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Abstract: Objective: To identify peripheral nerve abnormalities in hereditary spastic paraplegia (HSP) due to mutations in the spastin gene (spastic paraplegia 4, SPG4) using standard nerve conduction (NCS) and novel tests of axonal excitability. Methods: Eleven patients with known mutations in spastin were assessed with NCS for the upper and lower limbs, and axonal excitability testing on the median nerve. Results: Standard nerve conduction studies revealed a sensorimotor neuropathy in two patients. Excitability studies on median motor axons showed an isolated abnormality (increased strength-duration time constant), but those on sensory axons were normal in nine patients with normal routine nerve conduction studies. Conclusions: Peripheral neuropathy occurs in HSP patients with SPG4 mutations, but axonal excitability studies provide limited additional evidence for subclinical peripheral nerve dysfunction, and add little further to standard nerve conduction studies. Significance: The features of HSP due to SPG4 mutations include sensorimotor polyneuropathy. The value of excitability studies is limited in individual patients. [Copyright &y& Elsevier]

Objectives: We assessed the association between impaired olfaction and depressive symptoms and poor quality of life. Methods: A total of 1,375 participants aged 60 years or older bad their olfaction measured using the San Diego Odor Identification Test. Quality of life was assessed using the 36-Item Short-Form Survey (SF-36). Depressive symptoms were assessed by either the SF-36, which included the Mental Health Index, and/or the Center for Epidemiologic Studies Depression Scale (CES-D-10). Results: Among participants with olfactory impairment, 15.4% and 20.2% had depressive symptoms assessed by the Mental Health Index and CES-D-10, respectively. Among participants aged 70 years or older, olfactory impairment was associated it with depressive symptoms (assessed by the CES-D-10), multirariate-adjusted odds ratio, OK: 1.66 (95% confidence interval, CI: 1.03-2.66). Subjects with olfactory impairment compared to those without, bad lower SF-36 scores in six out of the eight indices. Conclusions: Olfactory impairment was independently associated with depressive symptoms and poorer quality of life. [ABSTRACT FROM AUTHOR]

The gastrointestinal microbiota (GM) have become an increasingly topical area in the quest to better understand the pathogenesis of Parkinson's disease (PD). Studying the GM of PD patients, they showed that the enzyme tyrosine decarboxylase (TDC), predominately found within the GM, decarboxylates l-tyrosine to form tyramine and converts l-dopa to dopamine [[4]]. They did however identify a small molecule inhibitor, -fluoromethyltyrosine (AFMT), that prevented in vitro TDC-dependent l-dopa decarboxylation, as well as within Enterococcus faecalis cultures and GM samples from PD patients [[5]]. [Extracted from the article]

Whispering dysphonia (DYT4 dystonia) is a dominantly inherited disorder previously described in an Australian family. The clinical phenotype is of spasmodic dysphonia associated with additional focal or generalised dystonia and a characteristic facies and body habitus. Recently, the cause of whispering dysphonia was found to be a mutation in the TUBB4 gene, which encodes for a neuronally expressed tubulin. We aimed to determine whether microtubular function was impaired as a consequence of this TUBB4 mutation. We studied olfactory neurosphere cell lines derived from three affected individuals and three controls. Tubulin end-binding protein (EB3) was fluorescently tagged, allowing us to assess microtubule dynamics using time-lapse imaging in live cells. We found that there was a significant reduction in the density of microtubules and in the speed of microtubule formation. The results suggest that the TUBB4 mutation leads to a reduction in microtubule density and a decrease in the speed of microtubule formation, supporting the notion that microtubule dysfunction can play a role in the pathophysiology of dystonia. [ABSTRACT FROM AUTHOR]

In autosomal dominant hereditary spastic paraplegia (HSP), mutations in the spastin (SPG4) gene account for 45% of all cases. The key diagnostic clinical findings are lower limb spasticity, hyperreflexia and extensor plantar responses. The main neuropathological finding in HSP is axonal degeneration in the terminal portions of the long descending and ascending tracts in the spinal cord. Current hypothesis suggest impairment of axonal transport or disturbance of mitochondrial function. We utilised the threshold tracking transcranial magnetic stimulation (TTTMS) technique to evaluate if cortical abnormalities may coexist in these patients. Cortical excitability studies were undertaken on 12 HSP patients with the SPG4 mutation (five males and seven females, mean age 56 years). Patients were compared with age-matched controls. The mean spastic paraplegia rating scale was 17.3 ± 3.0 and the mean upper motor neuron score was 13.5 ± 0.5. Short-interval intracortical inhibition was significantly reduced in HSP patients when compared to controls (HSP 5.0 ± 1.6%; controls 11.8 ± 1.0%, p < 0.001), as was the cortical silent period duration (HSP 189.6 ± 12.0 ms; controls 214.2 ± 3.9, p < 0.02). Resting motor threshold was significantly reduced amongst HSP patients (HSP 51.8 ± 2.3%; controls 60.3 ± 1.4%, p < 0.01). A significant increase in motor evoked potential amplitude was noted in HSP patients when compared to controls (HSP 40.3 ± 7.3%; controls 23.8 ± 2.4%, p < 0.02). Cortical dysfunction may be a feature of the pathophysiological process in HSP patients with the SPG4 mutation. Whilst axonal disruption and mitochondrial dysfunction are postulated to play major roles in the pathophysiological process of HSP patients, motor cortex dysfunction as suggested by our study may also play a role. [ABSTRACT FROM AUTHOR]

This study aimed to (1) characterise the mitochondrial phenotype in PINK1 mutant human olfactory neurospheres (HON), and (2) rescue mitochondrial dysfunction in PINK1 mutant HON with overexpression of PGC-1a. We generated HON cultures from a patient harbouring the homozygous c1309T>G, W437G PINK1 mutation, and an age and sex-matched control. Real time polymerase chain reaction was performed for relative expression of PGC-1a, Tfam and SOD1, and Western blot was performed for PGC-1a and b-actin. Assessment of mitochondrial mass, mitochondrial membrane potential and reactive oxygen species were performed. Adenosine triphosphate (ATP) synthesis rates were detected luminometrically, using a previously published protocol. For transfection of lentivirus, cells were plated at 600,000/plate for 24 hours, then transfected with adenovirus (60 million/plate) expressing PGC-1a and incubated for 5 days. Gene expression of PGC-1a in PINK1 HON was significantly lower than control HON. Western blot for PGC-1a protein revealed decreased protein levels in PINK1 compared with control. Mitochondrial mass, mitochondrial membrane potential and ATP production was significantly reduced in PINK1 HON compared with control HON, whereas ROS production was significantly increased. Lentiviral transfection increased PGC-1a gene expression in both PINK1 and control HON. PGC-1a overexpression resulted in increased mitochondrial mass and mitochondrial membrane potential in PINK1 HON. There was also a trend towards decreased ROS production and increased ATP production. This study provides evidence of mitochondrial dysfunction in PINK1 HON, associated with abnormalities in the gene expression of PCG-1a, the master regulator of mitochondrial biogenesis. Overexpression of PGC-1a lead to statistically significant improvements in mitochondrial mass and mitochondrial membrane potential, with a trend towards improvement in production in ATP and reactive oxygen species. Further studies are required to define the mechanisms underlying the abnormalities in mitochondrial function in PINK1 HON, and characterise the role of PGC-1a in PINK1 cells. [ABSTRACT FROM AUTHOR]

• Mitochondrial DNA abnormalities in the substantia nigra are associated with respiratory chain dysfunction. • There is a reciprocal interaction between alpha-synuclein aggregation and mitochondrial dysfunction. • There is strong evidence supporting a role for impaired mitophagy and mitochondrial biogenesis in Parkinson's disease. • Mitochondrial, mtDNA maintenance and lysosomal disease mechanisms may converge at the level of cell-mediated immunity. • Mitochondrial dysfunction is a target for novel drug therapies, although most clinical trials have failed to show benefit. New discoveries providing insights into mitochondrial bioenergetics, their dynamic interactions as well as their role in cellular homeostasis have dramatically advanced our understanding of the neurodegenerative process of Parkinson's disease (PD). Respiratory chain impairment is a key feature in sporadic PD patients and there is growing evidence that links proteins encoded by PD-associated genes to disturbances in mitochondrial function. Against the backdrop of latest advances in the development of PD treatments that target mitochondria, we aim to give an overview of the literature published in the last three decades on the significance of mitochondria in the pathogenesis of PD. We describe the contribution of mitochondrial genome alterations and PD-associated genes to mitochondrial maintenance. We highlight mitophagy as a key mechanism in neurodegeneration. Moreover, we focus on the reciprocal interaction between alpha-synuclein aggregation and mitochondrial dysfunction. We discuss a novel trafficking pathway involving mitochondrial-derived vesicles within the context of PD and provide a synopsis of the most recently emerging topics in PD research with respect to mitochondria. This includes the relationship between mitochondria and cell-mediated immunity, the ER-mitochondria axis, sirtuin-mediated mitochondrial stress response and the role of micro RNAs in the aetiology of PD. In addition, recent studies have challenged the neuro-centric view of PD pathology, moving microglia and astrocytes into the research spotlight. Greater insights into these mechanisms may hold the key for the development of novel targeted therapies, addressing the need for a disease-modifying treatment, which has remained elusive to date. [ABSTRACT FROM AUTHOR]

A 45-year-old woman presented with acute sequential optic neuropathy resulting in bilateral complete blindness. No significant visual recovery occurred. Past medical history was relevant for severe preeclampsia with resultant renal failure, diabetes mellitus, and sudden bilateral hearing loss when she was 38 years old. There was a family history of diabetes mellitus in her mother. Testing for common causes of bilateral optic neuropathy did not reveal a diagnosis for her illness. The maternal and personal history of diabetes and deafness prompted testing for mitochondrial disease. The 3 primary mitochondrial DNA mutations responsible for Leber hereditary optic neuropathy were absent, but the patient was subsequently found to have a disease causing mitochondrial DNA mutation, m.13513G>A. The case illustrates the importance of early testing for mitochondrial disease and demonstrates that Leber hereditary optic neuropathy–like presentations may be missed if testing is limited to the 3 primary mutations. [ABSTRACT FROM AUTHOR]

Abstract: Background: The diagnosis of mitochondrial disease requires a complex synthesis of clinical, biochemical, histological, and genetic investigations. An expanding number of mitochondrial diseases are being recognized, despite their phenotypic diversity, largely due to improvements in methods to detect mutations in affected individuals and the discovery of genes contributing to mitochondrial function. Improved understanding of the investigational pitfalls and the development of new laboratory methodologies that lead to a molecular diagnosis have necessitated the field to rapidly adopt changes to its diagnostic approach. Scope of review: We review the clinical, investigational and genetic challenges that have resulted in shifts to the way we define and diagnose mitochondrial disease. Incorporation of changes, including the use of fibroblast growth factor 21 (FGF-21) and next generation sequencing techniques, may allow affected patients access to earlier molecular diagnosis and management. Major conclusions: There have been important shifts in the diagnostic paradigm for mitochondrial disease. Diagnosis of mitochondrial disease is no longer reliant on muscle biopsy alone, but should include clinical assessment accompanied by the use of serological biomarkers and genetic analysis. Because affected patients will be defined on a molecular basis, oligosymptomatic mutation carriers should be included in the spectrum of mitochondrial disease. Use of new techniques such as the measurement of serum FGF-21 levels and next-generation-sequencing protocols should simplify the diagnosis of mitochondrial disease. General significance: Improvements in the diagnostic pathway for mitochondrial disease will result in earlier, cheaper and more accurate methods to identify patients with mitochondrial disease. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research. [Copyright &y& Elsevier]

Mitochondrial diseases are some of the most common inherited neurometabolic disorders, and major progress has been made in our understanding, diagnosis, and treatment of these conditions in the past 5 years. Development of national mitochondrial disease cohorts and international collaborations has changed our knowledge of the spectrum of clinical phenotypes and natural history of mitochondrial diseases. Advances in high-throughput sequencing technologies have altered the diagnostic algorithm for mitochondrial diseases by increasingly using a genetics-first approach, with more than 350 disease-causing genes identified to date. While the current management strategy for mitochondrial disease focuses on surveillance for multisystem involvement and effective symptomatic treatment, new endeavours are underway to find better treatments, including repurposing current drugs, use of novel small molecules, and gene therapies. Developments made in reproductive technology offer women the opportunity to prevent transmission of DNA-related mitochondrial disease to their children. [ABSTRACT FROM AUTHOR]

Background: Kufor-Rakeb syndrome (KRS) is an autosomal recessive, juvenile-onset Parkinson's disease (PD) caused by loss-of-function mutations in ATP13A2 (PARK9). Impaired energy metabolism is considered a pathogenic mechanism in PD and mitochondrial dysfunction resulting from Zn(2+) dyshomeostasis has been found in KRS patient-derived cells. In addition to mitochondrial energy production, glycolysis plays an important role in cellular energy metabolism and glucose hypometabolism has been reported in PD. However, glycolytic status in KRS remains undetermined despite its potential importance.Methods: We assessed glycolytic function in ATP13A2-deficient KRS patient-derived human olfactory neurosphere cells and fibroblasts and determined the effect of pyruvate supplementation on improving cellular energy production.Results: We found impaired extracellular acidification, reduction in pyruvate production and a decrease in the NAD(+)/NADH ratio, indicative of glycolytic dysfunction. In addition, gene expression analysis revealed an altered expression profile for several glycolytic enzymes. Glycolytic dysfunction was aggravated when the intracellular Zn(2+) concentration was increased, while ATP13A2 overexpression and pyruvate supplementation blocked the observed Zn(2+)-mediated toxicity. Moreover, supplementation with pyruvate significantly increased basal mitochondrial ATP production and abolished Zn(2+)-induced cell death.Conclusions: These findings indicate that glycolytic dysfunction contributes to pathogenesis and pyruvate supplementation improves overall cellular bioenergetics in our KRS patient-derived cell model, highlighting a therapeutic potential. [ABSTRACT FROM AUTHOR]

Kearns-Sayre syndrome (KSS) is a mitochondrial disorder characterised by onset before the age of 20 years, progressive external ophthalmoplegia, and pigmentary retinopathy, accompanied by either cardiac conduction defects, elevated cerebrospinal fluid protein or cerebellar ataxia. 50% of patients with KSS develop cardiac complications. The most common cardiac manifestation is conduction disease which may progress to complete atrioventricular block or bradycardia-related polymorphic ventricular tachycardia (PMVT). The management of cardiac electrical disease associated with KSS and mitochondrial cytopathy is systematically reviewed including the case of a 23 year-old female patient with KSS who developed a constellation of cardiac arrhythmias including rapidly progressive conduction system disease and monomorphic ventricular tachycardia with myocardial scarring. The emerging role of cardiac magnetic resonance imaging (CMR) in detecting subclinical cardiac involvement is also highlighted. This review illustrates the need for cardiologists to be informed about this rare but emerging condition. [ABSTRACT FROM AUTHOR]

Abstract: We aimed to establish the population prevalence of the MELAS 3243A>G mtDNA mutation in a large Caucasian-based population (n =2954; 99% Caucasian, 57% women and mean age of 66.4 years). All participants underwent comprehensive clinical evaluation including audiologic testing. We detected the 3243A>G mutation in seven subjects using standard polymerase chain reaction/restriction fragment length polymorphism methods, establishing a population prevalence of 236/100000 (0.24%; 95% CI 0.10–0.49%); much higher than previously reported. All had mild to moderate hearing loss. Our findings indicate that subjects with the 3243A>G mtDNA mutation could be markedly under-recognised in the community. [Copyright &y& Elsevier]

Abstract: Mutations in ATP13A2 cause autosomal-recessive parkinsonism (Kufor-Rakeb syndrome; KRS). Because several other parkinsonism-associated proteins have been connected to mitochondrial function and mitophagy, we studied the impact of endogenous mutations in ATPase type 13A2 (ATP13A2) on mitochondria in fibroblasts from KRS patients compared with controls. In patients, we detected decreased adenosine triphosphate (ATP) synthesis rates, increased mitochondrial DNA levels, a higher frequency of mitochondrial DNA lesions, increased oxygen consumption rates, and increased fragmentation of the mitochondrial network. Importantly, overexpression of wild-type ATP13A2 rescued the respiration phenotype. These findings collectively suggest that ATP13A2 contributes to the maintenance of a healthy mitochondrial pool, supporting the hypothesis that impaired mitochondrial clearance represents an important pathogenic mechanism underlying KRS. [Copyright &y& Elsevier]