Anesthetic Management of the Patient with Mitochondrial Disease: A Review of Current Best Evidence.

Anesthetic management of the patient with mitochondrial disease (MD) requires thoughtful preoperative planning and hypervigilant perioperative monitoring. MD affects 1 in 4,000 persons and is often an unfamiliar topic to the anesthesia provider. This review aims to inform the anesthetist on important considerations in perioperative management of MD. Patients with MD have impaired mitochondrial energy formation pathways affecting function of cardiac, central nervous, and musculoskeletal systems. All general anesthetics interfere with these mitochondrial bioenergetic pathways. MD patients exhibit hypersensitivity to volatile anesthetics. Propofol interferes with mitochondrial function via multiple pathways thus its use should be limited. MD is not at increased risk for malignant hyperthermia and should not be managed with prolonged propofol infusion. Succinylcholine is contraindicated due to hyperkalemia and myotonic risks. Nondepolarizing agents should be used with caution given unpredictable effects. No single anesthetic plan has been found to be safer than another in patients with MD. Intravenous and volatile anesthetics should be titrated incrementally while monitoring anesthetic depth clinically or via processed electroencephalogram (EEG). All MD patients should be optimized by minimizing fasting times, careful fluid selection to avoid lactate, and hypervigilant temperature management aimed at reducing the detrimental effects of catabolic stress during the perioperative period.

Outcomes of Living Kidney Transplantation for Mitochondrial Disease Patients: A Case Series.

PURPOSE: Mitochondrial disease can affect many organs, including the brain, nerves, heart, liver, eyes, ears, pancreas, and kidneys. Kidney transplantation is a treatment option for renal failure due to mitochondrial disease; however, the prognosis of patients who undergo kidney transplantation for mitochondrial disease is unknown. Here we evaluated the outcomes of kidney transplant recipients with mitochondrial disease. METHODS: Clinical data were obtained from 4 kidney transplantation recipients who were followed at our department. Of the 4 transplantations, 3 were performed in our department: 2 patients received kidneys from their fathers, and a third from his wife. The fourth recipient received a kidney from her mother-who had a mitochondrial genetic abnormality-at another hospital. Of the 4 recipients, 3 were diagnosed with mitochondrial disease before the transplantation, and the fourth was diagnosed after. All recipients had sensorineural deafness and diabetes mellitus, and only 1 had a history of encephalopathy and stroke-like episodes before the transplantation. RESULTS: One patient died 2 years after transplantation due to encephalopathy progression with stable kidney function. The grafted kidney of the patient who received it from her mother lost function at 5 years post-transplantation. A graft biopsy revealed focal segmental glomerular sclerosis due to mitochondrial disease. The other patients' kidney functions remained stable. None of the recipients experienced rejection. CONCLUSIONS: In kidney transplantation for mitochondrial disease, attention should be paid to the exacerbation of comorbidities, while careful consideration should be given to donors with a mitochondrial genetic abnormality.

Outcomes of liver transplantation for mitochondrial respiratory chain disorder in children.

AIM: Mitochondrial respiratory chain disorder (MRCD) can cause acute liver failure (ALF), which may necessitate liver transplantation (LT). However, MRCD is often difficult to diagnose before LT and the indications of LT are controversial due to the likelihood of progressive neurological disease. The present study further characterized the patient population and described the outcomes. METHODS: Thirteen patients who underwent LT for MRCD from November 2005 to May 2020 were enrolled in this study. RESULTS: Six of 13 MRCD patients were diagnosed with a mitochondrial inner membrane protein 17-related mitochondrial DNA depletion syndrome (MTDPS). Overall, nine survived with a median follow-up of 1.8 years (IQR, 1.3-5.1 years); four died within 2 years. In the long-term, seven survivors showed no progression of hypotonia after LT and attended a normal kindergarten or primary school. Neurological abnormalities were observed in two survivors, including vison loss related to Leber's hereditary optic neuropathy in one patient and psychomotor retardation related to Leigh syndrome in the other. Three non-survivors after LT were diagnosed with MTDPS and died of severe pulmonary hypertension, which had developed at 8, 9, and 18 months after LT (n=1 each). The remaining patient died of postoperative respiratory infection with respiratory syncytial virus. CONCLUSION: The long-term results support the performance of LT in patients with MRCD, although a genetic diagnosis is preferable for determining the accurate indications for LT in these patients. Furthermore, care should be taken to avoid complications due to mitochondrial dysfunction during the long-term follow-up.

Severe Deoxyguanosine Kinase Deficiency in Austria: A 6-Patient Series.

Mutations in the nuclear gene DGUOK, encoding deoxyguanosine kinase, cause an infantile hepatocerebral type of mitochondrial depletion syndrome (MDS). We report 6 MDS patients harboring bi-allelic DGUOK mutations, of which 3 are novel, including a large intragenic Austrian founder deletion. One patient was diagnosed with hepatocellular carcinoma aged 6 months, supporting a link between mitochondrial DNA depletion and tumorigenesis; liver transplantation proved beneficial with regard to both tumor treatment and psychomotor development.

mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases.

Mitochondrial diseases represent a significant clinical challenge. Substantial efforts have been devoted to identifying therapeutic strategies for mitochondrial disorders, but effective interventions have remained elusive. Recently, we reported attenuation of disease in a mouse model of the human mitochondrial disease Leigh syndrome through pharmacological inhibition of the mechanistic target of rapamycin (mTOR). The human mitochondrial disorder MELAS/MIDD (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes/Maternally Inherited Diabetes and Deafness) shares many phenotypic characteristics with Leigh syndrome. MELAS/MIDD often leads to organ failure and transplantation and there are currently no effective treatments. To examine the therapeutic potential of mTOR inhibition in human mitochondrial disease, four kidney transplant recipients with MELAS/MIDD were switched from calcineurin inhibitors to mTOR inhibitors for immunosuppression. Primary fibroblast lines were generated from patient dermal biopsies and the impact of rapamycin was studied using cell-based end points. Metabolomic profiles of the four patients were obtained before and after the switch. pS6, a measure of mTOR signaling, was significantly increased in MELAS/MIDD cells compared to controls in the absence of treatment, demonstrating mTOR overactivation. Rapamycin rescued multiple deficits in cultured cells including mitochondrial morphology, mitochondrial membrane potential, and replicative capacity. Clinical measures of health and mitochondrial disease progression were improved in all four patients following the switch to an mTOR inhibitor. Metabolomic analysis was consistent with mitochondrial function improvement in all patients.

Emerging therapies for mitochondrial disorders.

Mitochondrial disorders are a diverse group of debilitating conditions resulting from nuclear and mitochondrial DNA mutations that affect multiple organs, often including the central and peripheral nervous system. Despite major advances in our understanding of the molecular mechanisms, effective treatments have not been forthcoming. For over five decades patients have been treated with different vitamins, co-factors and nutritional supplements, but with no proven benefit. There is therefore a clear need for a new approach. Several new strategies have been proposed acting at the molecular or cellular level. Whilst many show promise in vitro, the clinical potential of some is questionable. Here we critically appraise the most promising preclinical developments, placing the greatest emphasis on diseases caused by mitochondrial DNA mutations. With new animal and cellular models, longitudinal deep phenotyping in large patient cohorts, and growing interest from the pharmaceutical industry, the field is poised to make a breakthrough.

Perioperative considerations in adult mitochondrial disease: A case series and a review of 111 cases.

Mitochondrial disease has been uncommon conditions, still results in death during childhood in many cases. The ideal anesthetic pharmacological management strategy for adult patients with mitochondrial disease is currently unclear. In this study, we presented features of the anesthesia methods employed and the perioperative complications of patients in our institution and in previously published case reports. We report the use of general anesthesia 7 times in 6 adult patients with mitochondrial disease during 2004-2014. All cases were performed with maintained intravenous anesthesia. One case was reintubated on the day after surgery, but the cause of death was not directly related to anesthesia. One hundred and eleven general anesthesia cases in 97 adult patients with mitochondrial disease were described in 83 the literature. Although several severe perioperative complications and deaths have been reported, malignant hyperthermia had not been reported in adult cases, and metabolic disorder called propofol infusion syndrome had also not been reported in adult patients undergone total intravenous anesthesia. Perioperative complications of lactic acidosis were reported more in inhalation anesthesia than intravenous anesthesia. Therefore we recommended intravenous anesthesia rather than inhalation anesthesia for adult mitochondrial disease.

Anesthetic agents in patients with very long-chain acyl-coenzyme A dehydrogenase deficiency: a literature review.

Very long-chain acyl-coenzyme A dehydrongenase deficiency (VLCADD) is a rare disorder of fatty acid metabolism that renders sufferers susceptible to hypoglycemia, liver failure, cardiomyopathy, and rhabdomyolysis. The literature about the management of these patients is hugely conflicting, suggesting that both propofol and volatile anesthesia should be avoided. We have reviewed the literature and have concluded that the source papers do not support the statements that volatile anesthetic agents are unsafe. The reports on rhabdomyolysis secondary to anesthesia appear to be due to inadequate supply of carbohydrate not volatile agents. Catabolism must be avoided with minimal fasting, glucose infusions based on age and weight, and attenuation of emotional and physical stress. General anesthesia appears to be protective of stress-induced catabolism and may offer benefits in children and anxious patients over regional anesthesia. Propofol has not been demonstrated to be harmful in VLCADD but is presented in an emulsion containing very long-chain fatty acids which can cause organ lipidosis and itself can inhibit mitochondrial fatty acid metabolism. It is therefore not recommended. Suxamethonium-induced myalgia may mimic symptoms of rhabdomyolysis and cause raised CK therefore should be avoided. Opioids, NSAIDS, regional anesthesia, and local anesthetic techniques have all been used without complication.

[Anesthetic management for patients with mitochondrial disease].

Mitochondrial diseases are caused by a decrease in ATP production due to mutations of mitochondrial or mitochondria-related nuclear DNA. Their effects are likely to appear in tissues with a high energy demand, including skeletal muscle, nervous, and cardiovascular systems. Cardiac manifestations of mitochondrial diseases can be divided into cardiomyopathies, which are primarily hypertrophic and dilated cardiomyopathies, and electropathies, which are primarily conduction system disease and ventricular pre-excitation. The first principle of anesthesia for patients with mitochondrial diseases is to avoid any additional burden on the already declined metabolic functions. Appropriate oxygenation, minimization of the oxygen demand, stable cardiovascular management, maintenance of a normal blood glucose level and body temperature, and effective perioperative pain control are of importance. Most anesthetics have been reported to reduce mitochondrial functions, and although enhancement of the sensitivity and prolongation of the duration of action have been reported, they are clinically used with no major problems. Detailed preoperative evaluation of the disease condition and careful intraoperative monitoring are important for the prevention of perioperative complications.

Long-term outcomes after liver transplantation for deoxyguanosine kinase deficiency: a single-center experience and a review of the literature.

Deoxyguanosine kinase (DGUOK) deficiency is a well-known cause of hepatocerebral mitochondrial DNA depletion syndromes, which include a broad spectrum of clinical presentations. Affected patients often develop life-threatening liver failure, but the benefits of liver transplantation (LT) are controversial because of the frequently severe neurological involvement due to the underlying mitochondrial disease. We describe the long-term clinical course of 2 patients from our institution and provide an update on their outcomes after LT with this condition. Another 12 pediatric patients were identified through a systematic search of the literature. All 14 reported patients underwent transplantation in infancy despite mild to moderate neurological impairment in some cases. The 2 DGUOK-deficient patients from our center displayed liver failure and mild to moderate neurological involvement. At the time of this writing, they had been followed for 5 and 8 years after LT, both patients were alive, and they had only mild neurological symptoms. Three of the 12 patients identified through the literature review survived for a long time (17, 12, and 23 years); 8 died during early follow-up; and for 1 patient, no follow-up information was available. The 1-year survival rate was 64%; 36% survived for more than 5 years. The long-term survivors had good quality of life. In conclusion, although survival after LT for DGUOK deficiency is lower than survival after LT for other indications, a significant proportion of patients benefit from LT with long-term survival and a stable neurological situation despite initial neurological abnormalities. Nevertheless, a decision to carry out LT for patients with DGUOK deficiency remains difficult because neurological symptoms may occur and worsen after LT despite their absence before transplantation.

Unusual case of Cowden-like syndrome, neck paraganglioma, and pituitary adenoma.

BACKGROUND: Pituitary tumors, paragangliomas, and Cowden syndrome do not usually occur together. METHODS: The synchronous presentation of papillary thyroid carcinoma and neck paraganglioma was revealed in a 43-year-old woman who had been diagnosed with a microprolactinoma one decade before and now presented with a constellation of characteristics that are components of Cowden syndrome, specifically macrocephaly, multiple skin papules, fibrocystic mammary disease, and uterine leiomyofibroma. RESULTS: Germline mutation analysis of phosphatase and tensin homolog (PTEN), succinate dehydrogenase subunit B (SDHB), succinate dehydrogenase subunit C (SDHC), and succinate dehydrogenase subunit D (SDHD) was performed with revelation of 3 polymorphic sites in introns 1, 4, and 8 of the PTEN gene and 1 polymorphic site in exon 1 of the SDHB gene, but absence of known pathogenic mutations. CONCLUSION: The coexistence of Cowden-like syndrome, neck paraganglioma, and pituitary adenoma is described for the first time, and could represent a novel genetic syndrome with an as yet unidentified common genetic basis.

Successful cochlear implantation in a patient with mitochondrial hearing loss and m.625G>A transition.

OBJECTIVE: We present a patient with mitochondrial hearing loss and a novel mitochondrial DNA transition, who underwent successful cochlear implantation. CASE REPORT: An 11-year-old girl showed epilepsy and progressive hearing loss. Despite the use of hearing aids, she gradually lost her remaining hearing ability. Laboratory data revealed elevated lactate levels, indicating mitochondrial dysfunction. Magnetic resonance imaging showed diffuse, mild brain atrophy. Cochlear implantation was performed, and the patient's hearing ability was markedly improved. Whole mitochondrial DNA genome analysis revealed a novel heteroplasmic mitochondrial 625G>A transition in the transfer RNA gene for phenylalanine. This transition was not detected in blood DNA from the patient's mother and healthy controls. Mitochondrial respiratory chain activities in muscle were predominantly decreased in complex III. CONCLUSION: This case indicates that cochlear implantation can be a valuable therapeutic option for patients with mitochondrial syndromic hearing loss.

Paediatric liver transplantation for metabolic disorders. Part 2: Metabolic disorders with liver lesions.

Liver based metabolic disorders account for 10 to 15% of the indications for paediatric liver transplantation. In the last three decades, important progress has been made in the understanding of these diseases, and new therapies have emerged. Concomitantly, medical and surgical innovations have lead to improved results of paediatric liver transplantation, patient survival nowadays exceeding 80% 10 year after surgery with close to normal quality of life in most survivors. This review is a practical update on medical therapy, indications and results of liver transplantation, and potential future therapies, for the main liver based metabolic disorders in which paediatric liver transplantation may be considered. Part 1 focuses on metabolic based liver disorders without liver lesions, and part 2 on metabolic liver diseases with liver lesions.

Drug management in emergent liver transplantation of mitochondrial disorder carriers: review of the literature.

BACKGROUND: Mitochondrial respiratory-chain disorders (MRCD) lead to progressive disabling of neurological and cellular conditions that involve muscles, brain, kidney, and liver dysfunction. Affected individuals may need surgery, including orthotopic liver transplantation (OLT). Surgery poses anesthesia challenges because of the prolonged use of anesthetic drugs and sedatives, which may inhibit oxidative phosphorylation, mimic mitochondrial cytopathic disorders, or unveil them ex novo. MATERIALS AND METHODS: We conducted a multilingual PubMed search of surgical and non-surgical anesthesia reports between the years 1992 and 2008, where anesthetic drugs were used in MRCD patients, especially for those undergoing urgent OLTs. RESULTS: There were 51 case reports of 210 anesthesia and critical care interventions in patients with MRCD, a large part of them were children. Data pertaining to the safe usage of anesthesia and perioperative drugs were limited and conflicting. We found no article that addressed the issue of perioperative handling of urgent OLT in MRCD patients. We therefore suggest our own - although limited - experience for such occasions. CONCLUSION: There are no randomized, controlled, trial-based indications regarding safe anesthetic drugs to be used perioperatively in MRCD carriers. Consultation among geneticists, anesthesiologists, intensivists, and surgeons is essential in patients with known/suspected metabolic syndrome for planning appropriate perioperative care.

Role of mitochondrial variation in maternally inherited diabetes and deafness syndrome.

Maternally inherited diabetes and deafness syndrome is caused by the mitochondrial deoxyribonucleic acid mutation 3243 A>G (where A = adenine and G = guanine). The degree of heteroplasmy of the mitochondrial deoxyribonucleic acid may correlate with the rate of progression of the hearing loss. This has important implications for counselling patients with this pathology. Cochlear implantation is a successful method of rehabilitation for patients with hearing loss as part of this syndrome.

Anestesia en enfermedades mitocondriales / No disponible

Las enfermedades mitocondriales son un raro grupo de enfermedades que se manifiestan a través de un defecto en la cadena de transporte de electrones o de la fosforilación oxidativa. Se trata de una alteración del ADN nuclear o del mitocondrial que provoca miopatía hipotónica, encefalopatía y aumento del ácido láctico. Para su correcto diagnóstico deben realizarse, entre otras pruebas, una biopsia muscular y una resonancia magnética. El anestesista debe realizar su trabajo en un paciente con miopatía sin diagnosticar y con riesgo de complicaciones cardiorrespiratorias y neurológicas, por ello es importante el conocimiento de las acciones sobre la cadena respiratoria de los agentes anestésicos. Presentamos el desarrollo esquemático de las enfermedades de la cadena respiratoria mitocondrial y su manejo anestésico

Diseases of the mitochondrial respiratory chain are a rare pathologic group that can be manifested through a defect in the transport chain of electrons or by oxidative phosphorylation alteration. It is a disturbance of the nuclear or mitochondrial DNA, causing hypotonic myopathy, encephalopathy and hyperlactacidemya. For its correct diagnosis must be performed muscle biopsy and magnetic resonance. The anaesthetist must do their work in a patient without a correct diagnostic of myopathy, and a high risk of cardiorrespiratory and neurologic complications. That’s why it’s important the knowledge of the actions of de anaesthetic agents by de respiratory chain. We present the schematic development of the mitochondrial respiratory chain diseases and its anaesthetic management

Stem cells and cardiac disorders: an appraisal.

The use of stem cells has proved to be an important tool in investigating the events of early cardiac development, differentiation, and morphogenesis. In addition, stem cell transplantation in the treatment of certain cardiac disorders has shown early promise. We have attempted to present a balanced review of both basic studies and clinical-therapeutic potential of stem cells transplantation in the damaged heart.