Loss of NRF2 accelerates cognitive decline, exacerbates mitochondrial dysfunction, and is required for the cognitive enhancing effects of Centella asiatica during aging.

The water extract of Centella asiatica (CAW) improves cognitive and mitochondrial function and activates the nuclear factor erythroid 2-related factor 2 (NRF2) regulated antioxidant response pathway in aged mice. Here we investigate whether NRF2 activation is required for the cognitive and mitochondrial effects of prolonged CAW exposure during aging. Five-month-old NRF2 knockout (NRF2KO) and wild-type mice were treated with CAW for 1, 7, or 13 months. Each cohort underwent cognitive testing and hippocampal mitochondrial analyses. Age-related cognitive decline was accelerated in NRF2KO mice and while CAW treatment improved cognitive performance in wild-type mice, it had no effect on NRF2KO animals. Hippocampal mitochondrial function also declined further with age in NRF2KO mice and greater hippocampal mitochondrial dysfunction was associated with poorer cognitive performance in both genotypes. Long-term CAW treatment did not affect mitochondrial endpoints in animals of either genotype. These data indicate that loss of NRF2 results in accelerated age-related cognitive decline and worsened mitochondrial deficits. NRF2 also appears to be required for the cognitive enhancing effects of CAW during aging.

Mental health and health related quality of life in mitochondrial POLG disease.

We aimed to assess the impact of POLG disease on mental health and quality of life in 15 patients using the Symptom Checklist-90-R (SCL-90-R) and Short-Form 36 Health Survey (RAND-36). We found increased scores in all nine subscales of SCL-90-R, particularly phobic anxiety, depression and somatization. Further, patients reported considerably lower scores in all RAND-36 domains. This study revealed a global decline in mental health and poor quality of life in patients with POLG disease and highlights the need for increased awareness and systematic assessment in order to improve their quality of life and mental health.

Systematic review of cognitive deficits in adult mitochondrial disease.

The profile and trajectory of cognitive impairment in mitochondrial disease are poorly defined. This systematic review sought to evaluate the current literature on cognition in mitochondrial disease, and to determine future research directions. A systematic review was conducted, employing PubMed, Medline, Psycinfo, Embase and Web of Science, and 360-degree citation methods. English language papers on adult patients were included. The literature search yielded 2421 articles, of which 167 met inclusion criteria. Case reports and reviews of medical reports of patients yielded broad diagnoses of dementia, cognitive impairment and cognitive decline. In contrast, systematic investigations of cognitive functioning using detailed cognitive batteries identified focal cognitive rather than global deficits. Results were variable, but included visuospatial functioning, memory, attention, processing speed and executive functions. Conclusions from studies have been hampered by small sample sizes, variation in genotype and the breadth and depth of assessments undertaken. Comprehensive cognitive research with concurrent functional neuroimaging and physical correlates of mitochondrial disease in larger samples of well-characterized patients may discern the aetiology and progression of cognitive deficits. These data provide insights into the pattern and trajectory of cognitive impairments, which are invaluable for clinical monitoring, health planning and clinical trial readiness.

Cognitive deficits in adult m.3243A>G- and m.8344A>G-related mitochondrial disease: importance of correcting for baseline intellectual ability.

OBJECTIVE: To determine the cognitive profile of adult patients with mitochondrial disease, and the effect of disease severity on cognition. METHODS: Using a prospective case-control design, we compared cognition of patients to normative data and to matched controls, assessed three times over 18 months. Forty-nine patients with m.3243A>G (N = 36) and m.8344A>G (N = 13) mtDNA mutations and 32 controls, matched by age (±5 years) and premorbid cognition (±10 WTAR FSIQ points), participated. Participants completed neuropsychological assessments of general cognition (WAIS-IV), executive function (D-KEFS), and memory (WMS-IV). Potential predictors of cognition were explored. RESULTS: Patients show mild-to-moderate premorbid cognitive impairment, but substantial impairment in current general cognition and distinct domains, including verbal comprehension, perceptual reasoning, working memory, processing speed, and memory retrieval. Executive dysfunction may be caused by slower decision-making. Patients performed worse than controls, except on memory tasks, indicating intact memory, when premorbid cognition is controlled for. Premorbid cognition and disease severity were consistent predictors of cognition in patients; however, cognitive decline appears slow and is unlikely in the short-term, when other disease-specific factors remain stable. INTERPRETATION: Patients should be monitored to facilitate early identification of a complex profile of cognitive deficits and individuals with higher disease burden should be followed up more closely. On development of cognitive difficulties, appropriate compensatory strategies should be determined through in-depth assessment. Using strategies such as slower presentation of information, multiple modes of presentation, active discussion to aid understanding and decision-making, and use of memory aids, may ameliorate difficulties.

Urogenital symptoms in mitochondrial disease: overlooked and undertreated.

BACKGROUND AND PURPOSE: Bowel symptoms are well documented in mitochondrial disease. However, data concerning other pelvic organs is limited. A large case-control study has therefore been undertaken to determine the presence of lower urinary tract symptoms (LUTS) and sexual dysfunction in adults with genetically confirmed mitochondrial disease. METHODS: Adults with genetically confirmed mitochondrial disease and control subjects were recruited from a specialist mitochondrial clinic. The presence and severity of LUTS and their impact on quality of life, in addition to sexual dysfunction and bowel symptoms, were captured using four validated questionnaires. Subgroup analysis was undertaken in patients harbouring the m.3243A>G MT-TL1 mitochondrial DNA mutation. A subset of patients underwent urodynamic studies to further characterize their LUTS. RESULTS: Data from 58 patients and 19 controls (gender and age matched) were collected. Adults with mitochondrial disease had significantly more overactive bladder (81.5% vs. 56.3%, P = 0.039) and low stream (34.5% vs. 5.3%, P = 0.013) urinary symptoms than controls. Urodynamic studies in 10 patients confirmed that bladder storage symptoms predominate. Despite high rates of LUTS, none of the patient group was receiving treatment. Female patients and those harbouring the m.3243A>G MT-TL1 mutation experienced significantly more sexual dysfunction than controls (53.1% vs. 11.1%, P = 0.026, and 66.7% vs. 26.3%, P = 0.011, respectively). CONCLUSIONS: Lower urinary tract symptoms are common but undertreated in adult mitochondrial disease, and female patients and those harbouring the m.3243A>G MT-TL1 mutation experience sexual dysfunction. Given their impact on quality of life, screening for and treating LUTS and sexual dysfunction in adults with mitochondrial disease are strongly recommended.

Cognitive characteristics of mitochondrial diseases in children.

INTRODUCTION: This retrospective descriptive study was undertaken to further define the intelligence profiles of children with mitochondrial disorders, in the context of seizures and age of symptom onset. METHODS: We retrospectively identified forty-nine pediatric patients with definitive mitochondrial disease diagnoses and complete intelligence or adaptive functioning testing data. Patients were 0-216 months at onset of symptoms and 61-250 months of age at testing. Twenty-four of 49 patients had seizures. Twenty-one of the 24 patients with seizures had medically intractable seizures. All patients had Wechsler Intellectual Quotient (IQ) testing, except nine patients with seizures who were unable to engage in IQ testing and were assessed with a structured parent interview measure, the Vineland Adaptive Behavior Scales. We used descriptive and exploratory data analysis methods to characterize test results. RESULTS: Distribution of ages for patients with the Vineland assessment was younger than those given the Wechsler. The median overall score (combining Wechsler and Vineland summary scores) for all patients was 85 (interquartile range [IQR]: 50, 102), with the group without seizures obtaining a higher median Full Scale IQ (FSIQ) of 100 (IQR: 86, 109), compared to the group with seizures with a median FSIQ of 67 (IQR: 49.5, 89), a difference that is both statistically and clinically different (Δ = 33; 95% CI: 9, 52). The adaptive function measure was composed of patients only with intractable epilepsy and yielded the lowest overall median summary score of 43 (IQR: 37, 50). This general trend in differences between the FSIQ scores of the groups with and without seizures was also seen across all subscale measures analyzed-IQ index scores and two subtest scores, Digit Span and Coding-though differences were not always statistically different. Vargha-Delaney's A effect sizes ranged between 0.68 and 0.90, trends that mirrored those of distributional and median differences. Groups without versus with seizures differed most distinctly in Performance IQ (PIQ), with the group without seizures' median PIQ being 100 (IQR 94, 112) versus the group with seizures' median PIQ being 63 (IQR 54, 84), a difference of 37 points (95% CI). DISCUSSION: Results suggest that patients with mitochondrial diseases with seizures and early onset disease represent a worse cognitive phenotype, as compared with those with no seizures, who can have average intelligence. Results are discussed in the context of current literature.

Mitochondrial disease patient motivations and barriers to participate in clinical trials.

BACKGROUND: Clinical treatment trials are increasingly being designed in primary mitochondrial disease (PMD), a phenotypically and genetically heterogeneous collection of inherited multi- system energy deficiency disorders that lack effective therapy. We sought to identify motivating factors and barriers to clinical trial participation in PMD. METHODS: A survey study was conducted in two independent mitochondrial disease subject cohorts. A discovery cohort invited subjects with well-defined biochemical or molecularly- confirmed PMD followed at a single medical center (CHOP, n = 30/67 (45%) respondents). A replication cohort included self-identified PMD subjects in the Rare Disease Clinical Research Network (RDCRN) national contact registry (n = 290/1119 (26%) respondents). Five-point Likert scale responses were analyzed using descriptive and quantitative statistics. Experienced and prioritized symptoms for trial participation, and patient attitudes toward detailed aspects of clinical trial drug features and study design. RESULTS: PMD subjects experienced an average of 16 symptoms. Muscle weakness, chronic fatigue, and exercise intolerance were the lead symptoms encouraging trial participation. Motivating trial design factors included a self-administered study drug; vitamin, antioxidant, natural or plant-derivative; pills; daily treatment; guaranteed treatment access during and after study; short travel distances; and late-stage (phase 3) participation. Relative trial participation barriers included a new study drug; discontinuation of current medications; disease progression; daily phlebotomy; and requiring participant payment. Treatment trial type or design preferences were not influenced by population age (pediatric versus adult), prior research trial experience, or disease severity. CONCLUSIONS: These data are the first to convey clear PMD subject preferences and priorities to enable improved clinical treatment trial design that cuts across the complex diversity of disease. Partnering with rare disease patient communities is essential to effectively design robust clinical trials that engage patients and enable meaningful evaluation of emerging treatment interventions.

[The power plants of the cell: Treatment of psychiatric symptoms in patients with mitochondriopathy]. / Die Kraftwerke der Zellen- über die Behandlung von psychiatrischen Symptomen bei Patienten mit Mitochondriopathien.

Introduction Mitochondriopathies are pathologies of cell organelles, which are essential for the formation of adenosine triphosphate (ATP), which is responsible for cellular energy stock. When mitochondrial mutations occur, symptoms arise frequently in those organs that rely on a continuous energy supply, such as the nervous system. Although psychiatric illness is increasingly prevalent in patients with mitochondrial disease, less attention has been paid to its psychiatric presentations. Case Report We describe a case of a 21-year-old woman who presented in our outpatient department with panic attacks and depression. The patient experienced major side effects after low-dose sertraline therapy. Conclusion Mitochondriopathies belong to the class of rare illnesses in psychiatry; nevertheless, they require adaptations of psychopharmacological therapy. Psychotropic drugs are potential respiratory chain inhibitors and could lead to distinct side effects.

Transcranial low-level laser therapy improves brain mitochondrial function and cognitive impairment in D-galactose-induced aging mice.

Mitochondrial function plays a key role in the aging-related cognitive impairment, and photoneuromodulation of mitochondria by transcranial low-level laser therapy (LLLT) may contribute to its improvement. This study focused on the transcranial LLLT effects on the D-galactose (DG)-induced mitochondrial dysfunction, apoptosis, and cognitive impairment in mice. For this purpose, red and near-infrared (NIR) laser wavelengths (660 and 810 nm) at 2 different fluencies (4 and 8 J/cm2) at 10-Hz pulsed wave mode were administrated transcranially 3 d/wk in DG-received (500 mg/kg/subcutaneous) mice model of aging for 6 weeks. Spatial and episodic-like memories were assessed by the Barnes maze and What-Where-Which (WWWhich) tasks. Brain tissues were analyzed for mitochondrial function including active mitochondria, adenosine triphosphate, and reactive oxygen species levels, as well as membrane potential and cytochrome c oxidase activity. Apoptosis-related biomarkers, namely, Bax, Bcl-2, and caspase-3 were evaluated by Western blotting method. Laser treatments at wavelengths of 660 and 810 nm at 8 J/cm2 attenuated DG-impaired spatial and episodic-like memories. Also, results showed an obvious improvement in the mitochondrial function aspects and modulatory effects on apoptotic markers in aged mice. However, same wavelengths at the fluency of 4 J/cm2 had poor effect on the behavioral and molecular indexes in aging model. This data indicates that transcranial LLLT at both of red and NIR wavelengths at the fluency of 8 J/cm2 has a potential to ameliorate aging-induced mitochondrial dysfunction, apoptosis, and cognitive impairment.

Preliminary Study of Neurodevelopmental Outcomes and Parenting Stress in Pediatric Mitochondrial Disease.

BACKGROUND: Little is known regarding the neuropsychological profiles of pediatric patients with mitochondrial diseases or their parents, information that is crucial for improving the quality of life (QOL) for both patients and parents. We aimed to delineate neurodevelopment and psychological comorbidity in children with mitochondrial diseases in the preliminary investigation of adequate intervention methods, better prognoses, and improved QOL for both patients and parents. METHODS: Seventy children diagnosed with mitochondrial diseases were neuropsychologically evaluated. Neurocognitive (development, intelligence) and psychological (behavior, daily living function, maternal depression, parenting stress) functions were analyzed. Clinical variables, including the first symptom, epileptic classification, organ involvement, lactic acidosis, brain magnetic resonance imaging findings, muscle pathology, biochemical enzyme assay results, and syndromic diagnosis of mitochondrial diseases, were also reviewed. RESULTS: Prediagnostic assessments indicated that cognitive and psychomotor developments were significantly delayed. Group mean full scale intelligence quotient (IQ) scores indicated mild levels of intellectual disability, borderline levels of verbal IQ impairment, and mild levels of intellectual disability on performance IQ. Many children exhibited clinically significant levels of behavioral problems, whereas mothers of children with mitochondrial diseases exhibited significant increases in parenting stress relative to mothers of healthy children. Furthermore, 65% of mothers exhibited significant levels of depression. Early onset of the first symptoms, diffuse brain atrophy, and drug-resistant epilepsy negatively influenced neurodevelopmental and adaptive functions. CONCLUSION: Better understanding of the functional levels and profiles of neurodevelopment and psychological comorbidity in children with mitochondrial diseases in the prediagnostic period is essential for adequate support and QOL of children with mitochondrial diseases and their parents.

Chrysin exerts neuroprotective effects against 3-Nitropropionic acid induced behavioral despair-Mitochondrial dysfunction and striatal apoptosis via upregulating Bcl-2 gene and downregulating Bax-Bad genes in male wistar rats.

3-Nitropropionic acid (3-NP) is an irreversible inhibitor of mitochondrial complex-II that causes transcriptional dysregulation, bioenergetics failure, protein aggregation and oxidative damage similar to Huntington's disease (HD) pathogenesis. Chrysin, a bioactive flavonoid reported to have anti-inflammation, antioxidant, vasorelaxant and neuroprotective property. The present study was framed to determine the neuroprotective efficiency of chrysin upon 3-NP induced oxidative stress, mitochondrial dysfunctions and neurodegeneration. 3-NP (10mg/kg b.w. i.p.) administration for 14days exhibited significant (P<0.01) behavioral alterations, mitochondrial dysfunction and oxidative damages to biomolecules, finally causes cell death. Chrysin at 50mg/kg b.w. orally for 14days improved all the behavioral performances and regulated the complex activities in mitochondria. Further, chrysin diminished the oxidative stress markers (lipid peroxidation, nitrite and protein carbonyls) by significantly (P<0.01) improving the antioxidant status (superoxide dismutase, catalase and reduced glutathione) in striatal mitochondria. Indeed, chrysin prevents apoptosis by upregulating the Bcl-2 mRNA expression and downregulating the pro-apoptotic (Bax, Bad) mRNAs in 3-NP induced condition. Furthermore, the survival of striatal neurons against 3-NP toxicity was enhanced upon chrysin treatment which was evidenced by observing histopathological studies. Hence, the present study collectively suggests that the chrysin can serve as a potential therapeutic agent on 3-NP induced mitochondrial deficits and subsequent apoptosis.

Confirmed versus suspected: The social significance of a genetic or non-genetic diagnosis of mitochondrial disease.

This study assessed attitudes and beliefs regarding the importance of a genetic versus non-genetic diagnosis within the mitochondrial disease community. Survey respondents were categorized into two groups - those with a genetic diagnosis, and those with a non-genetic diagnosis of mitochondrial disease. We found that while both groups perceive problems with the support available to adult mitochondrial disease patients, the non-genetic group experiences less medical and social support due to lack of a definitive diagnosis. Understanding the efficacy of existing resources for mitochondrial disease sub-groups will allow for the development or improvement of resources designed to meet patient needs.

Attitudes toward prevention of mtDNA-related diseases through oocyte mitochondrial replacement therapy.

STUDY QUESTION: Among women who carry pathogenic mitochondrial DNA (mtDNA) point mutations and healthy oocyte donors, what are the levels of support for developing oocyte mitochondrial replacement therapy (OMRT) to prevent transmission of mtDNA mutations? SUMMARY ANSWER: The majority of mtDNA carriers and oocyte donors support the development of OMRT techniques to prevent transmission of mtDNA diseases. WHAT IS KNOWN ALREADY: Point mutations of mtDNA cause a variety of maternally inherited human diseases that are frequently disabling and often fatal. Recent developments in (OMRT) as well as pronuclear transfer between embryos offer new potential options to prevent transmission of mtDNA disease. However, it is unclear whether the non-scientific community will approve of embryos that contain DNA from three people. STUDY DESIGN, SIZE, DURATION: Between 1 June 2012 through 12 February 2015, we administered surveys in cross-sectional studies of 92 female carriers of mtDNA point mutations and 112 healthy oocyte donors. PARTICIPANTS/MATERIALS, SETTING, METHODS: The OMRT carrier survey was completed by 92 female carriers of an mtDNA point mutation. Carriers were recruited through the North American Mitochondrial Disease Consortium (NAMDC), the United Mitochondrial Disease Foundation (UMDF), patient support groups, research and private patients followed at the Columbia University Medical Center (CUMC) and patients' referrals of maternal relatives. The OMRT donor survey was completed by 112 women who had donated oocytes through a major ITALIC! in vitro fertilization clinic. MAIN RESULTS AND THE ROLE OF CHANCE: All carriers surveyed were aware that they could transmit the mutation to their offspring, with 78% (35/45) of women, who were of childbearing age, indicating that the risk was sufficient to consider not having children, and 95% (87/92) of all carriers designating that the development of this technique was important and worthwhile. Of the 21 surveyed female carriers considering childbearing, 20 (95%) considered having their own biological offspring somewhat or very important and 16 of the 21 respondents (76%) were willing to donate oocytes for research and development. Of 112 healthy oocyte donors who completed the OMRT donor survey, 97 (87%) indicated that they would donate oocytes for generating a viable embryo through OMRT. LIMITATIONS, REASONS FOR CAUTION: Many of the participants were either patients or relatives of patients who were already enrolled in a research-oriented database, or who sought care in a tertiary research university setting, indicating a potential sampling bias. The survey was administered to a select group of individuals, who carry, or are at risk for carrying, mtDNA point mutations. These individuals are more likely to have been affected by the mutation or have witnessed first-hand the devastating effects of these mutations. It has not been established whether the general public would be supportive of this work. This survey did not explicitly address alternatives to OMRT. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study indicating a high level of interest in the development of these methods among women affected by the diseases or who are at risk of carrying mtDNA mutations as well as willingness of most donors to provide oocytes for the development of OMRT. STUDY FUNDING/COMPETING INTERESTS: This work was conducted under the auspices of the NAMDC (Study Protocol 7404). NAMDC (U54NS078059) is part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR) and NCATS. NAMDC is funded through a collaboration between NCATS, NINDS, NICHD and NIH Office of Dietary Supplements. The work was also supported by the Bernard and Anne Spitzer Fund and the New York Stem Cell Foundation (NYSCF). Dr Hirano has received research support from Santhera Pharmaceuticals and Edison Pharmaceuticals for studies unrelated to this work. None of the other authors have conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable.

Neuropsychiatric Features in Primary Mitochondrial Disease.

Mitochondrial diseases are a clinically heterogeneous group of disorders that ultimately result from dysfunction of the mitochondrial respiratory chain. There is some evidence to suggest that mitochondrial dysfunction plays a role in neuropsychiatric illness; however, the data are inconclusive. This article summarizes the available literature published in the area of neuropsychiatric manifestations in both children and adults with primary mitochondrial disease, with a focus on autism spectrum disorder in children and mood disorders and schizophrenia in adults.

The Parent Experience of Caring for a Child with Mitochondrial Disease.

UNLABELLED: Mitochondrial disease is a spectrum of progressive genetic disorders resulting from dysfunctions of cellular metabolism in the mitochondria that greatly compromise the lives of affected individuals, who are often children. PURPOSE: This study described the parent experiences unique to caring for a child with mitochondrial disease. METHODS: Internet surveys were made available to parents of children with a known mitochondrial disease. Surveys included demographic items and two questionnaires: Parent Experience of Child Illness (PECI) and Pediatric Inventory for Parents (PIP). Descriptive data were collected and correlations calculated to determine relationships between the parent experience and stress. RESULTS: The majority of participants (n=231) were mothers (95%) of children with mitochondrial disease around the age of 10 years (M=9.85). Elevated scores were found in parent adjustment illness-related concerns regarding Guilt and Worry (M=2.30, SD=.650), Sorrow and Anger (M=2.09, SD=.730), Long-term Uncertainty (M=2.56, SD=.690), and Emotional Resources (M=2.36, SD=.615). Scores indicated elevated feelings of stress in terms of both difficulty and frequency. Significant correlations (p<0.01) were found between parent illness-related concerns and parenting stress. CONCLUSIONS: The results of this study suggest that parents of a child with mitochondrial disease feel a burden of responsibility that exceeds the typical caregiver role, see their child as fragile, and have concerns about their child's future. Identification of these concerns can assist nurses to better meet the needs of these parents and families.

Acupuncture reversed hippocampal mitochondrial dysfunction in vascular dementia rats.

Hippocampal mitochondrial dysfunction due to oxidative stress has been considered to play a major role in the pathogenesis of vascular dementia (VD). Previous studies suggested that acupuncture could improve cerebral hypoperfusion-induced cognitive impairments. However, whether hippocampal mitochondria are associated with this cognitive improvement remains unclear. In this study, an animal model of VD was established via bilateral common carotid arteries occlusion (BCCAO) to investigate the alterations of cognitive ability and hippocampal mitochondrial function. BCCAO rats showed impairments in hippocampal mitochondrial function, overproduction of reactive oxygen species (ROS) and learning and memory deficits. After two-week acupuncture treatment, BCCAO-induced spatial learning and memory impairments as shown in Morris water maze were ameliorated. Hippocampal mitochondrial respiratory complex enzymes (complex I, II, IV) activities and cytochrome c oxidase IV expression significantly increased, which might contribute to the reduction of hippocampal ROS generation. In addition, acupuncture significantly improve mitochondrial bioenergy parameters such as mitochondrial respiratory control rate and membrane potential not PDH A1 expression. Placebo-acupuncture did not produce similar therapeutic effects. These findings suggested that acupuncture reversed BCCAO-induced hippocampal mitochondrial dysfunction, which might contribute to its prevention on cognitive deficits.

Perceived fatigue is highly prevalent and debilitating in patients with mitochondrial disease.

Perceived fatigue is a prominent symptom in patients with mitochondrial disease but to date its prevalence, impact and aetiology are poorly understood. Our aim was to determine the prevalence and assess for comorbidities associated with clinically relevant fatigue in patients with mitochondrial disease. A cross-sectional postal survey of patients with mitochondrial disease was undertaken using a validated self-completion, patient-reported outcome measures (response rate: 60%; n = 132). The prevalence and perceived functional impact of experienced fatigue were assessed using the Fatigue Impact Scale. Other putative biological mechanisms were evaluated using the Hospital Anxiety Depression scale and Epworth sleepiness scale. Data were compared with those for healthy control subjects and patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome matched for age and gender. Sixty-two per cent of patients with mitochondrial disease reported excessive symptomatic fatigue (Fatigue Impact Scale ≥ 40); whilst 32% reported severe, functionally limiting fatigue symptoms (Fatigue Impact Scale ≥ 80) comparable to perceived fatigue in patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome. Fatigue is common and often severe in patients with mitochondrial disease irrespective of age, gender or genotype. Future evaluation of causal factors in mitochondrial disease-associated fatigue is warranted with the potential to guide future treatment modalities.

A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity.

OBJECTIVE: Diseases due to mutations of POLG gene, encoding the mitochondrial DNA polymerase, are reputed to have very diverse clinical presentations and have been proposed to cause up to 25% adult mitochondrial diseases. Our objective was the evaluation of the specificity and sensitivity of the signs encountered with POLG mutations. DESIGN: Forty-four patients out of 154 with sequenced POLG gene had mutations affecting either one (POLG(+/-) group) or two POLG alleles (POLG(+/+) group). Phenotyping included clinical signs, electroneuromyography and brain imaging while mitochondrial investigations encompassed muscle histochemistry, respiratory chain assays and search for multiple mitochondrial deletions. The specificity and sensitivity of the signs associated with POLG mutations were analysed by comparison between POLG(+/+) and patients without POLG mutation. RESULTS: High sensitivity but low specificity was observed with single signs such as axonal sensory neuropathy, cerebellar syndrome, movement disorders and weakness involving ocular, pharyngeal, axial and/or limb muscles. Specificity was increased with combination of previous signs plus psychiatric symptoms, cognitive impairment and epilepsy. High specificity and sensitivity was only obtained with sensory neuronopathy associated with one of the following signs: weakness of ocular, pharyngeal, axial and/or limb muscles. Mitochondrial investigations did not suffice for diagnosis. The widespread neuromuscular signs were often present since disease onset and were the rule above 50 years of age leading to a very low probability of POLG mutations in patients with less than three signs and absent sensory neuropathy. CONCLUSIONS: Phenotypes associated with POLG mutations follow a reproducible pattern, which allows establishing a diagnostic flow chart.