Diagnosis Of Mitochondrial Encephalomyopathy Research Articles

SUN-683 Was Metformin the Culprit for This Lactic Acidosis?

IntroductionMetformin is the first-line drug for treatment of Type 2 diabetes. A meta-analysis of 70,490 patient-years of metformin use reported no lactic acidosis. We present a case of a patient who developed lactic acidosis while on Metformin; with other contributing factors.Case DescriptionA 72-year old male with dementia, diabetes, hypertension, hypothyroidism and “muscular dystrophy” was admitted with encephalopathy. Medications included levothyroxine, donepezil, insulin glargine and metformin. A Brain CT scan revealed frontal lobe atrophy and lacunar infarcts. Admission blood work revealed lactic acidosis of 5.6. Sepsis workup was negative. Metformin was discontinued, and the patient improved with intravenous hydration. Upon discharge, Metformin was restarted. Follow-up lactic acid was normal. After a subsequent hospitalization with similar presentation and peak lactic acid of 4.7, metformin was stopped altogether. The patient was referred to a neuromuscular specialist and a diagnosis of Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) was made. The “muscular dystrophy” was likely mitochondrial disease. A third hospitalization (while not on Metformin) saw a peak lactic acid of 2.8. We concluded that the lactic acidosis was secondary to MELAS, but Metformin had caused the significant spikes seen during the first two hospitalizations.DiscussionMitochondrial disorders must be in the differential diagnosis for patients diagnosed with muscular dystrophy. The hallmark of MELAS syndrome is stroke-like episodes that result in hemiparesis, hemianopia, or cortical blindness. Other features include seizures, recurrent headaches, vomiting, short stature, and muscle weakness. Patients with mitochondrial diseases also have a high incidence of diabetes. Lactic acidosis occurs during stress. DNA testing is the gold standard for diagnosis.ConclusionMetformin is contraindicated in patients with mitochondrial disease and diabetes due to the predisposition for lactic acidosis. This is not part of the current package inserts for prescribers and patients- and we strongly recommend inclusion of this language.

Expression and significance of respiratory chain enzyme of cells in urine sediment in MELAS syndrome

To explore the expression and significance of respiratory chain enzyme of cells in urine sediment in mitochondrial encephalopathy myopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. Through enzyme histochemistry, the authors analyzed the changes of respiratory chain enzyme in urine sediment in 20 MELAS patients due to mitochondrial A3243G mutation (MELAS group) and 20 health peoples (control group). And the impact on the expression of protein encoded by nuclear DNA (A21347) and mitochondrial DNA (A6404) was detected by immunochemistry. Image pro Plus 6.0 software was used for analysis of absorbance (A) of staining images as staining intensity. The data were expressed as M (Q1, Q3) and analyzed through statistical software. The staining intensity of complexes Iin the MELAS group was lower than that in the control group (0.06(0.01, 0.12) vs 0.12(0.01, 0.62), P = 0.010). The intergroup staining intensity of complex II showed no marked difference. Increased density of blue particle and cytoplasmic gathering was found in 13 cased (65%) of the MELAS group under light microscope. The staining intensity of complexes IV was expressed at a low level in the MELAS group (0.14(0.03, 0.32) vs 0.23(0.06, 0.43), P = 0.038). The expression of protein encoded by nuclear DNA (A21347) was lower than that in the control group (0.05(0.02, 0.45) vs 0.17(0.03, 0.70), P = 0.000). The expression of protein encoded by mitochondrial DNA (A6404) was also lower than that in the control group (0.03(0.01, 0.07) vs 0.15 (0.09, 0.23), P = 0.000). Abnormal change of respiratory chain enzyme in urine sediment in MELAS due to mitochondrial A3243G mutation and a low expression of proteins encoded by two kinds of DNA in complexes IV can help to confirm the genetic diagnosis of mitochondrial encephalomyopathies so that different subtypes may be classified and its pathogenesis elucidated.

Complex I spectrophotometric assay in cultured cells: Detailed analysis of key factors

The diagnosis of mitochondrial encephalomyopathies caused by complex I (C-I) deficiency relies mainly on the spectrophotometric C-I assay. Considered difficult, this assay lacks reliability and has high nonspecific activity. We studied the key factors of this assay in cultured cells (cybrid and fibroblast): ubiquinone analogues, rotenone inhibition to determine specific activity, and mode of permeabilization of mitochondrial membranes. We showed that ubiquinone 1 allows a more stable and reliable assay, better results were obtained with rotenone inhibition done in the same assay, and mitochondrial permeability was improved just by freeze/thawing the sample prior to the assay.

Evaluation of a Mitochondrial Disease Criteria Scoring System on Mitochondrial Encephalomyopathy in Chinese Patients

ABSTRACTDue to the complicated clinical features of mitochondrial encephalomyopathy, simplified mitochondrial disease criteria (MDC) have recently been established in Europe. This study evaluated the sensitivity and specificity of this scoring system in Chinese patients. Seventy-eight patients with suspected mitochondrial encephalomyopathy were recruited to be scored by the simplified MDC and were further classified into “possible” (2–4), “probable” (5–7), or “definite” categories (≥8). Significant differences were observed between the total scores in the mitochondrial encephalomyopathy group and the other myopathy group. In the mitochondrial encephalomyopathy group, 73.5% of patients had a score above 8, whereas in the other myopathy group, the “definite” percentage was only 3.2%, suggesting the proposed MDC scoring system has a high sensitivity for diagnosis of mitochondrial encephalomyopathy in China. Moreover, there were significant differences in the clinical scores and imaging portions of the MDC, suggesting that the simplified MDC may distinguish mitochondrial disorder from other multisystem disorders to aid in early diagnosis prior to a muscle biopsy.

Anti-NMDA receptor antibodies in a case of MELAS syndrome

A 42-year-old man presented with new-onset headache, global aphasia, anteroand retrograde memory deficits, stereotypic behavior, agitation and an inappropriate foolish affect in July 2007. Immediate MRI revealed a T2w lesion in the left temporal lobe with cortical and subcortical involvement, compatible with encephalitis (Fig. 1). CSF analysis showed normal cell count and negative herpes simplex virus type I PCR while protein and lactate levels were elevated (protein: 1.36 g/l; normal: 0.15–0.45 g/l; lactate: 5.6 mmol/l; normal: 0.55–2.2 mmol/l). Repeated history taking revealed progressive bilateral hearing loss for 8 years. Additional MRI investigations showed a hyperintense appearance of the observed lesion in diffusion weighted images (DWI), mixed increased and decreased diffusion on apparent diffusion coefficient (ADC) maps, and a strong lactate peak in MR spectroscopy (Fig. 1). Further work-up revealed myopathic changes in several muscles on electromyography, elevated serum lactate during lactate stress test, hypertrophic cardiomyopathy, and signs of mitochondrial disease in muscle biopsy specimens (increased fuchsinophilia and COX-negative fibers). Family history was negative for mitochondrial disorders, but genetic analysis from leucocytes revealed a heteroplasmic m.3243A[G point mutation in mitochondrial DNA (heteroplasmy rate, 30%), compatible with a diagnosis of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). No other family members were tested. During the next few years, the patient developed focal epilepsy and progressive cognitive deficits. In 2010, he sustained a stroke-like episode of the left occipital cortex causing right homonymous hemianopia (Fig. 1). At this time, the initial clinical presentation was reconsidered and archived CSF/serum samples obtained 6 days after symptom onset in 2007 were analyzed for autoimmune antibodies. Antibodies were determined by means of a recombinant immunofluorescence assay employing NMDAR transfected HEK cells as described previously [1]. IgG-antibodies against NMDAR were detected in the patient’s serum at a titer of 1:32 (score 2 according to Irani et al. [4]). No antinuclear antibodies (ANA) or antibodies against further neuronal surface antigens (i.e., AMPA receptor, GABAb-receptor) or VGKC-complex were detected in the patient’s serum. On follow-up in 2010, NMDAR antibodies were negative both in serum and CSF. A body-CT revealed no malignancies. Taken together, our patient presented with symptoms compatible with a first manifestation of MELAS syndrome in 2007 [2]. The patient’s lesion in the left temporal lobe likely accounts for his aphasia, memory disturbances, and behavioral changes. Imaging characteristics suggest a stroke-like lesion associated with MELAS syndrome [3]. At the same time, however, the patient tested positive for anti-NMDAR antibodies that are considered highly specific C. Finke (&) H. Pruss F. Ostendorf L. Harms C. J. Ploner Department of Neurology, Charite-Universitatsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany e-mail: carsten.finke@charite.de

Mitochondrial Encephalomyopathies in Children. Part II: Advanced MR Tools and the Importance for its Early Recognition in the Acute Clinical Setting

Background and Purpose: There is a need for new non-invasive quick test that provides physicians accurate information for the early diagnosis of mitochondrial encephalomyopathies (ME). Advances in MR technology have provided new insight in the diagnosis of metabolic and other complex metabolic diseases in children, therefore, we sought to see if new technological MR tools, namely Diffusion-Weighted imaging (DWI) and proton MR spectroscopy (1H-MRS) helped in the early diagnosis of ME. Methods: From a population of 55 patients diagnosed with ME, 10 patients also underwent DW imaging and/or 1HMRS, at 1.5 T, by means of PRESS monovoxel short TE acquisition (TE: 35 ms) or 2D multivoxel long TE acquisition (TE:144 ms). Results: On DW imaging, patients with acute clinical status showed statistically more lesions than on their conventional counterparts. On 1HMRS, all patients with acute clinical status showed brain lactate, which was superior to its detection on serum/CSF. Conclusion: Neuroradiologic information provided for current MR advanced tools is becoming the first para-clinical test in the early tentative diagnosis of ME, in children with acute onset of encephalopatic status.

Pathophysiology and Management of Syncope in Kearns-Sayre Syndrome

A 20-year-old woman with known Kearns-Sayre syndrome was transferred to the emergency department due to syncopal episodes. The electrocardiogram on admission showed complete atrioventricular block. The diagnosis of mitochondrial encephalomyopathy was made when she was 14 years old. At the time of the initial diagnosis, she displayed a normal electrocardiogram pattern. At the age of 17, electrocardiogram recordings demonstrated right bundle branch block with left anterior fascicular block and a prolonged QTc interval of 485 milliseconds (Figure). She was taking coenzyme Q10, oral nicotinamide adenine dinucleotide (reduced), piribedil, amantadine, and primidone. Transthoracic echocardiography revealed normal wall motion of both ventricles and mitral valve prolapse without regurgitation. A permanent dual-chamber pacemaker was immediately implanted.

Clinical and imaging manifestations of adult mitochondrial encephalomyopathy

Objective To investigate clinical manifestations and neuroimaging in the adult patients with mitochondrial encephalomyopathy (ME). Methods Systematic study was performed on the clinical features of six adult patients with ME with observations on electromyogram(EMG), electroencephalogram(EEG), the blood lactic acid level,muscle biopsies results and neuroimaging features of CT and MRI. Results The main clinical features were characterized by seizures, intolerance to exercise, audio-visual dysfunction, mental retardation, and so forth. EMG showed neurogenic damages(4/5 cases); EEG showed extensive mild to severe abnormal activities(3/3 cases)and lactic acidosis was also observed(4/4 cases). Neuroimaging findings included symmetric supratentorial multifoci lesions, located in frontal, temporal, parietal, and occipital lobes, thalami and basal ganglia with widening of ventricles and cerebral atrophy; the neuroimaging findings also included hyperintensity on T_2-weighted images and hypointensity/isointensity on T_1-weighted images; No stenosis and occlusion of main artery was displayed by magnetic resonance angiography(MRA). Muscle biopsies showed red ragged fiber (RRF)(4/6 cases). Conclusions Based on clinical features and neuroimaging, diagnosis of ME in early stage may be made in combination with muscle biopsy.

Cerebrospinal Fluid Neurone-Specific Enolase in Mitochondrial Encephalomyopathies

Whether cerebrospinal fluid (CSF) neurone-specific enolase (NSE) contributes to the diagnosis of mitochondrial encephalomyopathies (MEMs) is unknown. Aim of the present study was thus to assess the validity of CSF-NSE in the diagnosis of MEM. CSF-NSE was determined in 24 controls, aged 28-88 years; and 23 MEM patients, aged 47-81 years. In controls, CSF-NSE was independent of sex (p = 0.849) and age (p = 0.346). Twenty-one MEM patients had clinical CNS involvement and two CNS abnormalities on imaging investigations exclusively. CSF cells were increased in 7, CSF protein in 17, CSF glucose in 1, and CSF lactate in 2 MEM patients. The upper reference limit of CSF-NSE was 14.66 ng/mL. CSF-NSE was elevated in 6 (26%) MEM patients. CSF-NSE was increased in a single MEM patient with subclinical CNS involvement. This study shows that CSF-NSE is elevated in only one quarter of the MEM patients. Determination of CSF-NSE appears to be of minor importance for the assessment of clinical or subclinical CNS involvement in MEM.

Morphological Methods in the Diagnosis of Mitochondrial Encephalomyopathies: The Role of Electron Microscopy

Mitochondrial encephalomyopathies (MEs) encompass a heterogeneous group of disorders that frequently present a diagnostic challenge to clinicians. Historically, MEs were diagnosed by finding ragged red fibers in the muscle biopsy and confirmatory evidence was provided by the presence of numerical and/or ultrastructural abnormalities in mitochondria. In most centers diagnosis involves clinical evaluation and the morphological, histochemical, and biochemical investigation of a skeletal muscle biopsy. However, with the availability of mitochondrial DNA analysis, the necessity and role of morphological methods and, in particular, electron microscopy has been questioned. The aim of this study was to delineate the role of electron microscopy in the diagnosis of MEs.

Spasms in children with definite and probable mitochondrial disease.

The diagnosis of mitochondrial encephalomyopathies is complex and a system for classification of the diagnosis as definite, probable, and possible has been proposed. The objective of this study was to explore the spectrum of epileptic disorders associated with probable and definite mitochondrial disease in children using this classification system. The patient population with mitochondrial disease and epilepsy was selected from a tertiary care children's hospital. Interictal electroencephalograms and video-EEG recordings were used to characterize seizure types. Ten children fulfilled the criteria for probable or definite mitochondrial disease and had epilepsy. Four had siblings with a similar clinical phenotype. Spasms were the most common seizure type and were the initial seizure type in seven patients and two siblings. Four patients had only partial seizures, with or without generalization, and one patient had seizures that were difficult to classify. Blood lactate concentrations were elevated consistently in patients with partial seizures alone but were occasionally normal in children with spasms. Spasms were the most common presenting seizure type in children with probable and definite mitochondrial disease.

Ultrasonographic features of polypoid myoglandular hyperplasia of the gallbladder, that were difficult to distinguish from early gallbladder cancer.

The patient, a 50-year-old man, had been followed up by a neurologist under the diagnosis of mitochondrial encephalomyopathy. A gallstone detected by abdominal ultrasonography (US) had been present for several years, but localized protrusions of the gallbladder wall were first seen at the fundus in May 1995. Endoscopic US after abdominal US showed several small protruding lesions with maximum diameters of about 7 mm. These lesions had irregular surfaces and low internal echogenicity. An external high echoic layer, which represented the subserosa of the gallbladder, was intact. The lesions were enhanced on CT scanning. No anomalies of the pancreaticobiliary system were detected by endoscopic retrograde cholangiopancreatography. Selective cystic arteriography disclosed slight staining of the body of the gallbladder. Because of the high possibility of gallbladder carcinoma, surgery was carried out. Macroscopy showed several elevated or protruding lesions up to 7 mm in diameter at the fundus of the resected gallbladder. The lesions had rough surfaces and were yellowish in color. Histologic examination showed the lesions to be covered by columnar epithelium, and no cellular dysplasia was detected. Because both pyloric gland-like hyperplasia and smooth-muscle proliferation were observed, the lesions were diagnosed as polypoid myoglandular hyperplasia. We have encountered four other similar cases of this tumor. Accurate diagnosis of these lesions before surgery is sometimes difficult, and the sonographic features of myoglandular hyperplasia have to be recognized in order to distinguish it from early gallbladder cancer.

SPECT cerebral en la encefalomiopatía mitocondrial. Presentación de un caso y revisión de la bibliografía

We report a case of mitochondrial encephalomyopathy with a complex clinical picture followed-up in the Neurology Department, and fully investigated using different techniques, in whom the definite diagnosis was essentially based on finding ragged red fibres on muscle biopsy. The patient was 60 years old when the definite diagnosis was made. The illness had started in his youth and affected different systems and parts of the body. On laboratory investigation the serum lactic acid and lactic acid curve were normal, as were those of the cerebrospinal fluid. Further complementary tests were done, including imaging techniques (cerebral CAT, MR and SPECT). SPECT was done using 99Tc-HMPAO. Since it was a single case, we can affirm that the diagnosis of mitochondrial encephalomyopathy was made on muscle biopsy, supported by other complementary investigations, but without being able to classify the case among the various mitochondrial encephalopathies since the clinical features were common to several of them. More sequential studies are needed with different imaging techniques, in the same patient, carefully taking into account any slight modification in his clinical state, during the time elapsed between two consecutive serial follow-up studies.

Eye diseases in mitochondrial encephalomyopathies

Mitochondria are the principal site of generation of energy in form of adenosine triphosphate (ATP). They contain the enzymes of the Krebs and fatty acid cycles and the respiratory pathway. Ocular tissues with high energy consumption and dependence on oxidative energy production like the optic nerve, the retina, and the pigment epithelium are often involved in mitochondrial diseases. This article reviews the genetic mitochondrial diseases involving the visual system. Their most important ocular findings include: acute or slowly progressive bilateral visual loss and visual field loss due to an optic neuropathy or retinal degeneration, bilateral progressive decreased ocular motility, and bilateral upper lid ptosis. The following diseases are discussed: Leber's Hereditary Optic Neuropathy (LHON); Kearns-Sayre Syndrom (KSS); Chronic Progressive External Ophthalmoplegia (CPEO); Autosomal Recessive Cardiomyopathy, Ophthalmoplegia (ARCO); Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-Like Episodes (MELAS); Neuropathy, Ataxia, Retinitis Pigmentosa (NARP); Mitochondrial Neuropathy, Gastro-Intestinal Encephalomyopathy (MNGIE); Myoclonus Epilepsy, Ragged-Red-Fibers (MERRF); Wilson's disease; Friedreich's ataxia. Diagnosis of mitochondrial encephalomyopathies is established by screening for mutations in blood or muscle biopsy samples. No specific therapies which influence the course of mitochondrial encephalomyopathies are known. Drugs interacting with the mitochondria function, alcohol consumption and smoking should be avoided.

Ultrastructural Diagnosis of Mitochondrial Encephalomyopathies Revisited

Mitochondrial encephalomyopathies (MEs) are a heterogeneous group of multisystem disorders with extreme variability in clinical phenotype. Due to their complex nature, accurate diagnosis requires a coordinated approach, based on clinical and various laboratory data. Despite the introduction of biochemical assay of mitochondrial enzymes and the availability of mtDNA mutation analysis, the diagnosis of MEs still relies heavily on morphological methods. The latter include histology, histochemistry, and electron microscopy. A comparative study was undertaken to define the contemporary role of electron microscopy in the morphological diagnosis of MEs. Muscle biopsies from 20 patients with MEs, 9 children and 11 adults, were evaluated by histology, enzyme histochemistry, and electron microscopy. The results clearly demonstrate that electron microscopy is of importance in providing essential diagnostic information in pediatric patients, but is of lesser value in the diagnosis of adult cases, where it provides only supplementary information.

Diagnosis of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes in a Chinese family by PCR/restriction enzyme analysis

The clinical presentation and the biochemical and molecular genetic findings are described in a 13 year old Chinese boy with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). The diagnosis was initially suspected because of the characteristic clinical features and the strong family history of convulsions. Using polymerase chain reaction-restriction enzyme analysis, the heteroplasmic nt3243 A-->G mutation in mtDNA of peripheral blood leucocytes and a muscle sample was demonstrated. The oligosymptomatic relatives were then screened by this method and the degree of heteroplasmy was analysed. This appears to be the first report of a MELAS family in Hong Kong with this described mutation. Molecular genetic techniques are advantageous in the diagnosis of MELAS.