The discovery of new congenital disorders due to advances in medicine. This puts the anaesthesiologists in situations to deal with newly recognized syndromes patients that are not familiar with them.
The syndrome has these features: 3-methylglutaconic aciduria (MEG), deafness(D), encephalopathy (E), Leigh-like syndrome (L). This disorder is caused by biallelic mutations in serine active site-containing protein 1 (SERAC1) gene. When these patients experience hepatopathy (H) in addition to the above manifestations, the syndrome is referred to as MEGD(H)EL [1].
We discuss the pathology, genetics and significant aspects of this sporadic disease which is important for anaesthesiologist [2].
Anaesthesiologists often encountered mitochondrial disease patients in the theatre. This disease is presented with clinical symptoms and signs in major organs, such as the kidneys, lungs, brain and liver which consume a lot of ATP. Mitochondria is the main source of metabolism in humans [3].
So, mitochondrial syndrome is hectic for the anaesthesiologist because mitochondrial disease causes dysfunctions of multiple organs, including cardiorespiratory failure, and myopathy [3].
Anaesthetic agents’ selection is crucial because significant and unexpected complications can happen after anaesthesia, although various anaesthetic methods have been effectively employed for those patients [3].
Mitochondrial overview
Mitochondrial structure consists of four parts: the external membrane, the internal membrane, the intermembrane space, and the matrix. They do tasks, such as Krebs cycle, pyruvate oxidation, and the metabolism of amino acids, fatty acids, and steroids, nevertheless, the most important is energy creation as adenosine triphosphate (ATP), through the electron-transport chain and the oxidative-phosphorylation system (the “respiratory chain”). Mitochondria is the principal source of cell metabolism in humans. The cellular machinery necessary for the Krebs cycle, metabolism of amino acids, fatty acid oxidation and, most importantly, oxidative phosphorylation all exist within mitochondria, either in the mitochondrial matrix or mitochondrial membrane. Electrons usually join the electron transport chain via complex I or complex II and are then sequentially transferred to Coenzyme Q, complex III, cytochrome c, complex IV and finally to oxygen to form water [4, 5].
The energy regained during this transfer is employed to pump protons into the intermembrane space of the mitochondria, generating a gradient across the inner mitochondrial membrane. The proton gradient is then used as an energy source for phosphorylation of ADP to ATP by complex V [6].
The entire process is termed oxidative phosphorylation, and the complete system is termed the mitochondrial respiratory chain (MRC) (complexes I-V).
The respiratory chain is made up of five multiple protein complexes that are situated in the inner mitochondrial membrane: reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase-ubiquinone oxidoreductase (complex I, approximately 46 subunits), succinate dehydrogenase-ubiquinone oxidoreductase (complex II, 4 subunits), ubiquinone-cytochrome c oxidoreductase (complex III, 11 subunits), Cytochrome c oxidase (complex IV, 13 subunits), and ATP synthase (complex V, approximately 16 subunits). Ubiquinone (coenzyme Q10) and cytochrome c are two minor electron carriers that are essential for the respiratory chain [5].
Two coordinated processes take part in ATP synthesis, with electrons transported along complexes to molecular oxygen and producing water. Protons shifted from the matrix to the intermembrane space by complexes I, III, and IV simultaneously [5].
Genetics
Mitochondria are the only organelles that have their own DNA (mitochondrial DNA or mtDNA), and their own cellular machinery for producing RNA and protein. Since all mitochondria are maternally inherited, mutations in mtDNA are passed on to all offspring of an affected mother, but only transmitted further through her daughters [6].
Mitochondrial DNA codes only 37 genes (13 proteins, 22 transfer RNAs, 2 ribosomal RNAs); the other1100 or so gene products within the organelle are encoded by genes within the nuclear genome of the cell [4, 5]. and thus follow classical Mendelian inheritance patterns. Furthermore, mitochondria are under dual genetic control (Mendelian and mitochondria) [6].
Due to this dual genetic control, mitochondrial deficiencies may arise from many genetic causes, with different physiological presentations and modes of inheritance. Consequently, different offspring from a single mother may show strong variation in phenotype despite being genetically similar. So, it would be unsuitable to conclude that a drug or anaesthetic method being used safely with one patient having a mitochondrial defect would be similarly safe in all other patients with mitochondrial disease even in siblings with genetic variations resulting in identical mutations [6].
Mitochondrial disease and cochlear implant
It is merit repeating that mitochondrial disease is not one disorder but stands for hundreds of various enzymatic mitochondrial defects, both genetic and environmental in origin [7].
Clinical symptoms alone are not pathognomonic in mitochondrial disease, and although radiological and laboratory investigations give important clues, muscle biopsy stays a crucial part of the diagnostic process [8].
Mutations in the serine active site-containing protein 1 (SERAC1) gene cause MEGDEL syndrome [3-methylglutaconic aciduria (MEG), deafness (D), encephalopathy (E), Leigh-like syndrome (L). (H) is added to the above manifestations When those patients experience hepatopathy, the syndrome is labelled as MEGD(H)EL [2].
Wortmann et al., in 2006 describe the serine active site-containing protein 1 which codes a protein important for the transformation of monoacylglycerol phosphate, and phospholipid phosphatidylglycerol that are crucial for function of the mitochondrial and cholesterol metabolism [2].
This syndrome is presented by severe dystonia, deafness, seizures spasticity, failure to thrive, and delayed developmental milestones. About 50% of those with neonatal onset have hepatic involvement ranging from severely abnormal liver enzymes, direct hyperbilirubinemia, and hyperammonia to severe liver dysfunction, however this is usually transient and occurs mostly through the first year of life [9].
MEGD[H]EL syndrome shares manifestations which are related to organic acidurias, the SERAC1 gene mutation also impairs oxidative phosphorylation, a mechanism analogous to mitochondrial disease. Yet, this syndrome is unique [10].
This syndrome had mentioned in many literatures and is predictable worldwide to happen in 27 births annually with a male: female ratio of 1:1.3 [9, 11] and the survival is approximately 50% in the teenage group [9] There is no. treatment only supportive. They may need several interventions that require anaesthesia, for example, sedation for auditory brainstem response testing, gastrostomy tube placement and magnetic resonance imaging.
In recent times, no clinical studies describe the consequences perioperatively of this syndrome. Furthermore, familiarity with anaesthetic management for patients suffering from mitochondrial disease and organic aciduria, can be guided to put effective plan for of these patients [2]
Hearing loss has been seen often in those patients, However, due to life threatening features of this syndrome, there were fewer studies on the type and degree of severity of hearing loss in this disease. Gold and Rapin conducted a study in 1994, on correlation between deafness and mitochondrial disease, citing 32 from total 162 had hearing loss [12].
Cochlear implantation has been increasing rapidly, and now it is an efficient option for patients with severe hearing loss and deaf mutism. It had been one of the biggest advancements in otology. Cochlear implants are highly priced computerized electric prostheses that partially substitute for the functions of the cochlea [13].
The surgery is done under general anaesthesia through a trans-mastoid approach. The operative procedure requires the preservation of functional integrity of the facial and cochlear nerve. The anaesthesiologist is an integral part of the cochlear implant crew whose anaesthetic as well as communication skills are evaluated [13].
The anaesthesia technique plays a significant role in accomplishment of cochlear implant surgery as the anesthesiologist must produce circumstances which ease usage of nerve stimulators and management of post-operative complications such as nausea, vomiting and vertigo [13].
In recent years, no case reports or clinical trials are referring to the consequences perioperatively of this syndrome.
Additionally, familiarity with anaesthetic management of patients with mitochondrial disorders, organic acidurias, and fatty acid metabolism can provide insights and contribute to creating a plan that efficiently addresses potential difficulties.
Case presentation
We obtained written informed consent from the patient parents to publish this case report. We discuss the anaesthetic plan of a female diagnosed to be MEGD(HE)L syndrome aged 2 years, weighing 8kg, scheduled for cochlear implant under general anaesthesia.
Full term baby had been born through the caesarean section due to abnormal presentation and her weight was 3200g. Full investigations and work-up were done showed generalized muscular hypotonia elevated liver enzymes, hyperbilirubinemia, lactic acidosis, hypoglycemia and hyperammonemia.
She had been identified by genetic testing to have MEGD(H)EL syndrome. After adjustment of the metabolic abnormalities, she was released home on day 14 postnatal.
On physical examination revealed a grossly normal and age-appropriate airway with generalized hypotonia. She is currently taking l-carnitine, vitamin E, and coenzyme Q-10.
Built on existing data, there is no therapeutic treatment for this developing disease [2]. She experienced a generalized delay in developmental milestones, and a profound bilateral hearing loss. No evidence of seizure disorder existed. No previous exposure to anaesthesia.
A careful anaesthesia protocol was outlined, we decided to use infusion of dexmedetomidine for maintenance of sedation during the surgery. The anaesthesia machine had been prepared by a 60-minute highflow gas flush at 10 1. minute− 1, removing the vapourisers, and replacing the soda lime. On the morning of the surgery, she was allowed in the theatre with intravenous access in place and was fasting for at least 4h.
Intravenous (IV) dextrose 5% at the rate of 25ml. hour− 1 was started 2h before the surgery as maintenance fluid and continued till the anaesthesia induction. Preinduction glucose level was 70mg/dl in blood.
After preoxygenation, induction of anaesthesia intravenous with ketamine 2 mg.kg− 1 fentanyl 1µg.kg− 1 and dexmedetomidine 1µg.kg− 1. Intubation was done using cuffed tube of appropriate size. Anaesthesia maintenance had been done with IV infusion of dexmedetomidine at the rate of 0.5µg.kg− 1. hour− 1. Intraoperative facial nerve monitoring was performed. The starting temperature was 36.40C and the infant was cautiously warmed by a heating mattress. The surgery period was uneventful and was completed within 90min.
The haemodynamic and saturation had been checked and were within normal ranges. At the surgery end, brainstem evoked response audiometry (BERA) is employed to verify the integrity of the implant. Dexmedetomidine infusion was stopped at the end of procedure, and she was observed for recovery from anaesthesia, glucose level, vital signs and temperature.
After 10min, she recovered from anaesthesia and the hemodynamics were stable and the temperature was 36.60C. The temperature was measured pre and post operative rectally. Analgesia was achieved postoperatively with rectal suppositories of paracetamol. The patient’s postoperative course and recovery were uneventful with adequate pain management. The patient was shifted for observation postoperatively to the ICU for the first 24h [14].
The ICU period was smooth, and she was released the next day. The anaesthetic plan was tolerated without any complications.
In our literature, we would like to focus on the of dexmedetomidine usage as sole anaesthetic agent in MEGDEL syndrome patients. Dexmedetomidine had been employed as an alternative for anaesthetic drugs, to prevent mitochondrial dysfunction and malignant hyperthermia.
We also aimed to avoid any metabolic abnormalities at the perioperative and postoperative period, which includes hypoglycemia, hypovolemia and hypothermia [14, 15].
