Sunday, January 22, 2017

What is quality of life and how do we measure it? Relevance to Parkinson's disease and movement disorders

Pablo Martinez-Martin MD, PhD; Movement Disorders, Version of Record online: 2 DEC 2016 DOI: 10.1002/mds.26885

The objective of this review is to present the conceptual framework, the measures, and some of their most relevant applications in the field of Parkinson's disease and movement disorders. Health-related quality of life is a subjective, individual, and multidimensional construct, and its main dimensions are physical, mental, and social, besides global perceptions of health and personal domains. Health-related quality of life measurement is carried out by means of questionnaires or scales, ideally self-applied by patients, and has a diversity of important applications for clinical practice, research, and health policy.

The origins of the quality of life (QoL) concept are ancient and, in some way, controversial from the beginning. Around 4 centuries before Christ, Greek philosophers proposed the “good life” as a vital goal, an ancestry term of the current notion of QoL. Aristippus (435-350 BC) and the hedonists defended the achievement of pleasure as the basis of happiness, a view later nuanced by Aristotle (384-322 BC), who moved the concept of happiness to the pursuit of activities focused on more worthy objectives and values (eudaimonia: well-being, happiness). The controversy between hedonists and eudaimonics, influenced by new theoretical contributions and inspirations, has in some way continued until the present.

In the setting of movement disorders, it is recommended to increase the number of clinical trials focused on HRQoL, with HRQol acting as the mainendpoint of the study. For obtaining more complete information about HRQoL status and change, a combination of generic and specific measures is recommended. The contents of the generic scales may not be relevant for specific conditions, and their responsiveness may be low; however, the specific instruments can overlook important aspects of general health. For example, in the setting of PD, the SF-36 does not include evaluation of self-image or stigma, whereas the PDQ-39 does not include assessment for energy/fatigue. Finally, for the correct use and interpretation of outcomes, it is advisable to keep in mind the potential limitations that HRQoL instruments, their application, or analysis may present.

Saturday, January 21, 2017

New Health Technologies Managing Access, Value and Sustainability

OECD Publishing, Paris. DOI:10.1787/9789264266438-en

This report discusses the need for an integrated and cyclical approach to managing health technology in order to mitigate clinical and financial risks, and ensure acceptable value for money.

The proliferation of high-cost drugs and rising drug prices are raising pressure on public health services. Governments need to work with industry and regulators to define a new way of approaching the development and use of new health technologies that encourage innovation while making it more affordable and that justifies better the benefit that it brings.

According to the study, "the launch of cancer and rare diseases drugs is rising, sometimes without an assessment of the increased benefits they produce for the health of patients. In this sense, the OECD exemplifies this situation in the case of the United States "where the launch price of cancer drugs per year of life gained has increased fourfold in just 20 years, in constant terms, and already exceeds $ 200,000 ".

Friday, January 20, 2017

Two different genetic diseases in the same patient: Coincident, concomitant, or causally related

Graf, J., Hellenbroich, Y., Veelken, N., Figueroa, K. P., Wolff, S., Pulst, S. and Brüggemann, N. (2016). Mov. Disord., 31: 491–492. doi: 10.1002/mds.26539

A 17-year-old high school student started falling behind his peers and developed cramps at the age of 5 years, diagnosis of myotonic dystrophy was genetically confirmed. He developed progressive ataxia and prominent dysarthria. On examination, besides generalized muscle weakness and myotonic reactions, he showed saccadic pursuit, gaze-evoked nystagmus, dysmetria, gait ataxia, loss of deep-tendon reflexes, and an impaired sense of position and vibration. At the age of 15 years, genetic testing confirmed an additional diagnosis of Friedreich ataxia.
Our findings have several important implications: Although genetic testing is the gold standard for a large number of neurological diseases, it does not replace a detailed neurological examination and careful taking of the family history. In some patients, a broad phenotypic spectrum may be a result of the existence of more than 1 gene defect. Although the occurrence of mutations in 2 genes is most likely coincidental in our patients, the possibility of a potential common predisposition to mutations should also be considered.

Thursday, January 19, 2017

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

Nigel A. Calcutt, Darrell R. Smith, Katie Frizzi, Mohammad Golam Sabbir, Subir K. Roy Chowdhury, Teresa Mixcoatl-Zecuatl, Ali Saleh, Nabeel Muttalib, Randy Van der Ploeg, Joseline Ochoa, Allison Gopaul, Lori Tessler, Jürgen Wess, Corinne G. Jolivalt, Paul Fernyhough; J Clin Invest. doi:10.1172/JCI88321. Published January 17, 2017

Distal dying-back or degeneration of nerve fibers is observed in many axonopathic diseases, including diabetic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), Friedreich ataxia, Charcot-Marie-Tooth disease type 2, and HIV-associated distal-symmetric neuropathy. There are no therapies for any of these diseases, all of which display some degree of mitochondrial dysfunction. This is pertinent, as the growth-cone motility required to maintain fields of innervation consumes 50% of ATP supplies in neurons due to high rates of actin treadmilling. Maintenance of plastic innervation therefore requires high consumption of ATP for growth-cone motility and maintenance of terminals and synapses. Unmyelinated axons are also more energetically demanding than myelinated axons, consuming 2.5- to 10-fold more energy per action potential. Mitochondria are known to concentrate in regions of high metabolic demand and sensory terminal boutons are packed with mitochondria.

The blockade of muscarinic receptor–mediated inhibition of mitochondrial activity using antimuscarinic drugs may not represent a specific intervention against any one primary pathogenic mechanism and potentially allows broad therapeutic application to all conditions that show diminished energy capacity under stress. Peripheral neuropathy is a major, and largely untreated, cause of human morbidity, with huge associated health care costs. One particularly encouraging implication of our identification of the endogenous M1R-mediated suppression of sensory neuron metabolism is that drugs that modulate this process are already in widespread clinical use for other indications. Moreover, the safety profile of antimuscarinic drugs is well characterized, with over 20 years of clinical application for a variety of indications in Europe and the safe use of topical pirenzepine applied to the eye to treat myopia in children. The therapeutic application of M1R antagonists suggested by our studies could potentially translate relatively rapidly to clinical use.

Wednesday, January 18, 2017

Mitochondrial iron-sulfur cluster biogenesis from molecular understanding to clinical disease

Majid Alfadhel, Marwan Nashabat, Qais Abu Ali, Khalid Hundallah; Neurosciences (Riyadh). 2017 Jan;22(1):4-13. doi: 10.17712/nsj.2017.1.20160542.

Iron-sulfur assembly defects which include 5 disorders: Friedreich ataxia due to FXN gene defect, combined oxidative phosphorylation deficiency 19 due to LYRM4 gene defect, infantile complex II/III deficiency (IMC23D) due to NFS1 gene defect, hereditary myopathy with lactic acidosis due to ISCU gene defect and mitochondrial muscle myopathy due to Ferredoxin 1-Like protein (FDX1L) gene defect.
In conclusion, the combined clinical and advanced molecular diagnostic efforts will likely identify more disorders linked to the mitochondrial ISC biogenesis pathway, and potentially discover new genes in association with such diseases. Continued studies will help further elucidate mitochondrial iron homeostasis regulation, as understanding of mitochondrial iron overload could potentially yield better therapeutic approaches for such defects.

Tuesday, January 17, 2017

Team Led By The Ohio State University Researchers Publish Method in JoVE Video Journal to Standardize Protocol for Testing Mitchondrial Function

Cambridge, MA (PRWEB) January 16, 2017; Today, researchers at The Ohio State University in collaboration with scientists at the University of Pennsylvania and the National Institute of Aging published a reproducible method to noninvasively measure in vivo human skeletal muscle mitochondrial function in JoVE Video Journal.
Aberrant mitochondrial impairment is a hallmark of a wide range of metabolic syndromes and genetic diseases, from common conditions such as aging and diabetes to rare disorders such as Friedreich's ataxia.

Monday, January 16, 2017

Health-related quality of life in patients with spinocerebellar ataxia

Health-related quality of life in patients with spinocerebellar ataxia, C.R. Sánchez-López, L. Perestelo-Pérez, A. Escobar, J. López-Bastida, P. Serrano-Aguilar, Neurología (English Edition), Available online 9 January 2017, ISSN 2173-5808, doi:10.1016/j.nrleng.2015.09.002.

Spinocerebellar ataxia (SCA) comprises a group of clinically and genetically heterogeneous diseases characterised by cerebellar degeneration, including up to 17 types of SCA with an autosomal dominant inheritance pattern and 5 type sof SCA with autosomal recessive inheritance. Overall SCA prevalence in Spain is 20.2 cases per 100 000 population.The prevalence of the autosomal dominant types of SCA is 1.2 cases per 100 000; prevalence of Friedreich ataxia,the most frequent autosomal recessive type of SCA, is 4.7 per 100 000 population.
In summary, decreased HRQoL in SCA seems to beexplained, at least partially, by loss of gait-related motorskills and the likely presence of depression and sleepdisorders. Early detection and effective treatment ofthese variables may contribute to improving HRQoL inpatients with SCA. Our findings suggests that making rehabilitation moreaccessible and intensive would delay and limit thephysical deterioration leading to disability and loss of independence for walking and performing daily living activ-ities. Psychotherapy, a supplementary treatment frequentlyrequested by patients with SCA, may also contribute toreducing the impact of the disease on non-motor function. Likewise, using self-administered HRQoL questionnaires inroutine clinical practice may provide useful additional information rarely obtained from conventional clinical assessment. Using SF-36 to measure HRQoL in patients with SCA in our setting would be useful not only for evaluating theresults of studies and clinical trials, but also for assessingthe real needs of these patients and their carers, which will result in better healthcare planning and allocation of resources.

Sunday, January 15, 2017

Establishment and Maintenance of Primary Fibroblast Repositories for Rare Diseases—Friedreich's Ataxia Example

Li Yanjie, Polak Urszula, Clark Amanda D., Bhalla Angela D., Chen Yu-Yun, Li Jixue, Farmer Jennifer, Seyer Lauren, Lynch David, Butler Jill S., and Napierala Marek. Biopreservation and Biobanking. August 2016, 14(4): 324-329. doi:10.1089/bio.2015.0117.

Although classified as a neurodegenerative disease, Friedreich’s ataxia presents with a plethora of clinical symptoms, including ataxia, sensory abnormalities, heart dysfunction, diabetes, and auditory and visual loss.The variable number of GAA repeats among FRDA patients contributes to the clinical variability of the disease. Clinicians and scientists studying orphan diseases face the specific challenge of limited access to biospecimens due to the small number of patients suffering from the particular condition. Creating biorepositories of well-characterized patient samples and cell lines available for academic as well as commercial institutions is critical for developing successful therapeutic strategies to combat rare diseases.

Saturday, January 14, 2017

Friedreich's Ataxia and Variants

R. Bhidayasiri, Reference Module in Neuroscience and Biobehavioral Psychology, Elsevier, 2017, ISBN 9780128093245, doi:10.1016/B978-0-12-809324-5.00596-4.

Detailed genetic and family studies emphasize the potential heterogeneity in presenting phenotype as well as age of onset of patients with FRDA. The discovery of the frataxin gene has allowed genotype–phenotype correlations and confirmation that the FRDA expansion is responsible for classical FRDA, late-onset FRDA (LOFA), Friedreich's ataxia with retained reflexes (FARR), and Acadian ataxia.
Therapeutic approaches aimed at improving mitochondrial functioning and to increase frataxin expression, which may have lead to new realistic treatments in the future.

Friday, January 13, 2017

Friedreich Ataxia: Hypoplasia of Spinal Cord and Dorsal Root Ganglia

Arnulf H. Koeppen MD, Alyssa B. Becker BA, Jiang Qian MD, PhD, Paul J. Feustel PhD. Journal of Neuropathology & Experimental Neurology, DOI:10.1093/jnen/nlw111, First published online: 12 January 2017

The FA patients included a wide range of disease onset and duration suggesting that the SC undergoes growth arrest early and remains abnormally small throughout life. The results strongly support the conclusion that these neural tissues are small because of hypoplasia rather than atrophy and that their developmental delay occurs independently.
It is of interest that Friedreich had already proposed in 1877 that smallness of the clavae (gracile and cuneate nuclei) was developmental.