Mitochondrial DNA Point Mutations Research Articles

The Age Lipid A2E and Mitochondrial Dysfunction Synergistically Impair Phagocytosis by Retinal Pigment Epithelial Cells

Accumulation of indigestible lipofuscin and decreased mitochondrial energy production are characteristic age-related changes of post-mitotic retinal pigment epithelial (RPE) cells in the human eye. To test whether these two forms of age-related impairment have interdependent effects, we quantified the ATP-dependent phagocytic function of RPE cells loaded or not with the lipofuscin component A2E and inhibiting or not mitochondrial ATP synthesis either pharmacologically or genetically. We found that physiological levels of lysosomal A2E reduced mitochondrial membrane potential and inhibited oxidative phosphorylation (OXPHOS) of RPE cells. Furthermore, in media with physiological concentrations of glucose or pyruvate, A2E significantly inhibited phagocytosis. Antioxidants reversed these effects of A2E, suggesting that A2E damage is mediated by oxidative processes. Because mitochondrial mutations accumulate with aging, we generated novel genetic cellular models of RPE carrying mitochondrial DNA point mutations causing either moderate or severe mitochondrial dysfunction. Exploring these mutant RPE cells we found that, by itself, only the severe but not the moderate OXPHOS defect reduces phagocytosis. However, sub-toxic levels of lysosomal A2E are sufficient to reduce phagocytic activity of RPE with moderate OXPHOS defect and cause cell death of RPE with severe OXPHOS defect. Taken together, RPE cells rely on OXPHOS for phagocytosis when the carbon energy source is limited. Our results demonstrate that A2E accumulation exacerbates the effects of moderate mitochondrial dysfunction. They suggest that synergy of sub-toxic lysosomal and mitochondrial changes in RPE cells with age may cause RPE dysfunction that is known to contribute to human retinal diseases like age-related macular degeneration.

MGB probe assay for rapid detection of mtDNA11778 mutation in the Chinese LHON patients by real-time PCR

Leber's hereditary optic neuropathy (LHON) is a maternally inherited degeneration of the optic nerve caused by point mutations of mitochondrial DNA (mtDNA). Many unsolved questions regarding the penetrance and pathophysiological mechanism of LHON demand efficient and reliable mutation testing. This study aims to develop a minor groove binder (MGB) probe assay for rapid detection of mtDNA11778 mutation and heteroplasmy in Chinese LHON patients by real-time polymerase chain reaction (PCR). Forty-eight patients suspected of having LHON and their maternal relatives underwent a molecular genetic evaluation, with 20 normal individuals as a control group at the same time. A real-time PCR involving two MGB probes was used to detect the mtDNA11778 mutation and heteroplasmy. A linear standard curve was obtained by pUCmLHONG and pUCmLHONA clones. All 48 LHON patients and their maternal relatives were positive for mtDNA11778 mutation in our assay, 27 heteroplasmic and 21 homoplasmic. Eighteen cases did not show an occurrence of the disease, while 9 developed the disease among the 27 heteroplasmic mutation cases. Eleven did not show an occurrence of the disease, while 10 cases developed the disease among 21 homoplasmic mutation cases. There was a significant difference in the incidence between the heteroplasmic and the homoplasmic mutation types. The time needed for running a real-time PCR assay was only 80 min. This real-time PCR assay is a rapid, reliable method for mtDNA mutation detection as well as heteroplasmy quantification. Detecting this ratio is very important for predicting phenotypic expression of unaffected carriers.

Characterisation of the macular dystrophy in patients with the A3243G mitochondrial DNA point mutation with fundus autofluorescence

Introduction:The mitochondrial DNA A3243G point mutation is associated with a wide variety of systemic manifestations including a macular dystrophy. The characteristics of fundus autofluorescence (AF) in these patients are distinctive...

Myelin, mitochondria, and autoimmunity

Mitochondrial optic neuropathies are inherited nonsyndromic disorders characterized by selective degeneration of retinal ganglion cells leading to visual loss and optic nerve atrophy.1 The two most common are the maternally inherited Leber hereditary optic neuropathy (LHON, OMIM#535000) and the autosomal dominant optic atrophy (DOA, OMIM#165500). LHON, the first disease to be associated with a mitochondrial DNA (mtDNA) point mutation, is due in most cases to one of three mutations at positions 11778/ND4, 3460/ND1, and 14484/ND6 affecting complex I subunit genes. As a consequence there is a well documented defect of mitochondrial respiration, chronic increase in oxidative stress, and cell predisposition to apoptosis.1 As regards DOA, a large subset of patients present with a heterozygous mutation in OPA1 , a nuclear gene encoding a dynamin-related GTPase targeted to mitochondria and involved in mitochondrial fusion, cristae organization, and control of apoptosis. There is mounting evidence that there is defective mitochondrial respiration also in OPA1-related patients with DOA.2,3 Despite being a nonsyndromic optic neuropathy …

Hematological Abnormalities in Copper Deficiency.

Introduction: Copper deficiency can rarely present as anemia and leucopenia. Copper and iron are essential trace elements through their functions as co-factors in numerous biochemical reactions. Hephaestin is a transmembrane copper-dependent ferroxidase necessary for effective iron transport from intestinal enterocyte into the circulation. Copper is hence required for the efficient utilization of iron in the mammalian system. Copper enzymes such as superoxide dismutase and cytochrome oxidase have an essential role in red cell development and heme maturation. We present 4 patients of copper deficiency. The first patient presented with anemia and leucopenia and the bone marrow showed increased vacuolated erythroblasts with and erythroid dysplasia. This patient had a bone marrow picture resembling erythroleukemia. However, as this patient had undergone a gastric bypass, further studies in the form of vitamin B12, red cell folate and copper were performed. Patient was found to have low copper and low ceruloplasmin levels, with normal B12 and red cell folate levels. Three patients had anemia and neutropenia and showed dysplasia in erythroid lineage, ring sideroblasts, and abnormal accumulation of iron granules in plasma cells. In all four cases, repletion of copper resulted in normalization of peripheral counts and bone marrow showed normal trilineage hematopoiesis.Discussion: Copper deficiency is known to present with microcytic anemia. However we report three cases in which patients presented as normocytic anemia and neutropenia.Bone marrow findings in addition to dysplasia, also showed abnormal iron granules in plasma cells as well as ring sideroblasts. Presence of ringed sideroblasts in myelodysplasia is associated with numerous point mutations in mitochondrial DNA. Mutations identified to date involve among others the cytochrome oxidase subunits I and II. Cytochrome c oxidase is involved in oxidizing FE++ to Fe+++ and incorporation into heme. Copper is a component of cytochrome c oxidase and superoxide dismutase and its deficiency leads to low levels of these enzymes. We propose that copper deficiency plays role in causing dysplastic changes in bone marrow and increase in ringed sideroblasts. Any patient presenting with unexplained anemia or leucopenia, with dysplasia and ringed sideroblasts should be evaluated for copper deficiency. Abnormal iron granules in plasma cells have been reported in other conditions like ethanol toxicity, however we report two patients with copper deficiency who were found to have iron granules in plasma cells. We consider copper an important component of the work-up of patients thought to have myelodysplasia especially if they have undergone a gastric bypass and have normal cytogenetics which is not suggestive of clonal hematopoiesis.Hematological abnormalities in patients with copper deficiencypatient 1anemianeutropenianormocyticpatient 2anemianeutropenianormocyticpatient 3anemianeutropeniamicrocyticpatient 4anemianeutropenianormocyticbone marrow findings in patients with copper deficiencyerythroidsmyeloidring sideroblastsiron granules in plama cellspatient 1dysplastichypoplasianoneabnormal iron granules in plama cellspatient 2dysplasticdysplasia15%abnormal iron granules in plasma cellspatient 3dysplastichypoplasianonenonepatient 4dysplasticdysplasianonenone

A Single Nucleotide Polymorphism in the DNA Polymerase Gamma Gene of Saccharomyces cerevisiae Laboratory Strains Is Responsible for Increased Mitochondrial DNA Mutability

In the Saccharomyces cerevisiae strains used for genome sequencing and functional analysis, the mitochondrial DNA replicase Mip1p contains a single nucleotide polymorphism changing the strictly conserved threonine 661 to alanine. This substitution is responsible for the increased rate of mitochondrial DNA point mutations and deletions in these strains.

Point mutations in oocyte mitochondrial dna (mtDNA) and their relationship to changes in mitochondrial membrane potential (DYm), maternal age, infertility diagnosis and IVF cycle outcome

To determine if point mutations in oocyte mitochondrial DNA (mtDNA) located within the NADH dehydrogenase subunit 2 (S2) and cytochrome b (CYTO) are associated with changes in mitochondrial membrane potential (DYm), maternal age, infertility diagnosis and cycle outcome.

Age-related mitochondrial DNA point mutations in patients with mitochondrial myopathy

Mutations in the control region (D-loop) of mitochondrial DNA (mtDNA) have been described in normal old individuals and it is suggested that they originated from oxidative damage. Respiratory chain defects may lead to increased free radical generation, increased susceptibility to oxidative damage and further increased accumulation of age-related mutations. The objective of this study was to verify whether patients with a mitochondrial disease are more predisposed to accumulate the A189G and T408A mutations in the D-loop and confirm their age-associated nature. We evaluated the presence and levels of heteroplasmy of these two mutations in muscle DNA of 52 individuals with different ages (21 age-matched controls and 31 patients with single or multiple mtDNA deletions). The frequency of both mutations was significantly increased with age, but no differences were observed comparing the group of patients with their age-matched controls. We could not observe correlation of levels of heteroplasmy with age. Our results confirm the age-related nature of the A189G and T408A mutations in the D-loop in controls and patients with mitochondrial disease, but do not suggest that patients are more predisposed to the development of age-related point mutations.

Analysis of Rev1p and Pol ζ in mitochondrial mutagenesis suggests an alternative pathway of damage tolerance

Ultraviolet light is a potent DNA damaging agent that induces bulky lesions in DNA which block the replicative polymerases. In order to ensure continued DNA replication and cell viability, specialized translesion polymerases bypass these lesions at the expense of introducing mutations in the nascent DNA strand. A recent study has shown that the N-terminal sequences of the nuclear translesion polymerases Rev1p and Pol ζ can direct GFP to the mitochondrial compartment of Saccharomyces cerevisiae. We have investigated the role of these polymerases in mitochondrial mutagenesis. Our analysis of mitochondrial DNA point mutations, microsatellite instability, and the spectra of mitochondrial mutations indicate that these translesion polymerases function in a less mutagenic pathway in the mitochondrial compartment than they do in the nucleus. Mitochondrial phenotypes resulting from the loss of Rev1p and Pol ζ suggest that although these polymerases are responsible for the majority of mitochondrial frameshift mutations, they do not greatly contribute to mitochondrial DNA point mutations. Analysis of spontaneous mitochondrial DNA point mutations suggests that Pol ζ may play a role in general mitochondrial DNA maintenance. In addition, we observe a 20-fold increase in UV-induced mitochondrial DNA point mutations in rev deficient strains. Our data provides evidence for an alternative damage tolerance pathway that is specific to the mitochondrial compartment.

Clinical Expression of Leber Hereditary Optic Neuropathy Is Affected by the Mitochondrial DNA–Haplogroup Background

Leber hereditary optic neuropathy (LHON) is due primarily to one of three common point mutations of mitochondrial DNA (mtDNA), but the incomplete penetrance implicates additional genetic or environmental factors in the pathophysiology of the disorder. Both the 11778G-->A and 14484T-->C LHON mutations are preferentially found on a specific mtDNA genetic background, but 3460G-->A is not. However, there is no clear evidence that any background influences clinical penetrance in any of these mutations. By studying 3,613 subjects from 159 LHON-affected pedigrees, we show that the risk of visual failure is greater when the 11778G-->A or 14484T-->C mutations are present in specific subgroups of haplogroup J (J2 for 11778G-->A and J1 for 14484T-->C) and when the 3460G-->A mutation is present in haplogroup K. By contrast, the risk of visual failure is significantly less when 11778G-->A occurs in haplogroup H. Substitutions on MTCYB provide an explanation for these findings, which demonstrate that common genetic variants have a marked effect on the expression of an ostensibly monogenic mtDNA disorder.

Minocycline, a possible neuroprotective agent in Leber’s hereditary optic neuropathy (LHON): Studies of cybrid cells bearing 11778 mutation

Leber's hereditary optic neuropathy (LHON) is a retinal neurodegenerative disorder caused by mitochondrial DNA point mutations. Complex I of the respiratory chain affected by the mutation results in a decrease in ATP and an increase of reactive oxygen species production. Evaluating the efficacy of minocycline in LHON, the drug increased the survival of cybrid cells in contrast to the parental cells after thapsigargin-induced calcium overload. Similar protection was observed by treatment with cyclosporine A, a blocker of the mitochondrial permeability transition pore (mPTP). Ratiometric Ca(2+) imaging reveals that acetylcholine/thapsigargin triggered elevation of the cytosolic calcium concentration is alleviated by minocycline and cyclosporine A. The mitochondrial membrane potential of LHON cybrids was significantly conserved and the active-caspase-3/procaspase-3 ratio was decreased in both treatments. Our observations show that minocycline inhibits permeability transition induced by thapsigargin in addition to its antioxidant effects. In relation with its high safety profile, these results would suggest minocycline as a promising neuroprotective agent in LHON.

PRIMARY SPINAL CORD NEURODEGENERATION IN LEBER HEREDITARY OPTIC NEUROPATHY

Leber hereditary optic neuropathy (LHON) is a subacute bilateral optic neuropathy that typically presents in young adult men due to one of three point mutations of mitochondrial DNA (mtDNA, m.11778G→A, m.3460G→A, or m.14484T→C) affecting genes coding for complex I of the mitochondrial respiratory chain. Most patients only develop visual failure, but some develop additional neurologic features, including a multiple sclerosis (MS)–like illness.1 ### Case report. A 39-year-old woman developed a progressive gait and sensory disturbance 5 years after subacute bilateral visual failure. She smoked cigarettes and took regular alcohol, multivitamins, and folic acid. In addition to the reduced visual acuity (counting fingers), central scotomata, and optic atrophy, she had horizontal gaze-evoked nystagmus and symmetric pyramidal-pattern lower limb weakness. Tendon reflexes were brisk, ankle jerks absent, and plantar responses extensor. Vibration sensation was absent below the hips and elbows. She had a macrocytosis (110 fL), vitamin B12 level of 769 ng/L (normal = 160 to 600 ng/L), red cell folate level of 342 μg/L (normal = 95 to 570 μg/L), and alanine transaminase level of 198 μ/L (normal <45 μ/L), with a normal serum creatine kinase. Urine toxicology, HIV, VDRL, and hepatitis serology were all negative. Vitamin E, very long chain fatty acids, autoantibodies, and immunoglobulins were normal. The CSF was acellular, with a normal protein, glucose, and no oligoclonal bands. Her 12-lead EKG was normal. Brain MRI revealed symmetric high T2 signal in the substantia nigra, pontine tegmentum, inferior olives, and dorsal columns of the spinal …

Pathogenic mitochondrial DNA mutations in protein‐coding genes

More than 200 disease-related mitochondrial DNA (mtDNA) point mutations have been reported in the Mitomap (http://www.mitomap.org) database. These mutations can be divided into two groups: mutations affecting mitochondrial protein synthesis, including mutations in tRNA and rRNA genes; and mutations in protein-encoding genes (mRNAs). This review focuses on mutations in mitochondrial genes that encode proteins. These mutations are involved in a broad spectrum of human diseases, including a variety of multisystem disorders as well as more tissue-specific diseases such as isolated myopathy and Leber hereditary optic neuropathy (LHON). Because the mitochondrial genome contains a large number of apparently neutral polymorphisms that have little pathogenic significance, along with secondary homoplasmic mutations that do not have primary disease-causing effect, the pathogenic role of all newly discovered mutations must be rigorously established. A scoring system has been applied to evaluate the pathogenicity of the mutations in mtDNA protein-encoding genes and to review the predominant clinical features and the molecular characteristics of mutations in each mtDNA-encoded respiratory chain complex.

Male Prevalence of Acquired Color Vision Defects in Asymptomatic Carriers of Leber’s Hereditary Optic Neuropathy

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease resulting in loss of central vision and dyschromatopsia, caused by mitochondrial DNA point mutations. However, only a subset of the mutation carriers becomes affected, with a higher penetrance in males. This study was conducted to investigate chromatic losses in asymptomatic carriers of the LHON mutation. Monocular chromatic discrimination was studied with the Cambridge Colour Test (CCT; Cambridge Research Systems, Ltd., Rochester, UK) along the protan, deutan, and tritan cone isolation axes in 46 LHON carriers (15 men) belonging to the same LHON maternal lineage and 74 age-matched control subjects (39 men). Inclusion criteria were absence of ophthalmic complaints and clear ocular media. A detailed neuro-ophthalmic examination was performed in all the LHON carriers. The differences in threshold between carriers and control subjects were significant for the three cone isolation axes at P < 0.0001. Sixty-five percent of the carriers had abnormal protan and/or deutan thresholds; some of those with higher thresholds also had elevated tritan thresholds (13%). The male thresholds were higher and more frequent than those of the women for the protan and deutan axes (ANOVA; P < 0.05), but not for tritan thresholds. In the most severe losses, the women had instances of diffuse defect whereas all the men displayed a red-green defect. Male LHON asymptomatic carriers had color vision losses with the red-green pattern of dyschromatopsia typical of patients affected with LHON, which includes elevation of tritan thresholds as well. This predominantly parvocellular (red-green) impairment is compatible with the histopathology of LHON, which affects mostly the papillomacular bundle. In contrast with male losses, female losses were less frequent and severe. These gender differences are relevant to understanding LHON pathophysiology, suggesting that hormonal factors may be of great importance.

Impaired mitochondrial Ca 2+ homeostasis in respiratory chain-deficient cells but efficient compensation of energetic disadvantage by enhanced anaerobic glycolysis due to low ATP steady state levels

Energy-producing pathways, adenine nucleotide levels, oxidative stress response and Ca 2+ homeostasis were investigated in cybrid cells incorporating two pathogenic mitochondrial DNA point mutations, 3243A > G and 3302A > G in tRNA Leu(UUR), as well as Rho 0 cells and compared to their parental 143B osteosarcoma cell line. All cells suffering from a severe respiratory chain deficiency were able to proliferate as fast as controls. The major defect in oxidative phosphorylation was efficiently compensated by a rise in anaerobic glycolysis, so that the total ATP production rate was preserved. This enhancement of glycolysis was enabled by a considerable decrease of cellular total adenine nucleotide pools and a concomitant shift in the AMP + ADP/ATP ratios, while the energy charge potential was still in the normal range. Further important consequences were an increased production of superoxide which, however, was neither escorted by major changes in the antioxidative defence systems nor was it leading to substantial oxidative damage. Most interestingly, the lowered mitochondrial membrane potential led to a disturbed intramitochondrial calcium homeostasis, which most likely is a major pathomechanism in mitochondrial diseases.

Small-fiber neuropathy and the 3243A&gt;G mutation in mitochondrial DNA

Sirs: The 3243A>G point mutation in mitochondrial DNA (mtDNA) is associated with the MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) syndrome, and sometimes with additional phenotypes like a sensorimotor polyneuropathy [4, 6]. The occurrence of a small-fiber peripheral neuropathy as the presenting clinical manifestation of a 3243A>G point mutation in mtDNA has, according to our knowledge, not been described previously. A 35 year old man was referred to our neuromuscular clinic with a history of a tingling sensation in the toes of both feet, which has been present for two to three years, as well as a restless feeling in the legs for many years. One year before presentation he developed burning pain in the toes and then fingers bilaterally. He reported no weakness and had no complaints suggestive of an autonomic disturbance. There was no history of alcohol or drug abuse. He was otherwise healthy and used no medication. Previously, his mother was diagnosed with the 3243A>G point mutation in mitochondrial DNA at the age of 51 years after presenting with ptosis, external ophthalmoplegia, limbgirdle weakness and long-standing diabetes mellitus. She had a mtDNA mutation load of 0.8% in leukocytes and 50% in skeletal muscle. On examination no muscle atrophy or weakness was evident and all tendon reflexes, including the ankle jerks, were normal. All sensory modalities were intact, including vibration sense testing with a Rydel-Seiffer tuning fork. No ataxia was present and the gait was undisturbed. Extensive investigations including vitamins B1, B6, B12, folic acid, serum lactate, creatine kinase, thyroid function tests, fasting serum glucose and HbA1c, serum lipid profile, angiotensin converting enzyme levels and serum protein electrophoresis were normal. Anti-nuclear, anti-SS-A and SS-B, antigliadin, anti-endomysial and antineutrophil cytoplasmic (cytoplasmic and perinuclear) antibodies as well as cryoglobulins were all negative. Cranial magnetic resonance imaging and electrocardiography were normal. Leukocyte DNA examination revealed the 3243A>G mtDNA point mutation. The percentage of mutated mtDNA in leukocytes was 16%. Motor and sensory nerve conduction studies and F-responses were performed in the upper and lower limbs and were all normal, as was the Hoffman reflex of the soleus muscle. Concentric needle EMG of distal muscles in the upper and lower limbs was normal. Quantitative sensory threshold testing (CASE IV) of the left foot was performed according to the manufacturer’s protocols. Cold thermal threshold and heat pain was evaluated and the results were compared with normative data. For both cold thermal threshold and heat pain the values obtained were above the 99th percentile, indicating hypoesthesia. In addition, cardiovagal autonomic tests assessing sympathetic and parasympathetic responses were normal. After 18 months of follow-up, no progression of symptoms or involvement of large sensory or motor fibers is evident. We suggest a direct causal relationship between the documented mutation in mtDNA and the small-fiber neuropathy in this patient, as extensive investigations did not reveal another explanation. The exact prevalence of neuropathies in patients with MELAS and the 3243A>G mutation in mtDNA is unknown, but estimates range from 5 to 97% [1, 4, 5]. Small-fiber involvement, isolated or in combination with large-fiber involvement, is probably underrecognised. Most studies included only patients with abnormalities on nerve conduction studies, thereby effectively excluding patients with isolated small-fiber neuropathies. In patients presenting with sensorimotor neuropathies, small-fiber involvement may be overshadowed by large-fiber involvement and thus go undiagnosed. Furthermore, these studies provide no information regarding the prevalence of neuropathies in mutation carriers without the MELAS syndrome. Very little is known about the possible mechanism of peripheral nerve involvement in mitochondrial cytopathies. Mitochondrial failure may just be one of a number of upstream events ultimately leading to axonal degeneration via the activation of calpain, a final pathway probably common to many neuropathies [2]. Furthermore, in a study of vinblastinetreated mice mitochondrial dysfunction correlated strongly with and preceded neurite degeneration [3]. In conclusion, we describe a patient with the MELAS 3243A>G point mutation in mtDNA who presented with clinical and electrophysiological findings suggestive of an isolated small-fiber neuropathy. We postulate that mitochondrial cytopathies should be considered in the differential diagnosis of small-fiber neuropathies. Further studies are needed to confirm the relationship between mitochondrial disorders and small-fiber neuropathies.

Ocular Motor Disorders in Mitochondrial Encephalopathy With Lactic Acid and Stroke-Like Episodes With the 3271 (T-C) Point Mutation in Mitochondrial DNA

Ocular motor function can provide insights into areas of dysfunction within the nervous system. There are no published eye movement recordings in patients with mitochondrial encephalopathy with lactic acid and stroke-like episodes (MELAS). Our purpose in this study was to analyze the ocular motor features of a family with MELAS with a (T-C) mutation at nucleotide position 3271 in the mitochondrial tRNA-Leu gene. The search coil method was used to record visually-guided saccades, antisaccades, and triangular pursuit tasks in the horizontal and vertical planes in three patients in a Japanese family with MELAS. The patients showed saccadic dysmetria and prolonged saccadic reaction times, deficits in the ability to suppress reflex eye movements, and increased reaction time during antisaccades, downbeat nystagmus, square wave jerks, and impairment in pursuit. On the basis of eye movement recordings, patients with MELAS have frontal cortex as well as cerebellar dysfunction.

Clinical and molecular survey in 124 Chinese patients with Leigh or Leigh‐like syndrome

Leigh syndrome is the most common mitochondrial disorder in children characterized by necrotic lesions in the central nervous system. Both mitochondrial DNA (mtDNA) and nuclear DNA defects in the mitochondrial respiratory chain can lead to this disease. To characterize the clinical and genetic traits of Leigh or Leigh-like syndrome patients in China, 124 unrelated cases were collected between 1992 and 2005. Seventy-seven cases (62.1%) met the typical criteria of Leigh syndrome, including symmetrical bilateral abnormal signals in the basal ganglia, thalamus and brain stem, etc. Other cases (37.9%) belonged to Leigh-like syndrome with atypical clinical or radiological manifestations. Late-onset patients accounted for 20.2%, which is more than previously reported. Movement disorder was the most common symptoms in our patients. Thirty-two patients (25.8%) were confirmed to carry mutant genes. Among them, six cases (4.8%) have been demonstrated to have point mutations in mitochondrial DNA. Two separate patients were detected to have mutations on A8344G and A3243G. The T8993G point mutation was identified in one patient and T8993C in one other patient. SURF1 mutations associated with cytochrome-c oxidase deficiency were identified in 25 patients (20.2%). Four unreported variations have been identified in SURF1 gene from three patients. G604C was found in 22 patients. Only one patient had C214T mutation in the pyruvate dehydrogenase E1alpha subunit gene. In the remaining 92 patients (74.2%), a specific molecular dysfunction or underlying metabolic abnormality could not be identified.

Common mitochondrial DNA and POLG1 mutations are rare in the Chinese patients with adult-onset ataxia on Taiwan

Background and purpose Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative disorders with common features of adult-onset cerebellar ataxia. Many patients with clinically suspected SCA are subsequently diagnosed with common SCA gene mutations. Previous reports suggest some common mitochondrial DNA (mtDNA) point mutations and mitochondrial DNA polymerase gene ( POLG1) mutations might be additional underlying genetic causes of cerebellar ataxia. We tested whether mtDNA point mutations A3243G, A8344G, T8993G, and T8993C, or POLG1 mutations W748S and A467T are found in patients with adult-onset ataxia who did not have common SCA mutations. Methods Four hundred seventy-six unrelated patients with suspected SCA underwent genetic testing for SCA 1, 2, 3, 6, 7, 8, 10, 12, 17, and DRPLA gene mutations. After excluding these SCA mutations and patients with paternal transmission history, 265 patients were tested for mtDNA mutations A3243G, A8344G, T8993G, T8993C, and POLG1 W748S and A467T mutations. Results No mtDNA A3243G, A8344G, T8993G, T8993C, or POLG1 W748S and A467T mutation was detected in any of the 265 ataxia patients, suggesting that the upper limit of the 95% confidence interval for the prevalence of these mitochondrial mutations in Chinese patients with adult-onset non-SCA ataxia is no higher than 1.1%. Conclusions The mtDNA mutations A3243G, A8344G, T8993G, T8993C, or POLG1 W748S and A467T are very rare causes of adult-onset ataxia in Taiwan. Routine screening for these mutations in ataxia patients with Chinese origin is of limited clinical value.

Atypical Clinical Picture in a Patient with Benign Occipital Epilepsy: Diagnostic Contribution of Morpho-Functional MR

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a maternally inherited disease due to mitochondrial DNA (mtDNA) point mutations. The clinical phenotype varies in relation to the systems affected, age at onset and disease severity. The characteristic signs of MELAS are nausea and vomiting due to acidosis, headache, epilepsy, ataxia or generalized weakness, ophthalmoplegia, motor and sensory focal neurological deficits. The clinical course may improve due to partial regression of the typical lesions, but the prognosis is usually adverse. A 19-year-old man with a diagnosis of benign occipital epilepsy and resumption of seizure activity with focal occipital attacks since the age of 14 years came to our attention for the recent onset of drug-resistant electroclinical seizures of long duration with complex symptoms, where the dominant clinical feature was an intense, persistent bilateral periorbital migraine with nausea and vomiting, scintillation scotomata and blurring of vision. MR studies were performed at our institution in the immediate post-seizure phase and then at one week, three and six months. The acute-phase morphological scans showed a right cortical-subcortical area with altered signal in the occipitopolar region that was hypointense on T1 and hyperintense on T2 and FLAIR, with cortical thickening and effacement of the sulci. Contrast-enhanced scans did not demonstrate BBB alterations. The DWI scans showed a right temporo-occipital cortical area with higher signal intensity. In the subsequent examinations the area with altered signal shrank gradually and significantly in parallel with improvement in clinical conditions. The diagnostic hypothesis of benign occipital epilepsy was consistent neither with the clinical course, characterized by persistent headache, visual disturbance and refractoriness to antiepileptic drugs, nor with the temporal-occipital cortical MR findings, which resembled ischemic lesions but displayed a non-territorial pattern as well as reversibility over time. These elements guided in the diagnosis of MELAS, which was subsequently confirmed by identification of the typical gene mutation. On DWI the stroke-like lesions of MELAS are seen more frequently as focal hyperintense areas compared with healthy parenchyma. Such high signal intensity likely corresponds to T2 shine-through rather than cytotoxic edema. Indeed, several studies have demonstrated that in acute-phase scans of MELAS stroke-like lesions DWI hyperintensity is associated with increased ADC values that are not associated with restricted water diffusivity, reflecting the metabolic rather than anoxic-ischemic nature of these changes. In the present case, morphological MR associated with DWI was very helpful in guiding the diagnosis by demonstrating some pathognomonic features of MELAS stroke-like lesions such as cortical-subcortical involvement of the posterior hemispheres, the non-territorial pattern, lesion reversibility and the pathophysiological role of vasogenic edema in inducing an increase in extracellular water and thus in diffusion values.