrophy in a Chinese man with mitochondrial myopathy: a case report

BackgroundMitochondrial myopathies (MMs) are a group of multi-system diseases caused by abnormalities in mitochondrial DNA (mtDNA) or mutations of nuclear DNA (nDNA). The diagnosis of mitochondrial myopathy (MM) is reliant on the combination of history and physical examination, muscle biopsy, histochemical studies, and next-generation sequencing. Patients with MMs have diverse clinical manifestations. In the contemporary literature, there is a paucity of reports on cardiac structure and function in this rare disease. We report a Chinese man with MM accompanied with both acute right heart failure and left ventricular hypertrophy.Case presentationA 49-year-old man presented with clinical features suggestive of MM, i.e., ophthalmoparesis, weakness of the pharyngeal and extremity muscles, and respiratory muscles which gradually progressed to respiratory insufficiency. He had a family history of mitochondrial myopathy. He had increased levels of serum creatine kinase and lactate. Muscle biopsy of left lateral thigh revealed 8% ragged red fibers (RRF) and 42% COX-negative fibers. Gene sequencing revealed a novel heterozygote TK2 variant (NM_001172644: c.584T>C, p.Leu195Pro) and another heterozygous variant (NM_004614.4:c.156+958G>A; rs1965661603) in the intron of TK2 gene. Based on these findings, we diagnosed the patient as a case of MM. Echocardiography revealed right heart enlargement, pulmonary hypertension, left ventricular hypertrophy, and thickening of the main pulmonary artery and its branches. The patient received non-invasive ventilation and coenzyme Q10 (CoQ10). The cardiac structure and function were restored at 1-month follow-up.ConclusionsThis is the first report of reversible cardiac function impairment and left ventricular hypertrophy in a case of adult-onset MM, nocturnal hypoxia is a potential mechanism for left ventricular hypertrophy in patients with MM.

"Myo-neuropathy" is commonly associated with mitochondrial tRNALysine mutation.

The mitochondrial tRNALys (mt-tRNALys) mutation is initially associated with myoclonic epilepsy and ragged-red fibers (MERRF). The clinical, laboratory, morphologic and molecular findings from 22 mt-tRNALys mutation carriers from local database in East China were analyzed retrospectively. We identified 13 symptomatic and 9 asymptomatic individuals with a known pathogenic mitochondrial tRNALys mutation. The most common mutations were m.8344 A>G (81.8%), m.8363G>A (9.1%), m.8356 T>C (4.5%) and m.8356 T>G (4.5%). The degree of mutation heteroplasmy in blood was high both in symptomatic (mean 64.5%, range 41-82%) and asymptomatic individuals (mean 53.1%, range 21-78%). Age at onset ranged from 6year-old to the age of 66years (mean 35.8 ± 16.4years old). The most frequent symptoms were muscle weakness (76.9%), exercise intolerance (76.9%), elevated creatine kinase levels (61.5%), peripheral neuropathy (69.2%) and cerebellar ataxia (61.5%), while myoclonus was only present in 23.1% of symptomatic patients. A diagnosis of mitochondrial myopathy (MM) and neuropathy ataxia and retinitis pigmentosa (NARP/NARP-like) syndrome was made in 77% of symptomatic patients, whereas the classic syndrome of myoclonic epilepsy with ragged-red fibers (MERRF) was rare (23%). In this cohort of patients with mt-tRNALys mutation, more than one third of our patients did not develop signs and symptoms of central nervous system involvement even in later stages of the disease, indicating the necessity to investigate the mt-tRNALys gene in 'pure' mitochondrial 'myo-neuropathy'.

Whole exome sequencing of a patient with suspected mitochondrial myopathy reveals novel compound heterozygous variants in RYR1.

BackgroundPathogenic variants in ryanodine receptor 1 (RYR1, MIM# 180901) are the cause of congenital myopathy with fiber‐type disproportion, malignant hyperthermia susceptibility type 1, central core disease of muscle, multiminicore disease and other congenital myopathies.MethodsWe present a patient with global developmental delay, hypotonia, myopathy, joint hypermobility, and multiple other systemic complaints that were noted early in life. Later she was found to have multiple bone deformities involving her spine, with severe scoliosis that was corrected surgically. She was also diagnosed with ophthalmoplegia, chronic hypercapnic respiratory failure, and hypertension. At 22 years of age she presented to the genetics clinic with a diagnosis of mitochondrial myopathy and underwent whole exome sequencing (WES).ResultsWhole exome sequencing revealed two novel compound heterozygous variants in RYR1 (c.7060_7062del, p.Val2354del and c.4485_4500del, p.Tyr1495X).ConclusionReview of her clinical, pathologic, and genetic findings pointed to a diagnosis of a congenital myopathy with fiber‐type disproportion.

Index of Suspicion

The reader is encouraged to write possible diagnoses for each case before turning to the discussion. We invite readers to contribute case presentations and discussions. Please inquire first by contacting Dr. Deepak Kamat at DKamat@med.wayne.edu. A 2-year-old boy with a history of eczema and food allergies to nuts and soy presents to the emergency department with a 10-day history of generalized edema. The swelling began in the periorbital area but soon progressed to involve his entire body. There have been no fevers or any recent illnesses other than 1 day of cough and a few watery stools. He has had no new exposures to foods or other substances. His family history is remarkable for multiple allergies and eczema. Physical examination reveals a temperature of 98.8°F (37.1oC), heart rate of 98 beats per minute, respiratory rate of 36 breaths per minute, blood pressure of 103/65 mm Hg, and an oxygen saturation of 97% on room air. His weight is 12.6 kg (34th percentile). He is noted to have a moderate amount of periorbital edema, decreased breath sounds at the lung bases bilaterally, a protuberant abdomen, and 2+ pitting edema on his lower extremities. The rest of his physical examination findings are within normal limits. Laboratory evaluation reveals a white blood cell count of 23,800/μL (23.8 × 109/L), with 37% neutrophils, 49% lymphocytes, 4% bands, 7% monocytes, and 3% eosinophils; hemoglobin level of 13.3 g/dL (133 g/L); and platelet count of 427 × 103/μL (427 × 109/L). Serum electrolyte, blood urea nitrogen, and creatinine levels are normal. Sodium level is 132 mEq/L (132 mmol/L). Serum albumin level is 1.7 g/dL (17 g/L) (reference range, 3.4-5.4 g/dL [34-54 g/L]). Total protein level is 3.8 g/dL (38 g/L). Aspartate aminotransferase, alanine aminotransferase, and coagulation profiles …

Mitochondrial immunofluorescence assay as an adjunctive tool in the diagnosis of mitochondrial myopathy

In the modified Walker criteria, the diagnosis of mitochondrial myopathy is supported by decrease in respiratory chain complex (RCC) enzyme activity below the 30th percentile. Due to heteroplasmy, many symptomatic patients with clinical suspicion of mitochondrial disorders do not have biochemical assay levels meeting this criterion, thus requiring sensitive adjunctive assay methods for the detection of reduced RCC protein expression in these patients. We present the results of a mitochondrial immunofluorescence (MIF) assay using frozen muscle tissue for the detection of specific RCC enzyme defects. A total of 31 muscle biopsies from patients with suspected mitochondrial myopathy were analyzed for Complex I, II, III and IV specific proteins by MIF and for enzyme activity by standard biochemical methods. The frequency of abnormal expression of RCC proteins by MIF was Complex I ‐ 66.7%; Complex II ‐ 61.3%; and complex IV ‐ 35.5% compared with 12.9 %, 12.9% and 19.4%, respectively, using the recommended 30th percentile cutoff for reduced enzyme activity. Widespread or regional reduced expression of RCC proteins was seen in many biopsies with biochemical enzyme activities ranging between the 30th and 65th percentiles (Complex I – 54.8%; Complex II – 48.4%; Complex III – 45.2%; Complex IV – 16.1%). We recommend the use of MIF assay as a supplement to current diagnostic methods for the detection of mitochondrial disorders.

Mania as a first presentation in mitochondrial myopathy

Mitochondrial cytopathies are a genetically and phenotypically heterogeneous group of disorders that range from systemic, lethal pediatric disease to late-onset, tissue-specific neurodegenerative disorders.1 Neurological complications such as mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS) have been described.2 Psychiatric symptoms reported to be occasionally associated with mitochondrial myopathies include dementia, atypical psychosis, depression and schizophrenia-like psychosis.3,4 We report a case of mitochondrial disease that presented with manic, catatonic and neurological symptoms. A 16-year-old adolescent boy presented with an illness of 8 months duration that started acutely with symptoms of cheerfulness, overtalkativeness, overfamiliarity, grandiosity, imcreased self-care, echopraxia, decreased need for sleep and increased appetite for initial 4 weeks followed by refusal to eat, decreased speech output, decreased sleep, generalized rigidity of all four limbs, left-sided limb weakness, flexion and internal rotation at elbow and hemiplegic gait for the next 7 months. The patient’s paternal uncle had symptoms suggestive of a psychotic illness. The patient was started on multiple anticonvulsants, antipsychotics and antidepressants by a general physician, who discontinued these medications after 3 days because the patient developed drooling of saliva, painful hyperextension of neck and back, worsening of rigidity, staring, posturing, stereotypic movements of hand, negativism, mutism and impairment in activities of daily living, for which he underwent five sessions of electroconvulsive therapy. At presentation to Postgraduate Institute of Medical Education and Research, Chandigarh, India, the patient was also noted to have gegenhalten, extensor posturing, episodes of opisthotonous (up to 40 episodes of approx. 10–75 min per day) and dynamic contractures at the knee, ankle and wrist joints. Routine investigations did not reveal any abnormality. Serum lactate was elevated (approx. twice the upper limit of normal range). Magnetic resonance imaging (MRI) of the brain showed hyperintensities in bilateral basal ganglia in both T1 and T2 images and single-photon emission computed tomography (SPECT) revealed grossly impaired perfusion in right-sided thalamus. Electron microscopic examination of muscle tissue obtained on biopsy showed sub-sarcolemmal and inter-myofibrillar accumulations of abnormal-looking mitochondria, consistent with the diagnosis of mitochondrial myopathy. Patient had negative KF ring, and serum ceruloplasmin, serum copper, urinary copper and liver ultrasound were normal. Cerebrospinal fluid cytology, biochemistry, adenosine deaminase, and polymerase chain reaction for tuberculosis were negative. He was treated with diazepam 40 mg/day and quitiapine 175 mg/day, on which his rigidity, episodes of opisthotonous, gegenhalten, posturing and motor stereotypy improved. Improvement was maintained even after decreasing diazepam to 5 mg and quetiapine to 100 mg. Physiotherapy for knee and ankle contractures was initiated and partial improvement in activities of daily living was noted. The classical form of MELAS is characterized by early onset stroke-like episodes (before age 40), encephalopathy (seizures, dementia), lactic acidosis, and ragged red fibers on muscle biopsy.5 The index patient had most features of MELAS but was atypical in that he initially had manic and then catatonic symptoms and it was difficult to comment on his cognitive functions (owing to catatonic symptoms like muteness). Absence of family history of mitochondrial myopathy in the index case should not be considered an atypicality.2 Hyperintensities in bilateral basal ganglia (MRI) may explain the presence of prominent extrapyramidal symptoms, and gross impairment of perfusion of right-sided thalamus (SPECT) may explain the manic symptoms. The present report highlights the fact that in patients presenting with psychiatric and neurological symptoms, the possibility of mitochondrial encephalomyopathy should be considered.

Errance diagnostique dans les myopathies mitochondriales : étude de 12 patients thymectomisés

Myasthenia gravis and mitochondrial myopathies have common symptoms (fatigability, ophthalmoplegia) that could lead to diagnosis confusion. We systematically reviewed medical history and ancillary investigations regarding 12 patients (7F/5M, mean age 47+/-14 years) having a mitochondrial myopathy but who were previously misdiagnosed as autoimmune myasthenia gravis and in whom a thymectomy was performed. Ocular palsy, ptosis and bulbar palsy were present in all patients. Limb fatigability was present in 9 cases. Symptoms were fluctuant but without remission. The misdiagnosis of myasthenia was based on the following arguments: 1) decremental EMG response (2 cases); 2) positive injectable anticholinesterase drugs test (3 cases); 3) partial response to oral anticholinesterase medications (2 cases); 4) AChR antibodies titer of 0.6 nM considered as positive (1 case). A multisystemic involvement was present in 5 patients: peripheral neuropathy (2 cases), deafness (2 cases), cardiopathy (3 cases), cerebellar involvement (2 cases) and myoclonia (1 case). The diagnosis of mitochondrial myopathy (at a mean age of 38+/-12 years) has been certified on the results of muscle biopsy showing mitochondrial proliferation (12 cases) and deleted mitochondrial DNA (8 cases). In a patient presenting with oculomotor symptoms and muscle fatigability, progressive course and multisystemic involvement are major arguments for a mitochondrial myopathy. In the absence of relevant criteria arguing for Myasthenia Gravis (significant variability of muscle weakness, positive titer of anti-AChR or anti-MuSK antibodies, decremental EMG response), a muscle biopsy is required before indication of thymectomy to exclude a mitochondrial disease.

Extraocular Mitochondrial Myopathies and their Differential Diagnoses

The diagnosis of mitochondrial myopathy depends upon a constellation of findings, family history, type of muscle involvement, specific laboratory abnormalities, and the results of histological, pathobiochemical and genetic analysis. In the present paper, the authors describe the diagnostic approach to mitochondrial myopathies manifesting as extraocular muscle disease. The most common ocular manifestation of mitochondrial myopathy is progressive external ophthalmoplegia (PEO). To exclude myasthenia gravis, ocular myositis, thyroid associated orbitopathy, oculopharyngeal muscular dystrophy, and congenital fibrosis of the extraocular muscles in patients with an early onset or long-lasting very slowly progressive ptosis and external ophthalmoplegia, almost without any diplopia, and normal to mildly elevated serum creatine kinase and lactate, electromyography, nerve conduction studies and MRI of the orbits should be performed. A PEO phenotype forces one to look comprehensively for other multisystemic mitochondrial features (e.g., exercise induced weakness, encephalopathy, polyneuropathy, diabetes, heart disease). Thereafter, and presently even in familiar PEO, a diagnostic muscle biopsy should be taken. Histological and ultrastructural hallmarks are mitochondrial proliferations and structural abnormalities, lipid storage, ragged-red fibers, or cytochrome-C negative myofibers. In addition, Southern blotting may reveal the common deletion, or molecular analysis may verify specific mutations of distinct mitochondrial or nuclear genes.

The usefulness of lactate stress testing in the diagnosis of mitochondrial myopathy

The usefulness of lactate stress testing in the diagnosis of mitochondrial myopathy

Lactate stress test in the diagnosis of mitochondrial myopathy.

The aim of the study was to determine the sensitivity and specificity of the lactate stress test in the detection of mitochondrial myopathies. Thirty one healthy subjects, 10 patients with non-mitochondrial myopathy and 26 patients with mitochondrial myopathy underwent lactate stress testing at a standardized workload of 30 W during 15 min on a bicycle ergometer. Lactate was determined before the exercise (R1), 5, 10, 15 min after starting the exercise (S5, S10, S15) and 15 min after finishing the exercise (R2). A result was interpreted as pathologic if more than two of the five lactate values were above the corresponding upper reference limits. The upper reference limits for the venous lactate at R1, S5, S10, S15 and R2 were 1.9, 2.0, 2.1, 2.0 and 1.7 mmol/l respectively. The lactate stress test was pathologic in 1/10 of the non-mitochondrial myopathies and in 18/26 of the mitochondrial myopathies. The sensitivity of the lactate stress test was 69%. The specificity of the test was 90%. In conclusion, the lactate stress test proved to be helpful for evaluating the integrity of the oxidative metabolism in the majority of patients with mitochondrial myopathy.

Standardized aerobic walking on the treadmill by healthy probands and patients with mitochondrial and non-mitochondrial myopathies

Mitochondrial myopathies are characterized by an abnormal aerobic metabolism. The present study examines the serum lactate concentration during standardized aerobic treadmill ergometry and evaluates its relevance for the diagnosis of mitochondrial myopathies. The present study includes 50 volunteers without neuromuscular disorders (control group), 13 patients with mitochondrial, and 14 patients with non-mitochondrial neuromuscular disorders. All members of the control group were able to walk 15 minutes on the treadmill at a constant velocity of at least 5 km/h without exceeding the aerobic threshold (2 mMol/l lactate, venous blood). Ten patients with mitochondrial myopathies and 4 patients with non-mitochondrial myopathies already exceeded the aerobic threshold at walking velocities of 4 or 5 km/h. Though indicating a reduced aerobic endurance, a pathological test result does not prove the diagnosis of a mitochondrial myopathy. Sensitivity and specificity of treadmill ergometry did not differ significantly from those reported for bicycle ergometry. Thus, using the most common aerobic activity in daily life, treadmill ergometry can be considered as an alternative to bicycle exercise tests in the assessment of mitochondrial abnormalities.

Sensitivity to Mivacurium in a Patient with Mitochondrial Myopathy

Sensitivity to Mivacurium in a Patient with Mitochondrial Myopathy

Functional characterization of mitochondrial oxidative phosphorylation in saponin-skinned human muscle fibers

The conditions of treatment of human skeletal muscle fibers from M. vastus lateralis with saponin were optimized to achieve complete permeabilization of cell membrane at intact mitochondrial oxidative phosphorylation. After 30 min of incubation with saponin all lactate dehydrogenase, 50% of creatine kinase, 30% of adenylate kinase and less then 20% of citrate synthase was released into the permeabilization medium. These skinned fibers behave similar to isolated mitochondria from human skeletal muscle: (i) the respiration with mitochondrial substrates can be stimulated by ADP, (ii) inhibited by carboxyatractyloside and (iii) it is possible to detect fluorescence changes of mitochondrial NAD(P)H on additions of substrates, uncoupler and cyanide. From a comparison of rates of respiration per cytochrome aa 3 content of isolated human skeletal muscle mitochondria and saponin-skinned muscle fibers it was possible to calculate that almost 85% of mitochondria in those fibers are accessible for the investigation of oxidative phosphorylation. As shown by the investigation of biopsy samples of two patients with undefined myopathies these fibers are a suitable object for the replacement of isolated mitochondria in the diagnosis of mitochondrial myopathies and encephalomyopathies.

Ptosis et asthénie révélateurs d'une myopathie mitochondriale

We report a case of mitochondrial myopathy discovered in a 55-year old woman who was being investigated for the cause of her asthenia. Physical examination showed ptosis of the upper eyelid and proximal muscle deficit. Histological examination of a muscle biopsy disclosed rare fibres with mitochondrial aggregates. Biochemical exploration of muscle tissue revealed a double enzyme deficit involving complexes I and IV of the respiratory chain. Clinical improvement was obtained after the patient was put on coenzyme Q10. We conclude that a diagnosis of mitochondrial myopathy must be considered in patients, including middle-aged adults, presenting with muscular asthenia.

Detection of mitochondrial DNA deletions in blood using the polymerase chain reaction: non‐invasive diagnosis of mitochondrial myopathy

Southern hybridisation demonstrates deleted mitochondrial DNAs (mtDNAs) in muscle but not in blood in a subgroup of patients with mitochondrial myopathy. The polymerase chain reaction (PCR) was used to search for low levels of rearranged mitochondrial DNAs in blood in 24 patients with mitochondrial myopathy, and 15 asymptomatic relatives, all of whom have no detectable abnormality on restriction enzyme analysis of blood mitochondrial DNA. In eight patients and two of their relatives, PCR products were obtained consistent with deletions of mitochondrial DNA. The presence or absence of a deletion was correctly predicted in 10 out of 11 patients from whom information was available from muscle DNA. No false positives were obtained in 43 controls. PCR analysis of blood may be applicable as a non-invasive screening test of affected individuals and in carrier detection.