Katarzyna Baranowska, Monika Walankiewicz, Beata Gajda, Ewa Papuć,
Marta Tynecka-Turowska, Konrad Rejdak
Mitochondrial encephalopathy as serious confounder
of human wellbeing - case report and literature study
Department of Neurology, Medical University of Lublin, Lublin, Poland
Katedra i Klinika Neurologii, Uniwersytet Medyczny w Lublinie
Katarzyna Baranowska, Monika Walankiewicz,
Beata Gajda, Ewa Papuć, Marta Tynecka-Turowska, Konrad Rejdak
Mitochondrial encephalopathy as serious confounder
of human wellbeing- case report and literature study
Encefalopatie mitochondrialne jako schorzenia o istotnym wpływie
na funkcjonowanie człowieka
- prezentacja przypadku i analiza literatury
Mitochondrial encephalomiopathies are diseases that occur generally in the central nervous system and muscles. They are a group of genetic disorders that affect cellular energy metabolism. They manifests in tissues and organs with high-energy requirements such as brain, muscles, heart, eyes, kidneys and liver. [9, 17]
Up to 1 in 5000 people suffer from the mitochondrial disorders. This information shows that many more people are affected by this disease than was previously reported. It was even confirmed that mitochondropathies occur more often than other popular genetic diseases, for example cystic fibrosis (1 in 31 000). In spite of that, the latter is more commonly known by clinicians. Because of a huge variety of nuclear genes responsible for mitochondrial function, it is estimated that 1 in 5 people might carry nuclear gene mutations connected with this disorder. Most of these genes do not present with clinical symptoms due to the fact that they are recessive.
Unlike other structures in human cells, mitochondria are highly dynamic organelles. They are partially autonomous and possess their own genome with the potential of transcription and translation.  They are also the place where oxidative phosphorylation takes place, which generates a proton gradient from NADH and FADH2 by the electron transport chain. The principal function of mitochondria is to produce adenosine triphosphate, the cellular energy currency.  The human mitochondrial genome is a double stranded molecule which is replicated and transcribed in the mitochondrial matrix. Each organelle contains between 2-10 copies of mtDNA. Mitochondrial DNA contains 37 genes out of which 22 encode tRNA and 2 encode rRNA for protein synthesis. Another 13 genes encode the proteins of the respiratory chain. Nuclear DNA is inherited according to Mendel’s law and it encodes complex II of the respiratory chain and the rest of proteins. It also codes a few genes that control mtDNA replication, transcription and translocation. 
Mitochondrial genetics has its unique characteristic due to the fact that it is not inherited by Mendel’s law. It helps to understand the mechanism of mtDNA-related diseases. Maternal inheritance means that all the mtDNA mutations are inherited from mothers and only their daughters will transmit it to their progeny. Heteroplasmy means that there are thousands of copies of mtDNA in every cell. However, when there is a deletion, both, normal and mutated mtDNA may coexist. Before clinical signs and tissue dysfunction are visible, there must be present a critical percentage of mtDNA mutation. This is called a threshold effect. mtDNA has also a high mutation rate. .
Mitochondrial gene mutations can be divided into the mutations of the mitochondrial deoxyribonucleic acid (mtDNA) and nuclear deoxyribonucleic acid (nDNA). They can be inherited or sporadic. The percent of both of these mutations in adults is the same. In children, the nDNA mutations are 80%. mtDNA mutations are divided into large-scale rearrangements and inherited point mutations. The first ones are usually sporadic, heteroplasmic and affect several genes, while the inherited mutations can be heteroplasmic or homoplasmic. 
Diagnosing mitochondriopathies can be difficult because of the many different symptoms of the disease. Usually the recognition is based on clinical signs, blood chemistries, imaging, electrophysiologic, histological, biochemical, magnetic spectroscopic and genetic analysis. 
In the central nervous system we can observe microcephaly, mutual and symmetrical damage of the basal nuclei and thalamus, multifocal encephalomalacia, spongiform encephalopathy and calcification of basal nuclei. They manifest as strokes, seizures, optic atrophy, ataxia, migraines and dementia.  In many cases we can notice the similiar symptoms, such as low growth, hearing loss and diabetes.  Other signs may include ophthalmoplegia, gastroesophageal reflux, diabetes mellitus, bone marrow failure, immunodeficiency, renal tubulopathy, and mental retardation. Deviations in laboratory testings usually include lactic acidosis in blood and cerebrospinal fluid. Very often patients present with multisystemic disorders. 
If an adult patient has typical manifestations of mitochondriopathy, his or her physician should perform an analysis of their mtDNA or nDNA, according to specific clinical symptoms.
If a person presents with non-syndromic mitochondriopathy, the diagnosing process is more complicated since there is no gold standard for identifying the disease. A patient has to undergo all the basic tests as well as sequencing of their entire mtDNA. These exams are taken from blood, however, in some cases, studying the muscle DNA brings more secure molecular diagnoses. 
A 45-year-old male presented to the neurology department with manifestations of speech and movement disorder including upper limbs dystonia, general rigidity, and myoclonic movements. The first symptoms of the disease had occurred at the age of 27 and had been progressing. The clinical picture was additionally aggravated by the patient’s history of alcohol abuse and use of antipsychotic drugs. No family history of neurologic diseases was reported.
Neurological examination showed that the patient suffered from dysarthria and had a facial nerve palsy. Ocular mobility was restricted and was associated with visual disturbances. The patient had a segmental dystonia which encompassed the head, neck and left upper limb muscles. General rigidity, tremor and temporary myoclonic movements were observed. The patient had a broad based gait due to spasticity of the lower limbs. These symptoms suggested extrapyramidal dysfunction as an origin of the disease. General physical examination was unremarkable. In ophthalmoscopic examination, green deposits were seen, which might indicate Wilson’s disease.
The patient was initially investigated as follows. His routine blood counts were normal as well as levels of electrolytes and renal functions. The serum level of the liver enzyme GGTP was elevated while ASP and ALT were normal. Lactic acid level was raised in blood – 29,6 mg/dl( reference range 5,7-22). Its presence in cerebrospinal fluid(CSF) was also detected in an abnormal range - 13,4mg/dl. The CSF cytochemistry showed no abnormalities. Antibody titers against Borrelia were normal. Further metabolic studies revealed accurate serum level of Ceruloplasmin - 0,243 ( reference range 0,2-0,6) which excluded Wilson’s disease.
MRI scans were taken with FAST, FSE and FLAIR sequence before and after administration of contrast. MRI examination showed nonspecific, symmetrical, pathologic changes in basal ganglia specially in the putamen which were amplified in T2 and FLAIR. Atrophic areas were found in the fronto-parietal lobe and cerebellar vermis. Typical localization of these changes might suggest metabolic neurodegneration as a primary background for the illness. Among the most probable differential diagnoses were MELAS and Leigh Syndrome although primary vessel dysfunctions could not be excluded.
Doppler examination of lower limbs was performed but no abnormalities were found.
On psychological examination, the patient was fully oriented but judgment and executive functions were slowed. Diminished ability to think and to concentrate also occurred. He seemed to be in a depressed mood and in constant fear of an unknown diagnosis and the course of the disease process.
Muscle biopsy was done and genetic examinations were taken. The results are still in progress.
Differentiation diagnosis encompassed a number of conditions including the following: Wilson’s disease, mitochondrial encephalopathy, toxic damage of the brain and drug induced syndrome. In this case report, atypical signs in addition to other circumstances like alcohol abuse and taking antipsychotic drugs, could confound and complicate the diagnostic process.
There is no current effective drug therapy for mitochondrial disease but interesting treatment methods are in the process of being developed. Despite the fact there was no diagnosis made, our patient received Botulinum toxin to minimize rigidity. Also, 300 units of the drug Xeomin was administered intramuscularly to the head, neck and left upper extremity muscles.
Mitochondrial diseases are a diverse group of illnesses caused by inheritable genetic mutations, acquired somatic mutations, and exposure to toxins (including some prescription medications). While each mitochondrial disease is very rare in the population, hundreds of causes of mitochondrial diseases are known.  One classification of mitochondrial disease splits them into three groups; mtDNA mutations, predominantly nDNA mutations and both nDNA and mtDNA mutations. Mutations in mtDNA genes impair the respiratory chain exclusively, whereas mutations in nDNA genes impair various mitochondrial molecules, structures, or pathways in addition to the respiratory chain, such as mtDNA-replication, beta-oxidation, the coenzyme-Q metabolism, mitochondrial biogenesis, carrier-proteins or pore-proteins
Mitochondrial disorders are rarely considered as an initial diagnosis [16, 7, 13]. This is because of their sporadic appearance, especially in the adult neurological population, as was seen in our case report. Additionally, low awareness among clinicians hinders making the proper diagnosis 
Due to the variety of existing mutations, there are several syndromic disorders, although the vast majority of the MIDs present with the non-symptomatic form. Multisystem abnormalities can be divided into central or peripheral nervous system disease. Central manifestations include stroke-like episodes, epilepsy, migraine-like headaches, movement disorders, cerebellar ataxia, visual impairment, encephalopathy, cognitive impairment, dementia, psychosis, hypopituitarism, and aneurysms [7, 1,3]. Peripheral nervous system disease manifests as myopathy, neuropathy, or neuronopathy as well as non-neurological manifestations affecting the ears, endocrine organs, heart, gastrointestinal tract, kidneys, bone marrow, and the skin. Evaluation of these disorders is expensive, and not without false-negative and false-positive results that can lead to many diagnosing difficulties among the physicians . Most of the common inherited mitochondrial disorders have been well-described in the literature but can be overlooked by many clinicians if they are uneducated about these disorders  In general, the evaluation of the classic mitochondrial disorders has become straightforward if the clinician recognizes the phenotype and orders appropriate confirmatory testing. However, the majority of patients considered for a mitochondrial evaluation do not have a clear presentation that allows for rapid identification and testing 
In reported cases, there were no special findings that could help clinicians make a proper diagnosis. Additional tests including MRI and biochemical tests have previously aided neurologists in suspecting mitochondrial disorders as the culprit of a disease. Within this group of disorders, MELAS, MERFF and Leigh syndrome are the most probable.
Leigh syndrome (LS, subacute necrotizing encephalomyelopathy) was first described in 1951 by Daniel Leigh.  Seven month old patients was administer to the hospital with neuropathologic features. Necropsy showed focal, bilaterally symmetric, spongiform, necrotic lesions associated with vascular proliferation and demyelination in basal ganglia, cerebellum, or cerebral white matter .
This mitochondrial encephalopathy is inherited. Until now, 35gene with mutations responsible for Leigh Syndrome have been isolated . Associated mutations affect genes of the nuclear (nDNA) and mitochondrial (mtDNA) genome. This leads to dysfunction of mitochondrial enzymes such as: pyruvate dehydrogenase, Coenzyme Q and the I, II, IV,V complexes of the respiratory chain. The most typical histopathological changes in the central and peripheral nervous system are necrosis and demyelinization of cells and vessel proliferation . The incidence of Leigh syndrome is 1 in 77000 live births. The prevalence rate is 1 in 34000 and is higher in males than females (3:2) . The first manifestations of the disease typically occur between 3 and 12 months of life . However, as in our case report, there have been previous reports of patients in whom the earliest symptoms manifested in adulthood.
In infants, initial symptoms might be atypical and include difficulty breathing, feeding and vomiting. Further progression of the disease leads to blurred vision, nystagmus, ataxia, seizures, excessive fatigue, hypotonia, dystonia, developmental delay or respiratory impairment.  Other abnormalities include retinitis pigmentosa , deafness, polyneuropathy and myopathy. Acute respiratory failure affects 64-72% of individuals .
Leigh syndrome in adulthood is very rare and the course of the disease may be variable. Adult patients manifest with external ophthalmoplegia, dystonia, and ataxia as shown in our case report. Extra neurological features, which are called Leigh-like syndrome, include diabetes, short stature, hypertrichosis, anemia, cardiomyopathy (hypertrophic or dilated), hepatomegaly, renal tubulopathy or diffuse glomerulocystic kidney damage. To the features of the disease we can include also optic atrophy, retinitis pigmentosa and ophthalmoplegia which occurred in reported patient.
Biochemical investigation shows an elevated level of lactate, pyruvate, and protein levels in cerebrospinal fluid. The most typical changes on CT scan are hypoechogenic areas in the basal ganglia and thalamus. The ventricular system may be enlarged. MRI may shows focal hyperechoic areas in the basal ganglia, thalamus, substantia nigra, nucleus ruber, brainstem, cerebellar white matter, cerebellar cortex, cerebral white matter, or spinal cord onT2 images. [8 ,12 ,14]
Another suspected diagnosis was MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) caused by several mutations of mtDNA. It is one of most widely studied of mitochondrial diseases. There are currently 29 linked mutations known, however about 80% of the cases carry an adenine-to-guanine transition mutation (A324G) located in the region of mtDNA that codes for tRNAleu(UUR). Symptoms often present in childhood although disease onset can occur at any age, even adu lthood. There are a few known adult cases with an atypical course, which left this disease as an option on our differential .
Traditional phenotype is associated with strokes, visual disturbances, focal or generalized seizures and hemiplegia. Metabolic strokes in MELAS typically occur due to an acute, relatively intense energy deficiency in small cerebral vessels leading to a decrease in nitric oxide and a lack of regional vasodilation with secondary ischemia. If not presenting with focal weakness, strokes in patients with MELAS can present with focal or generalized seizures. Our patient presented with ophthalmological disorders including retinal pigmentary changes, which is rare but specific for asymptomatic-adult onset . However MRI changes did not confirm presence of ischemic regions of the brain, which are common for strokes. We could find focal encephalomalacia in the parietal lobe, which is essential for MELAS. Metabolic strokes in MELAS occur due to an acute energy deficiency in small cerebral vessels leading to a decrease in nitric oxide and a lack of regional vasodilation with secondary ischemia. It might have been helpful to measure levels of nitric oxide, but measurements were not taken in this case [3, 5].
Main laboratory tests used for diagnosing this process are the presence of lactic acidosis in blood, spinal fluid or both, commonly increasing after exercise, and elevated CSF protein levels. Those findings occurred partially in our patient. Lactic acid level was elevated in blood tests but was not monitored in the CSF.
Due to a lack of specific biochemical markers for each of these syndromes along with the atypical clinical manifestation of our case, only genetic examination could differentiate which MID was present in our patient
Substantial progress was made in the diagnosing of mitochondrial diseases in late 2012. Falk MJ and colleagues developed a one-step, optimized tool for whole-exone analysis of nuclear and mtDNA genes, relevant to the diagnostic evaluation of mitochondrial disease. Additionally this kit can detect heteroplasmic mutations that reach levels as low as 8 percent. This will likely shorten the diagnostic process and will give opportunity for discovering novel disease genes. However, this method is not widely available and costs remains very high. 
Among the many mitochondrial disorders we can also feature the MERRF syndrome. It is a myoclonic epilepsy with ragged red fibers, which is a very rare disease among the population. It is associated in 80% of patients with maternally-inherited A8344G mutation of tRNA Lys gene. The other cases are caused by multiple mutations of nuclear DNA which result in mitochondrial DNA deletions. All the mutations effect in broken synthesis of proteins of the respiratory chain. The disease may affect many parts of the body, but main symptoms are from skeletal muscles and nervous system.
The MERRF syndrome usually presents between childhood and early adulthood. The typical first clinical picture includes myoclonus, seizures, cerebellar ataxia and myopathy. To confirm the disaese the skeletal muscle biopsy must be done. The results usually show multiple ragged red fibres. They are concentrations of diseased mitochondria that are accumulated in subsarcolemmal region of the muscle fiber when being stained with the modified Gomori trichrome and viewed microscopically.
Among the other symptoms we can mention multiple symmetric lipomatosis, dementia, corticospinal tract deficitis, bilateral deafness, peripheral neuropathy, optic atrophy, renal tubular dysfunction and cardiomyopathy.
Like in other encephalomyopathies there is also presented lactic acidosis in the blood. In morphology we can observe pancytopenia. However, unlike in MELAS, we do not observe blindness, hemiparesis and vomiting. The disease can progress, from minor, nondisabling manifestations to progressive clinical picture.
The treatment is primarily symptomatic, because, like in many other mitochondrial disorders there is no effective cure. Coenzyme Q10 is usually prescribed and given in high doses by the clinicians .
Not only diagnosis but also treatment of the MIDs is challenging. Although, many new strategies of the treatment have been developed, there is still no causative therapy. Before new methods of therapy were introduced, patients with this kind of diseases could be treated only via symptomatic treatment. In the case of endocrine problems, they got hormone substitution. When diabetes occurred, hypoglycemic treatment was integrated. If they presented with digestive symptoms, they received antiemetic drugs, substitution of pancreatic enzymes, and domperidone or cisapride for gastrointestinal dysmotility. Usually the substitution of potassium and sodium was also essential. In severe cases of patients presenting with cachexia, dysphagia and repeated vomiting, clinicians even considered percutaneous gastroenterostomy.
Although, admistration of certain drugs is essential, even more important in treatment is to avoid many of them. We can distinguish β-blockers, acetyl-salicylic-acid, bupivacaine, carvedilol, tetracycline, corticosteroids because all of them affect the respiratory chain. Biguanides cause lactic acidosis. Zidovudine, doxorubicine, carboplatin and interferon influence mtDNA. Patients are also required to avoid ozone exposure .
These days, patients can be treated with new methods of treatment. Despite the fact that many of them appeared to be ineffective or underpowered, there is a huge need to continue studies and trials in this field.
Among these new methods, we can distinguish enhancement of mitochondrial biogenesis. This is applied to transcriptional co-activators, such as PGC (peroxisome proliferator-activated receptor γ co-activator)-1α and -1β and PRC (PGC-related co-activator). They have been identified as components of the signaling cascade that controls the expression of mtDNA. The PGC agonist and bezafibrate upregulates its signal and leads to a rise in the total number of mitochondria in a cell. It boosts mitochondrial bioenergetics to normal levels.
Another new method of treatment is supplementation of CoQ10. This is a very common therapy due to its safety and wide availability. Besides, the substrate is an important component of the respiratory chain. The therapy is performed mainly among patients with mitochondrial and lipid storage myopathy, central nervous system diseases, and recurrent myoglobinuria. It was demonstrated, that supplementation of CoQ10 can be an effective treatment when given during the presence of symptoms, as well as a preventive measure in predisposed patients.
In mitochondrial diseases such as MERRF and Leigh syndrome, we observe aberrant calcium homeostasis. In both cases, treating patients with calcium channel blockers caused their remarkable improvement .
Going by all previous reports about the treatment of MIDs and based on our patient history, we can conclude that there is no effective cure for this kind of disorder. However, treating people with Botulinum toxin or other symptomatic medications has helped to reduce their ailments and improved their quality of life. Moreover, our case confirmed this observation as well.
Despite the fact that mitochondriopathies are diagnosed more often these days than in previous years, they are still a big problem to clinicians. This is due to lack of information about these disorders in literature and publications. Also, the diagnostic process causes a lot of difficulty for many reasons. Among them we can distinguish: lack of standard procedure for neurologists to make a proper recognition, no characteristic symptoms, both neurologic or from other organs systems. Besides this, we can mention, that clinicians do not usually consider MIDs at the beginning of the diagnostic process. All these factors cause the disease to go undiagnosed and this process leads to the deterioration of a patient’s condition.
Continuous efforts to improve the recognition and effective treatment of these disorders have brought mixed reviews. Results of many of them are not satisfactory; however, further studies and examinations are still essential. There is still no causal treatment or standard procedure for diagnosis due to the fact that there are many different genetic mutations within one syndrome. This leads to failure in introducing a standardized therapy. Moreover, high costs of new investigations mean that implementation of new therapy will be also very expensive for each patient.
Among the patients with MIDs, there are many new atypical cases. Like in our case, they can include adults, who present with symptoms of disorders that are characteristic for children. Diagnosing these patients is a big challenge for both general practitioners, as well as for experienced neurologists.
All these facts and observations lead us to conclude that our knowledge about mitochondrial disorders is still insufficient. However, their increased incidence proves that they will soon stand out from the other neurological disorders.
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Mitochondrial encephalomiopathies are a group of genetic disorders that affect cellular energy metabolism. They manifests in organs with high-energy requirements such as brain, muscles. We report a case of 45-year-old male presented to the neurology department with manifestations of speech disorders, upper limbs dystonia, general rigidity and myoclonic movements. No family history of neurologic diseases was reported. Extensive investigations helped to establish provisional diagnosis of Leigh Syndrome. Currently, genetic assessment is in progress to set final diagnosis. To conclude, physicians knowledge about mitochondrial disorders is still insufficient. However, their increased incidence proves that they will soon stand out from the other neurological disorders.
Encefalomiopatie mitochondrialne są grupą zaburzeń dotyczących metabolizmu wewnątrzkomórkowego tkanek. Objawy tych chorób występują w tkankach wysokim metabolizmie, takimi jak mózg i mięśnie. Prezentujemy przypadek 45 letniego pacjenta, przyjętego na oddział neurologii z objawami zaburzeń mowy, dystonią kończyn górnych, uogólnioną sztywnością i ruchami mioklonicznymi. Wywiad rodzinny w kierunku chorób neurologicznych był ujemny. Wnikliwa diagnostyka pozwoliła na postawienie wstępnego rozpoznania – choroba Leigh, jednak ostateczną diagnozę potwierdzą badania genetyczne. Poziom wiedzy lekarzy na temat chorób mitochondrialnych jest wciąż niski. Jednakże, coraz częstsze ich występowanie dowodzi, że wielu z nich w przyszłości spotka się z tego typu schorzeniem.
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