A Systematic Review of the Role of Mitochondria in Cleft Pathology: A Forgotten General?

ABSTRACT@#Orofacial clefts (OFC) are one of the most common birth defects that affects the lip, palate, or lip and palate of an infant. The deterioration of clefts is multifactorial involving multiple genes, various interactions from environmental factor and most forgotten, mitochondrial abnormality. The aim of this review is to highlight the importance of mitochondrial activity related to non-syndromic OFC deformity. Despite its important role in cells, the study on mitochondrial activity in cleft pathology was scarce and almost forgotten compared to other genetic investigations. This systematic review was completed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. The literature search was done via the following databases: Google Scholar, Pubmed and Scopus with a total of nine studies of mitochondrial abnormalities were included. We hypothesise that mitochondria play an important role in early craniofacial development. A decreased in its function or activity may result in cleft lip formation. Hence, we would like to shed light on the remarkable role of mitochondria activity in the pathogenesis of non-syndromic OFC.

Mitochondrial myopathy with ataxia caused by MSTO1 gene mutation: a family case report and literature review / 中华实用儿科临床杂志

The clinical characteristics and gene variations of a family with mitochondrial myopathy and ataxia caused by MSTO1 gene mutation who visited Xiangya Hospital of Central South University in October 2019 were retrospectively analyzed.The proband was an 11-year-old female, who was found to have delayed motor and language development and dysarthria at the age of 1 year and 6 months.The 9-year-old younger brother of the proband had similar symptoms at the age of 1 year and 3 months.Both the proband and her younger brother had muscle weakness and ataxia.Their head magnetic resonance imaging showed cerebellar atrophy, and their electromyography showed neuroge-nic changes.Genetic testing revealed compound heterozygous mutations in MSTO1: c.1259delG; p.G420VfsX2 and c.571 C > T; p.R191X, which were inherited from their parents, respectively.The same site mutations were found in the younger brother.After 2 weeks of " cocktail therapy" , the symptoms of the children were alleviated, and their language and movement improved.

Principal component determination and analysis of urine organic acid metabolism spectrum of two diseases / 基础医学与临床

Objective Analysis of 22 kinds of organic acid metabolites in urine samples of patients with myasthenia gravis, mitochondrial myopathy and of healthy controls was performed so to provide data and basis for clinical screening .Methods The principal component and the corresponding principal component equation were obtained , the physical and chemical significance of the principal component was explained .Results The cumulative contri-bution rate of the first five principal components reached 86.89%, was identified as the main component , then es-tablished the principal component function expression , and analyzed the relationship between the principal compo-nent and the original variable .It was found that the phenyl saturated acid might be a potential biomarker of the two diseases , and the hippuric acid was an early warning bio-marker of the two diseases .Conclusions Urine organic acid metabolic profile principal component analysis is helpful to find biomarker of disease and may support clinical diagnosis basis .

Clevudine Induced Mitochondrial Myopathy

Clevudine was approved as an antiviral agent for hepatitis B virus, which showed marked, rapid inhibition of virus replication without significant toxicity. However, several studies have reported myopathy associated with clevudine therapy. Also, we experienced seven patients who suffered from myopathy during clevudine therapy. To characterize clevudine-induced myopathy, we collected previously reported cases of clevudine myopathy and analyzed all the cases including our cases. We searched electronic databases that were published in English or Korean using PubMed and KoreaMed. Ninety-five cases with clevudine myopathy, including our seven cases, were selected and analyzed for the demographic data, clinical features, and pathologic findings. The 95 patients with clevudine-induced myopathy comprised 52 women and 43 men aged 48.9 years (27–76 years). The patients received clevudine therapy for about 14.2 months (5–24 months) before the development of symptoms. Weakness mainly involved proximal extremities, especially in the lower extremities, and bulbar and neck weakness were observed in some cases (13.7%). Creatine kinase was elevated in the majority of patients (97.9%). Myopathic patterns on electromyography were observed in most patients examined (98.1%). Muscle biopsy presented patterns compatible with mitochondrial myopathy in the majority (90.2%). The weakness usually improved within about 3 months after the discontinuation of clevudine. Though clevudine has been known to be safe in a 6-month clinical trial, longer clevudine therapy for about 14 months may cause reversible mitochondrial myopathy. Careful clinical attention should be paid to patients with long-term clevudine therapy.

Effect of L-carnitine on exercise performance in patients with mitochondrial myopathy

Exercise intolerance due to impaired oxidative metabolism is a prominent symptom in patients with mitochondrial myopathy (MM), but it is still uncertain whether L-carnitine supplementation is beneficial for patients with MM. The aim of our study was to investigate the effects of L-carnitine on exercise performance in MM. Twelve MM subjects (mean age±SD=35.4±10.8 years) with chronic progressive external ophthalmoplegia (CPEO) were first compared to 10 healthy controls (mean age±SD=29±7.8 years) before they were randomly assigned to receive L-carnitine supplementation (3 g/daily) or placebo in a double-blind crossover design. Clinical status, body composition, respiratory function tests, peripheral muscle strength (isokinetic and isometric torque) and cardiopulmonary exercise tests (incremental to peak exercise and at 70% of maximal), constant work rate (CWR) exercise test, to the limit of tolerance [Tlim]) were assessed after 2 months of L-carnitine/placebo administration. Patients with MM presented with lower mean height, total body weight, fat-free mass, and peripheral muscle strength compared to controls in the pre-test evaluation. After L-carnitine supplementation, the patients with MM significantly improved their Tlim (14±1.9 vs 11±1.4 min) and oxygen consumption ( V ˙ O 2 ) at CWR exercise, both at isotime (1151±115 vs 1049±104 mL/min) and at Tlim (1223±114 vs 1060±108 mL/min). These results indicate that L-carnitine supplementation may improve aerobic capacity and exercise tolerance during high-intensity CWRs in MM patients with CPEO.

Relationship between work rate and oxygen uptake in mitochondrial myopathy during ramp-incremental exercise

We determined the response characteristics and functional correlates of the dynamic relationship between the rate (Δ) of oxygen consumption ( VO2) and the applied power output (work rate = WR) during ramp-incremental exercise in patients with mitochondrial myopathy (MM). Fourteen patients (7 males, age 35.4 ± 10.8 years) with biopsy-proven MM and 10 sedentary controls (6 males, age 29.0 ± 7.8 years) took a ramp-incremental cycle ergometer test for the determination of the VO2 on-exercise mean response time (MRT) and the gas exchange threshold (GET). The ΔVO2/ΔWR slope was calculated up to GET (S1), above GET (S2) and over the entire linear portion of the response (S T). Knee muscle endurance was measured by isokinetic dynamometry. As expected, peak VO2 and muscle performance were lower in patients than controls (P < 0.05). Patients had significantly lower ΔVO2/ΔWR than controls, especially the S2 component (6.8 ± 1.5 vs 10.3 ± 0.6 mL·min-1·W-1, respectively; P < 0.001). There were significant relationships between ΔVO2/ΔWR (S T) and muscle endurance, MRT-VO2, GET and peak VO2 in MM patients (P < 0.05). In fact, all patients with ΔVO2/ΔWR below 8 mL·min-1·W-1 had severely reduced peak VO2 values (<60 percent predicted). Moreover, patients with higher cardiopulmonary stresses during exercise (e.g., higher Δ ventilation/carbon dioxide output and Δ heart rate/ΔVO2) had lower ΔVO2/ΔWR (P < 0.05). In conclusion, a readily available, effort-independent index of aerobic dysfunction during dynamic exercise (ΔVO2/ΔWR) is typically reduced in patients with MM, being related to increased functional impairment and higher cardiopulmonary stress.

Síndrome de MELAS: TC y RM como herramienta diagnóstica no invasiva / MELAS syndrome: CT and MRI as a noninvasive diagnostic tool

Se presenta el caso de un paciente masculino, de 16 años, con hipoacusia bilateral, miopatías y alteración neurológica focal. Desde los 9 años, presenta deficiencia en el desarrollo muscular con episodios repetidos de intolerancia al ejercicio, así como miocarditis viral. Tras descartar etiología infecciosa se realizaron TC y RM, las cuales arrojaron datos positivos a nivel de los ganglios basales y del parénquima encefálico. Los hallazgos radiológicos junto con la clínica del paciente sugirieron una encefalopatía de origen mitocondrial. El examen genético confirmó el diagnóstico de síndrome de MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke like events).

We report on a 16-year-old male with bilateral hypoacusia, myopathy and focal neurological disorder. Since 9-year-old, he showed muscle development deficiency with repeated episode of exercise in tolerance and viral myocarditis. After ruling out an infectious etiology, CT and MRI were performed and yielded positive data about basal ganglia and brain parenchyma. The patient's radiological and clinical findings suggested mitochondrial encephalopathy. Genetic testing confirmed the diagnosis of MELAS syndrome (lactic acidosis with mitochondrial encephalomyopathy and stroke-like events).

A Case of Mitochondrial Myopathy Showing Severe Hypoxemia during REM Sleep / 수면정신생리

Mitochondrial myopathy is characterized by variable clinical manifestations from mild limb weakness to fatal respiratory failure and central nervous system sequela. But it is a rare event that sleep disordered breathing become a clue of diagnosis for mitochondrial myopathy. We report a case of a 21 year-old man who was diagnosed as mitochondrial myopathy during the investigation for the possible cause of chronic hypoventilation syndrome. Before being admitted to our hospital, he was suspected as having sleep apnea syndrome in another hospital. We re-evaluated the history, physical examination, laboratoy findings and polysomnography in detail. Severe hypoxemia was noted during REM sleep on nocturnal polysomnography and the diagnosis of mitochondrial myopathy was made by muscle biopsy in rectus abdominis muscle. We treated him with bilevel positive airway pressure therapy during sleep and it could reverse the hypoxemia during REM sleep. He could be discharged with improved condition and is being well with the use of this ventilatory assistance.

General Anesthesia with Sevoflurane for a Patient with MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, Stroke-like Episodes) Syndrome: A case report / 대한마취과학회지

We describe the anesthetic management of a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes (MELAS) syndrome, and a form of mitochondrial myopathy. A 14 year-old-male with MELAS syndrome underwent tracheostomy under general anesthesia. Anesthesia was managed with thiopental sodium, nitrous oxide, sevoflurane, and rocuronium. His reactions to anesthetics and muscle relaxant were within normal limits. No serious complication was observed. The implication of MELAS syndrome for anesthesia are discussed.

Ultrastructural study of the levator veli palatint muscle in cleft palate patients

A Case of Rhabdomyolysis and Acute Renal Failure Associated with Mitochondrial Myopathy / 대한신장학회잡지

Mitochondrial myopathies are diseases caused by defects in metabolic pathway of mitochondria. Mitochondrial myopathy is known as one of the causes of recurrent myoglobinuria, while clinically, rarely causes acute renal failure requiring medical treatments. We report a case of rhabdomyolysis and acute renal failure associated with mitochondrial myopathy. A 58-year-old male was presented with dyspnea and hypotensive shock. The patient had a history of recurrent dark colored urine and cramping leg pain after prolonged fasting. Laboratory findings showed hyperkalemia, azotemia, metabolic acidosis, and elevated AST, ALT, and creatinine kinase. He had no history of trauma or medication. Muscle biopsy showed "ragged red fibers" in modified Gomori staining. On electron microscope, increased number of mitochondria and abnormal mitochondria were seen. He received hemodialysis and his renal function recovered after 1 month.

Study on genetic origin of mitochondrial dysfunction in patients with mitochondrial myopathy / 临床神经病学杂志

Objective To study the genetic origin of mitochondrial dysfunction in patients with mitochondrial myopathy.Methods The esphagus carcinoma cells were cultured by ethidium bromide, and established stabile,cell line of long term survival mitochondrial DNA(mtDNA).The platelets of patients with mitochondrial myopathy and the normal controls were carried out cell fusion.the mitochondrial function of fusion cell was determined. Results The esphagus carcinoma cells were cultured by ethidium bromide for 12 days, the cells were completely depleted of mtDNA,which can be passed stably. The respiratory capacity of transformants derived from patients with mitochondrial myopathy was lower than those from the control.Conclusion The mtDNA mutation can play a role in the pathogenesis of mitochondrial myopathy.

Pathologic Findings of Mitochondrial Myopathy

Mitochondrial myopathy (MM) has been applied to muscle disease in which mitochondria have abnormal structure, function or both. To characterize the pathologic findings of MM, we examined the ultrastructural and histochemical findings of 24 cases of MM. The ultrastructures of the MM were characterized by abnormal mitochondria in number (pleoconia) and size (megaconia), and showed predominant accumulation of mitochondria in the subsarcolemmal space of myofibers in all cases. Mitochondria contained abnormally shaped cristae (concentric form and gyriform) in 79% of cases. Paracrystalline inclusion which was known to be a characteristics of MM were seen only in 7 cases (29%). Electron dense deposits were more frequently found (77%) in abnormal mitochondria of chronic progressive external opthalmoplegia and Kearn-Sayre syndrome. But, other findings were not specific for the specific clinical entities. On succinate dehydrogenase (SDH) stain, ragged red fibers (RRF) showed more intense positivity than modified Gomori-trichrome stain and definite strong reactive products were present along the periphery of myofibers which showed normal findings on modified Gomori-trichrome stain. In conclusion, ultrastructural findings such as mitochondria showing pleoconia with megaconia, and bizarre shaped cristae may be helpful for the diagnosis of MM and SDH stain is more useful for identification of RRF than modified Gomori-trichrome stains.

Enzyme histochemical study of germanium dioxide-induced mitochondrial myopathy in rats

The purpose of this study were 1) to determine the earliest pathological changes of germanium dioxide (GeO2)-induced myopathy; 2) to determine the pathomechanism of GeO2-induced myopathy; and 3) to determine the minimal dose of GeO2 to induce myopathy in rats. One hundred and twenty five male and female Sprague-Dawley rats, each weighing about 150 gm, were divided into seven groups according to daily doses of GeO2. Within each group, histopathological studies were done at 4, 8, 16, and 24 weeks of GeO2 administration. Characteristic mitochondrial myopathy was induced in the groups treated daily with 10 mg/kg of GeO2 or more. In conclusion, the results were as follows: 1) The earliest pathological change on electron microscope was the abnormalities of mitochondrial shape, size and increased number of mitochondria; 2) The earliest pathological change on light microscope was the presence of ragged red fibers which showed enhanced subsarcolemmal succinate dehydrogenase and cytochrome c oxidase reactivity; 3) GeO2 seemed to affect the mitochondrial oxidative metabolism of muscle fibers; 4) GeO2 could induce mitochondrial myopathy with 10 mg/kg of GeO2 for 4 weeks or less duration in rats.

Metabolic Abnormalities in Patients with Mitochondrial Myopathy Evaluated by In Vivo 31P Magnetic Resonance Spectroscopy

PURPOSE: To investigate the phosphorus metabolic abnormalities in skeletal muscle of patients with mitochondrial myopathy using in vivo 31P magnetic resonance spectroscopy(MRS). MATERIAL AND METHODS: Patients with mitochondrial myopathy(N=10) and normal control subjects (N=10) participated. All in vivo 31P MRS examinations were performed on 1.5T whole-body MRI/MRS system by using an image selected in vivo spectroscopy (ISIS) pulse sequence that provided a 4 X 4 X 4 cm3 volume of interest (VOI) in the right thigh muscle tissue. Peak areas for each phophorus methabolite were measured using a Marquart algorithm. RESULTS: The specific features in patients with mitochondrial myopathy were a significant increase of Pi/PCr ratio (p=0.003) and a significant decrease of ATP/PCr ratio (p=0.004) as compared with normal controls. In particular, the beta-ATP/PCr ratio between controls and patients with mitochondrial myopathy was predominantly altered. CONCLUSIONS: In vivo 31P MRS may be a useful modality in the clinical evaluation of patients with mitochondrial myopathy based on ATP/PCr and Pi/PCr ratios in skeletal muscle tissue and provides a valuable information in further understanding disorders of muscle metabolism.

Chronic progressive external ophthalmoplegia type of mitochondrial myopathy(report of 3 families) / 临床神经病学杂志

Objective To investigate the clinical,genetic and pathological features of familial chronic progressive external ophthalmoplegia (CPEO) type of mitochondrial myopathy.Methods Clinical manifestations, family histories and pathological findings of 21 patients with CPEO type of mitochondrial myopathy from 3 families constellations were analyzed retrospectively.Results All the patients had ptosis and movement disorder of eyeball, with or without myasthenia. An autosomal dominant pattern of transmission was deduced from one family and a maternal transmission appeared most likely in the other two families. The striking and common pathologic findings were presence of ragged red fibers and cytochrome C oxidase (COX) deficiency fibers under microscope. Ultrastructural alterations included subsarcolemmal accumulation of mitochondria, increase of mitochondria with abnormal shape, disarrangement of cristae and paracrystaline inclusion bodies.Conclusions The clinical and pathological features between generations and families seem to be similar. It is suggested that different genetic mode of CPEO may lead to similar clinical and pathological features.

A case of MELAS syndrome

MELAS syndrome is a rare but distinct clinical entity belonging to a group of mitochondrial encephalomyopathies characterized by the tetrad of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. We experienced a case of MELAS syndrome in an 8 year-old boy who showed headache, pain of the eyeball, vomiting, stroke-like episodes such as visual disturbance and dysarthria, myoclonic seizure, confusion, and walking disturbance. His serum lactate level was elevated up to 48 mg/dl. MRI findings showed high signal intensities T2-weighted image and low signal intensities in T1-weighted image in the right thalamus and parietooccipital lobe and bilateral symmetric high signal intensity in T1-dweighted image in the basal ganglia. We have seen the dispersed ragged-red fibers with modified Gomori trichrome staining on light microscope, and abundant and dysmorphic mitochondria on electon microscope in the specimen of muscle biopsy. esis of SLE.

Diagnosis value of minimum exercise test of lactic acid and pyruvic acid for mitochondrial myopathy / 临床神经病学杂志

17.The abnormal results of METLP were found in 6(100%) patients with other myopathy.Most of them showed a high concentration of lactic acid post-aerobic exercise(L2),and sustainable to after rest,or even more higher(L3).3(21.4%)patients without myopathy showed abnormal results of METLP.Conclusions In all the indexes of METLP,the value of L2/P1 is the reliable index for diagnosis mitochondrial myopathy or no-myopathy;the value of L3/L2 is the most important index in differential diagnosis of mitochondrial myopathy and other myopathy.METLP plays a certain role in the diagnosis of the mitochondrial myopathy,but the clinical and pathological data ought to be combined.

Clinical and pathological characteristics of pure type mitochondrial myopathy / 临床神经病学杂志

Objective To investigate the clinical and pathological features of pure type mitochondrial myopathy.Methods Clinical manifestations and pathological features of biopsied muscle specimens were summarized retrospectively in 9 cases of pure mitochondrial myopathy. 6 of them were followed up on the purpose of prognostic analysis.Results 9 cases of pure mitochondrial myopathy were clinical characterized by exclusive skeletal muscle involvement and fluctuating proximal muscle weakness. Extraocular muscles were spare. Most patients had moderately increased creatine phosphokinase level (539～2 913U/L). Electromyography examination showed myogenic changes in 6 cases and neurogenic in 3 cases. Pathologically, 8 cases had typical ragged red fibers (RRF) accounting for 5% to 60%. Mitochondrial intracristal inclusion bodies were observed by electron microscope in the patient with atypical RRF. Focal cytochrome C oxidase (COX) deficiency was seen in 4 cases and total deficiency in 2 cases. To a certain degree, the percentage of RRF was parallel to muscle weakness. Following-up data from 6 patients showed that symptoms had improved in 5 patients after treatment with vitamin B, vitamin E, CoQ 10 and inosine. One had a sudden death with unknown reason.Conclusion Pure mitochondrial myopathy may be a distinct subset of mitochondrial diseases that preferentially affects trunk and proximal muscles,Pathological charactoristic had typical RRF and COX deficiency,and RRF is related to patient's condition.It has relative chronic process and benign prognosis.