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There have been a number of articles recently in the scientific journals about this issue. We are beginning to be very attentive to this, so that rigorous preclinical studies should be done for the new therapeutics and can prevent prioritization from occurring among studies. Although that is true, we do not have the ideal animal model for Friedreich ataxia. The animal models reproduce some parts of the disease to varying degrees, and they can be used to test certain treatments. The right model needs to be used to test a certain treatment.

For example, the condition of knockout animals may not show sign of oxidative stress so antioxidants cannot be tested on these animals. Treatments to regulate frataxin in the presence of the expansion cannot be done since it is complicated, but the ability to test these treatments is evolving. Better animal models and studies conducted correctly with these animal models is still a major need in the field studying Friedreich ataxia. How will histone deacetylase inhibitors be administered to patients? Is there documented improvement in the function of the cerebellum in those mice, and how would it be measured?

To answer the first question, RepliGen Corporation has developed an oral dosing formulation as a pill and is in full preclinical studies in canines. Brain penetration does occur after oral dosing. These drugs have been tested on 2 animal models. One is the knock-in model. They have a very discrete phenotype, which is biochemical. These drugs correct the biochemical phenotype.

For instance in gene expression profiles, frataxin deficiency is mostly corrected in the brain, including the cerebellum. The other animal model is a knock-out mouse model that develops some mild but identifiable abnormalities, but within 6 months on these drugs, there was improvement in a number of parameters. Dr Perlman, do you have any specific recommendations on how to shorten the trials? Is there a survival advantage for Friedreich ataxia heterozygotes as there is with diseases such as cystic fibrosis?

Is there information about why Friedreich ataxia is prevalent?

Carriers of one defective Friedreich ataxia gene show some changes in expression of other genes as seen on microarrays. Some of those genes are anti-aging genes. One of my patients, after reading this literature, suggested the possibility of families with known carriers may consist of family members with fewer diseases of aging or longer life expectancies. An epidemiologic study would take thousands of patients to show anything significant, and recruitment would be difficult. To make clinical trials more efficient and cost-effective, distinguishing between effective drugs from ineffective drugs could be done if biomarkers are correlated with the disease pathophysiology.

With nerve stress and nerve damage, a minimum of 6 months is required to observe any change to the brain, which can limit the duration of clinical trials. What is the value of frataxin as a biomarker for a surrogate endpoint to be able to get early readouts on your gene-modifying therapies? Frataxin is a biomarker. The frataxin level is a valuable biomarker and will be used in a number of trials.

If a drug increases frataxin level such as histone deacetylase inhibitors or erythropoietin, then changes in frataxin will be the first biomarker used. For other drugs that act on downstream mechanisms, we can check that they do not further decrease levels of frataxin. Development of a drug for Friedreich ataxia requires a target. The level of frataxin can be affected through transcription or by slowing frataxin breakdown.

A drug can target a downstream function such as iron accumulation, reactive oxygen species production, or mitochondrial function. Organ function can be another viable target. Every clinical research study needs to be measureable. It is important to note the location of the measurements and if the measurements are relevant to the biological or clinical question. Western blots and mRNA levels can measure the level of frataxin. Data of reactive oxygen species in blood or urine is inconclusive. Measurements of neurological function and cardiac function need to be relevant to the question being studied.

Understanding measures is important for ensuring that biological functions are measured in clinical trials. Every person, particularly a patient with Friedreich ataxia, has variability from day-to-day; thus, measurements need to be reproducible. Dr Lynch described the measures in clinical trials. Phase 1 trials are safety trials. Phase 2A trials are proving the principle being tested, such as histone deacetylase inhibitors increasing the level of frataxin in tissue. Phase 2B trials prove the concept; for example, analysis of insulin-resistant markers might change over the course of therapy, which alone may not be clinically relevant.

Phase 3 trials is the registration phase, where measurements are reproducible, accurate, and clinically relevant to patients. When the first idebenone trial was proposed in , no prior measures existed to validate the trial. A natural history study was required, which followed patients over time to track whether those measurements correctly exhibited disease progression.

The participating centers follow a cohort of about individuals and have been able to propose and validate different types of measures. The long-term natural history study consists of some patients participating in their eighth year. When an individual enrolls in the study, initial measures are validated, but it is important to conduct a long-term follow-up and perform the next measures. Information about the patient is acquired such as demographics, genetics, and medical history. Performance measures are timed or quantifiable tests that measure a specific domain of neurologic function.

For example, the 9-Hole Peg Test requires patients to place pegs in a pegboard under timed conditions to measure upper limb function. The Timed Foot Walk measures the ability of walking. The PATA test measures speech, whereas the low-contrast letter acuity tests visual function. Information for various biomarkers is also collected. Clinical exam-based measures are conducted in the clinic setting and may seem less relevant to daily life than other types of measures.

Performance measure simulate skills found in daily activities and are under timed conditions. For drug-approval registration to the U. Food and Drug Administration, clinical exam-based measures and performance measures are allowed, but biomarkers are rarely accepted as registration endpoints. Even when biomarkers are from biologically relevant tissue, vast amounts of correlative data are required.

CLINICAL ISSUES

The goal of the natural history study is to obtain year longitudinal data that match the cross-sectional data. Three types of measurements are being conducted worldwide, which are quantified versions the neurological exam. Subramony developed the Friedreich Ataxia Rating Scale. Scale for the Assessment and Rating of Ataxia is frequently used in Europe. The advantages of these 3 types of measurements are validity and familiarity. The rating scales are valid through testing large populations across the world, patients were tracked over time, and changes were proportional.

Regulatory agencies are familiar with these rating scales. The disadvantages of these rating scales are reproducibility and sensitivity. The factors of interrater reproducibility and variability with patients from day-to-day affect the measurements. With the scales, patients may change on an average of 3 points per year, so in turn, longer trials should be piloted to reach a level that pharmaceutical companies denote as an acceptable level of change divided by changes in standard deviation. In that case, a trial would include 50 to patients per arm and last for 2 years. The scales, although not sensitive, are acceptable for registration.

In contrast, performance measures are different from rating scales, since performance measures focus on one domain of neurologic function. A statistical sum of the performance measures results in a functional composite, which was originally developed for multiple sclerosis studies. Each number is specific so it is highly sensitive in many situations, and the data are easy to collect. However, most regulatory agencies are not familiar with the types of performance measures, and performance measures are less helpful when used individually.

Evidence has shown that performance measures reflect real-world function. Physical therapists consider pegboards as the best objective test for arm function. Delatycki has shown that Timed Foot Walk best reflects home-based measures of ambulation. Specific loss of visual abilities correlates with visual quality of life. For drug approval through the Food and Drug Administration, a clinical trial can be designed around a type of measurement that was discussed or a different approach of focusing on a subdomain. For example, in the area of neurologic stabilization or improvement, the goal for a trial could be improving vision in patients with Friedreich ataxia and the target is measured by the low-contrast letter acuity test.

Improvements of cardiac health, which include decrease in mortality, decreased progression of congestive heart failure, and decreases in arrhythmias, could be possible goals if predictability can be measured. In principle, exercise tolerance could be an approvable outcome if patients with varying progressions of Friedreich ataxia are capable of completing a specifically designed single task. Biological tests can measure nerve cell loss, which is mainly for phase 2 trials; for example, ocular coherence tomography looks at the retina.

Patient-driven outcomes are important neurological measures in Friedreich ataxia. Subjective questionnaires gather information from patients but are age-dependent. The Friedreich Ataxia Impact Scale compiles questions related to the disease through a psychometric design, but is long and not validated against the Friedreich Ataxia Rating Scale or performance measures. In the long-term natural history study, the focus is currently on whether mitochondrial enzymes change, but the data are inconsistent so far. Reactive oxygen species production is not easily detected.

RNA profiling can establish new biochemical markers. Muscle spectroscopy shows abnormal adenosine triphosphate production in patients with Friedreich ataxia, but a protocol needs to be designed that is suitable for a phase 3 trial. Validation of measures means that phase 3 trials are implemented, but there is a lack of biomarker identification in clinical trials. The type of measure used is based on the experiment, the subgroup of patients, the biological agent, and the target age. Diabetes mellitus is a lifelong disease marked by high levels of sugar in the blood, which can be caused by the lack of insulin, insulin resistance, or both.

Other classifications of diabetes fall under the categories of gestational diabetes, maturity onset diabetes of youth, and diabetes secondary to other conditions, due to genetic syndromes, and due to pancreatic disease. The pathogenesis of type 1 diabetes is a chronic autoimmune inflammation of the islet cells.

The disease has a genetic predisposition with possible unknown environmental triggers. Cellular infiltration of lymphocytes and macrophages occurs with autoantibodies to islet cell antigens. The onset of other autoimmune disease typically occurs with type 1 diabetes. In contrast, the pathogenesis of type 2 diabetes is more complex than type 1 diabetes. A number of metabolic processes are affected, which can lead to hyperglycemia. Insulin production is decreased in the pancreas, which correlates with the decrease of glucose uptake in muscle and liver.

The progression of type 2 diabetes begins with insulin resistance, where there is suboptimal insulin-stimulated glucose uptake by tissue. The disease progresses to an impaired glucose tolerance or pre-diabetic state where compensatory hyperinsulinemia with normoglycemia develops into hyperglycemia.

Childhood Ataxia: Clinical Features, Pathogenesis, Key Unanswered Questions, and Future Directions

Type 2 diabetes is characterized by impaired insulin action combined with impaired insulin secretion with subsequent hyperglycemia. In comparison, type 1 diabetes is an absolute insulin deficiency whereas type 2 diabetes is insulin resistance with relative insulin deficiency. The development of type 1 diabetes occurs quickly and typically in young people. Type 2 diabetes onset is associated with increasing age and obesity. The pathogenesis of Friedreich ataxia results in mitochondrial disease due to the variable number of GAA repeats, which affects the function of various tissues.

The tissues that are most relevant to diabetes would be the pancreas as well as the skeletal muscles. Impairment of either of these pathways attributes to mitochondrial dysfunction. Several studies have examined the pathophysiology of diabetes. A study back in demonstrated a compensatory increase in insulin production as a response to insulin resistance. In another study, insulin resistance was documented with an abnormal drop in the level of glucose measured by an insulin tolerance test, although this was replaced by other techniques.

Several tests are conducted to evaluate the risk of diabetes developing in individuals. Many population-based studies use the fasting glucose and insulin value. The homeostatic model assessment model estimates insulin production and insulin function. A more updated model, called the quantitative insulin sensitivity check index model, is appropriate for population-based studies. The intravenous glucose tolerance test is used in clinical research to calculate the insulin sensitivity index and acute insulin response to glucose, and the disposition index is calculated from these 2 values.

Measurements of glucose and insulin are tracked over time. The response of insulin that is produced by the patient is referred to as the first phase of insulin release and is the response to the rapid rise of glucose. With the decline in glucose, an injection of insulin is augmented at approximately 20 minutes.

The data are used in clinical research to assess the ability of a person to produce insulin in the acute insulin response to glucose, which addresses the adequacy of insulin secretion.

The insulin sensitivity index quantifies the capacity of insulin to promote glucose disposal. The disposition index is the product of the acute insulin response and the insulin sensitivity index. The acute insulin response and the insulin sensitivity index assume a hyperbolic relationship in humans such that insulin sensitivity decreases and the secretion by the pancreas increases. Studies have shown a heritability of greater than 50 percent in several populations and the disposition index can be a predictor of type 2 diabetes risk and onset.

As part of a clinical trial to evaluate the effect of an investigational agent in Friedreich ataxia, the glucose metabolism was assessed in 31 nondiabetic patients with Friedreich ataxia. The relation between various clinical and biochemical markers of the disease and insulin dynamics were examined.

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In graphing insulin sensitivity against acute insulin response to glucose, most patients with Friedreich ataxia had decreased disposition indices falling in the 23rd percentile of the entire population, which is consistent with increased risk of diabetes. An association was found between younger age of onset and decreasing disposition index, which validates that severity of disease is reflected in the disposition index. When looking at minimum GAA repeats and disposition index, an inverse relationship was found such that the disposition index was higher in individuals with lower number of GAA repeats, a reflection of disease severity.

The preliminary results of the study suggest the disposition index is significantly decreased in the non-diabetic group of patients with Friedreich ataxia. In patients with Friedreich ataxia who were compared with a control group matched for age and body mass index. A commensurate increase in insulin production resulted in disposition indices that were not quite significantly different than the disposition indices in the control group.

In reference to the medication, the measures did not demonstrate a tangible change in the predisposition to the development of diabetes as measured by the disposition index. Cardiac disease in Friedreich ataxia is nearly universal by histopathology. The clinical severity varies; patients may experience a volume overload during surgery.

A comprehensive natural history has only recently been published, in The electrocardiogram in patients with Friedreich ataxia is usually abnormal so it does not provide specific information. The echocardiogram is not as predictive either. Cardiovascular magnetic resonance imaging detects phenotypic trait, such as hypertrophy. For example, changes can be detected efficiently through magnetic resonance imaging if the intervention is targeting left ventricular hypertrophy.

Left ventricular hypertrophy has normative values, whereas concentric remodeling due to thick muscle walls has filling volumes that are relatively small. New therapeutic approaches require identifications of new targets. Cardiovascular magnetic resonance imaging can detect microvascular disease in the heart through first-pass perfusion imaging. This procedure acquires serial cross-sections through the heart during administration of evasive dilators to test the microvascular reserve. These images are compared with images taken under resting conditions.

Qualitatively, the subendocardium with microvascular disease has absent profusion compared with the subendocardium at resting conditions. The data can be quantified to a graph of signal intensity versus time, which is called the myocardial perfusion reserve index. Cardiovascular magnetic resonance imaging has the ability to characterize myocardial fibrosis and tissue fibrosis through the fact that fibrotic myocytes and normal myocytes have measurable differences in T1 characteristics.

Fibrosis is substrate for diastolic dysfunction, which is true for a variety of cardiovascular diseases. This information is applicable to Friedreich ataxia if the primary mode of cardiac dysfunction is due to impaired filling or diastolic dysfunction. It is important to recognize that fibrosis is also a substrate for arrhythmia.

Dr Raman and colleagues conducted a prospective study at Ohio State University with a cohort of patients with Friedreich ataxia ranging from 18 to 57 years old with no antecedent cardiac disease. The minimum GAA repeat lengths ranged from 41 to Most of the patients had nonspecific electrocardiographic abnormality. None of the patients had diabetes, but they had metabolic abnormalities. All except 4 of the patients had at least one metabolic syndrome factor, and 8 had 3 or more. A strong correlation exists between relative wall thickness in concentric remodeling and the minimum GAA repeat length.

The impaired myocardial perfusion reserve index decreases with increasing number of metabolic syndrome factors. Myocardial fibrosis was present in more than half of the patients with Friedreich ataxia that was not present in the control group. She showed functional images and late gadolinium-enhanced images.

In the concentric remodeling, the muscle was thick relative to the size of the ventricle, but no significant fibrosis. Images of advanced cardiomyopathy showed poor contractile function of the heart with white regions in the muscle as evidence of fibrosis. The most concerning part was the left ventricular thrombus that developed in the akinetic scarred region of the left ventricle. Relative negative findings were poorly correlated with overall left ventricular mass, which is the marker for left ventricular hypertrophy, and GAA repeat length. Cardiovascular disease occurs independently of the severity of neurological disease.

To correlate myocardial disease and Friedreich ataxia, metabolic pathways are affected. Changes in metabolism decrease capillary density, which contributes to impaired myocardial perfusion reserve. In a different pathway, a frataxin mutation leads to mitochondrial iron accumulation. Iron accumulation results in mitochondrial dysfunction, which decreases flow-mediated vasodilation and results in impaired myocardial perfusion reserve.

With chronic subendocardial ischemia, abnormal remodeling occurs. In review, decreased levels of frataxin lead to metabolic abnormalities or microvascular disease, which causes structural and functional changes in the heart and may result in arrhythmias, heart failure, and death. Although therapeutic designs specific to Friedreich ataxia and cardiovascular diseases are yet to be developed, therapeutic options are available to treat specific conditions.

Available therapeutic options for microvascular disease are calcium channel blockers, nitrates, and beta-blockers. Dr Payne had shown that a small ventricle with an impaired stroke volume might not respond well with beta-blockers because cardiac output is being maintained at an elevated heart rate. Therapeutic options for metabolic abnormalities are statins, fibrates, and treatments for glucose intolerance or diabetes mellitus.

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Statins could be used, although low-density lipoprotein levels were not significantly elevated in the studied cohort. Fibrates can target high triglycerides and low high-density lipoproteins. Agents such as metformin can treat glucose intolerance in patients. Agents for fibrosis or cardiac remodeling include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists.

Aldosterone antagonists have recently shown effectiveness in patients with Duchenne muscular dystrophy. Muscle physiology measurements showed that treatment significantly reduced the amount of fibrosis at 8 weeks of life; when treatment was started earlier, results showed minute detectible fibrosis. The results of cardiovascular magnetic resonance imaging on the mice with treatment and measurements of ejection fraction were normal.

Measurements of strain, which measure deformation at a regional level, were significantly improved when treatment was started prior to 8 weeks of life. By understanding the mechanisms of cardiomyopathy in Friedreich ataxia, more refined and targeted treatments will be developed. A novel approach involves metabolic modulators such as ranolazine, which is a sodium channel inhibitor. Ranolazine improves diastolic function, improves microvascular function, and reduces ischemia. The agent it is particularly appealing to study for cardiomyopathy in Friedreich ataxia because it has potential benefit at the myocardial energetic level.

In addition to randomized trials for these therapeutic agents, lifestyle changes such as diet and exercise can improve cardiovascular health in patients with Friedreich ataxia. These approaches have minimal potential risk and may yield significant benefit. In collaboration with the National Institute of Neurological Disorders and Stroke, guidelines have been developed for cardiac outcomes common data to minimize burden of data collection and maximize uniformity of data acquisition.

Typical data acquired in the clinic are from electrocardiograms, echocardiograms, and Holter monitor. Periodic testing should include fasting lipid profile and capillary blood glucose. Cardiovascular magnetic resonance imaging has increased in availability and this data will be informative. For example, testing on a patient with structural heart disease at stage B identifies concentric remodeling, impaired myocardial perfusion reserve, and fibrosis.

Development of targeted therapeutics can prevent disease progression. Nearly all children and adults with Friedreich ataxia have some degree of auditory neuropathy-type hearing loss. In this situation, patients have normal sound detection and normal peripheral function, meaning that their ears functionally work fine. The peripheral function can be measured in terms of pre-neural response coming from the cochlear microphonic and the otoacoustic emissions, which are sounds produced by a healthy cochlear.

Furthermore, because patients with Friedreich ataxia have normal sound detection, results from an audiogram are perfectly normal. In contrast, patients will have abnormal neurotransmission through the cochlear nerve and the auditory brain stem, producing abnormalities in the auditory brainstem response, which is a pattern of the electrical activity that occurs within the first 10 milliseconds after sensing an audible stimulus.

As an example, Dr Rance reviewed auditory brainstem responses from non-affected and affected subjects with Friedreich ataxia. Next, Dr Rance showed what an auditory brainstem response looks like for a patient that is in the early stages of the disease process. Rather than having the normal sequence of peaks and troughs along the wave form, these patients will have some of the same wave forms present, but the amplitudes will be much smaller, particularly in the late brain stem regions. Lastly, an auditory brainstem response for a patient later in the disease course is entirely absent.

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To this end, there is full potential at the start of the auditory brainstem response due to the cochlear microphonic, which means that the sound presented is loud enough to generate activity at the cochlear level so there should be something measurable within the brainstem region. However, this is not the case, indicating that something may be going wrong in terms of neural transmission since these are patients late in the course of disease. Dr Rance has 2 ideas as to what may be going on. First, he believes it could be due to the fact that there are too few neuronal elements available to produce a response that can be measured from the scalp, or it could be due to a desynchronization of the electrical activity as it passes up through the auditory brainstem, leading to disrupted timing of varying degrees.

Unfortunately, there are some consequences as a result of the absence of the auditory brainstem response. There is disrupted neural synchrony in the auditory pathway. Subsequently, this leads to a loss of timing cues in the neural representation of an auditory signal. This is particularly important in terms of a functional sense when looking at the neural representation of complex signals such as speech. Interestingly, the degree of auditory deficit does correlate with overall disease progression in Friedreich ataxia.

There are 3 aims to this study. The first aim is to measure speech perception ability in both quiet listening conditions and background noise conditions in a group of children who have Friedreich ataxia. The second aim is to look at binaural speech perception ability, focusing on the ability to combine signals that are presented to both ears at the same time. This study consists of 9 children ranging from 9 to 18 years of age with Friedreich ataxia as well as a group of control subjects who match the patients in terms of age, gender, and hearing level. Furthermore, all of the children had normal sound detection, so they could all hear sounds perfectly normally.

Results for the first aim came from a monaural speech perception test, which is a test that presents sounds or a series of words to one ear at a time. The results were analyzed from a graph comparing the consonant-nucleus-consonant phoneme score and the sound-to-noise ratio measured in decibels. The consonant-nucleus-consonant phoneme score measures the number of phonemes speech sounds that the child perceives and imitates correctly, whereas the sound-to-noise ratio measures the listening ability in environments ranging from completely quiet with no competing signals to environments in which the sound-to-noise ratio are the exact same.

In terms of the control group, subjects fell within the typical range for quiet environments and those environments where speech and background noise were at the same level. On the other hand, subjects with Friedreich ataxia scored on the lower end of the normal range in quiet environments and scored significantly lower than the normal range when sound and background noise were indistinguishable.

This finding shows that children with Friedreich ataxia truly have a problem in terms of hearing perception when they are trying to distinguish sounds from background noise. The Listening in Spatialized Noise Test is used to look at binaural speech perception. All of the testing is done using headphones in which the sound stimuli are modified to simulate a 3D listening environment. Furthermore, the parameter of this test is called the spatial difference, which is the effect of the simulated sound direction or the difference between a speaker located directly in front of the patient compared with one on the righthand side.

Interestingly, this timing difference is useful in normal listeners, as it allows them to compare the signal that is incident on the 2 sides and use the difference to extract what they are listening for from within the background noise. However, patients with Friedreich ataxia have an issue with binaural integration because there is neural dyssynchrony and they are not able to distinguish the sound from the background noise. To look at everyday listening and communication of these patients, the third aim, the Abbreviated Profile of Hearing Aid Benefit was used. This test looks at the degree to which the child experiences auditory difficulties in day-to-day life.

There are 4 aspects of auditory function that this test focuses on: Results for patients with Friedreich ataxia were much worse than controls. In summary, these findings show that Friedreich ataxia does cause functional deficits in hearing and communication in children. To sum up, Friedreich ataxia does affect the perception of complex signals, especially speech. Furthermore, this has a significant clinical impact on everyday listening and communication among these patients, especially because many are school-aged children in environments where they are unable to distinguish sounds from background noise.

In addition, it seems that the measurement of binaural integration may offer insights into central auditory pathway function and be a potential biomarker for drug trials. Dr Yoon addressed new dilemmas in diagnosing Friedreich ataxia focusing on presymptomatic genetic testing. Presymptomatic genetic testing can be defined as genetic testing of an at-risk individual who has no clinical symptoms of the disease. There is an increasing body of literature on the various ethical issues involved in presymptomatic genetic testing, and Dr Yoon discussed 4 important publications from various genetic societies and genetic bodies that summarize currently accepted recommendations regarding presymptomatic genetic testing.

Next, this publication gave a nice overview of how the role of parental authority has changed over the years. To this end, as late as the early s, children were considered property of their parents, specifically their father, and any decisions regarding the child was exclusively the right of the parent with no consideration for the child.

Obviously, this has changed over the years, but this publication points out that the ethical principles of justice, nonmaleficence, autonomy, and beneficence need to be considered when addressing issues of genetic testing. A second publication by the Canadian Pediatric Society and the Canadian College of Medical Genetics from issued a position statement on presymptomatic testing in healthy children. This publication reviewed the literature in regard to the problems associated with presymptomatic genetic testing in terms of psychosocial, ethical, and legal difficulties.

In addition, this publication commented on the problem of presymptomatic genetic testing in children who were being considered for adoption. Another publication discussed by Dr Yoon was from the Human Genetics Society of Australasia in , which laid out the foundation of the criteria that should be used when considering genetic testing for emancipated minors or adolescents that did not apply to the traditional models of genetic testing at the time.

Lastly, Dr Yoon commented on a publication from the European Society of Human Genetics that reviewed all of the literature of the ethical, legal, and psychosocial implications of genetic testing in asymptomatic minors, opinions of clinical geneticists, as well as other stakeholders. Since Friedreich ataxia is a disease without any definitive treatments, the guidelines for presymptomatic genetic testing are different than those used for a disease that can be treated. If iTunes doesn't open, click the iTunes application icon in your Dock or on your Windows desktop.

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