A decade in review – tracing the pathogenesis of movement disorder diseases Since 2005, there have been substantial advances in our understanding of the pathophysiology and natural history of movement disorder diseases, such as Parkinson’s disease and Huntington’s disease. However, disease-modifying treatments are really elusive, and therefore, the treatment of such disorders remains primarily symptomatic. Over the past few decades, an increasing number of movement disorder disorders have been recognized as a subspecialty, which has contributed to the development of clinical diagnosis and management of Parkinson’s disease (PD), Huntington’s disease (HD), dystonia, tics, and tremor. The establishment of multinational collaborative research organizations, such as the Parkinson’s Study Group and the Huntington Study Group, has further increased awareness of the diseases and facilitated the expansion of research. Despite a better understanding of the pathophysiology, etiology and evolution of these diseases, treatment options remain symptomatic. Immune factors contribute to paroxysmal and nonparoxysmal movement disorders Parkinson’s disease is one of the most common age-related neurodegenerative disorders with a prevalence of 1 in 100 in people over 55 years of age.Clinical diagnosis is still based on recognized motor symptoms and defined diagnostic and exclusion criteria [1]. It has been recognized over the last decade that the formation of Lewy vesicles within neurons and the deposition of α-synuclein predicted the onset of motor symptoms decades ago. Pathological changes can be found in the anterior olfactory nucleus, the glossopharyngeal nerve, the dorsal nucleus of vagal motor nerve and the gastrointestinal nerve in the pre-symptomatic phase of PD. This pathological alteration then extends to the lower brainstem nucleus and then to the substantia nigra. Thus, olfactory disturbances, anxiety, depression, REM sleep behavior disorder and constipation have been identified as prodromal symptoms of PD, and the presence of motor symptoms indicates entry into the middle stage of the disease (Braak stage) [2]. PRIAMO study [3] noted that NMS was present in more than 98% of PD patients and that the number and severity of symptoms increased with the duration of the disease. Autonomic dysfunction (constipation, urinary urgency, and postural hypotension), sleep disturbances, and pain need to be recognized promptly, as many of these symptoms are treatable. Approximately 50% of patients with PD present with apathy, fatigue, depression and/or anxiety [4]; most patients in advanced stages present with cognitive dysfunction and dementia. The development of validated motor symptoms and NMS grading scores has improved the monitoring of symptoms. However, there are still no reliable biomarkers that can accurately assess disease progression in PD. Although descriptions of PD date back 5000 years, the exact etiology remains unknown. Various environmental factors, including traumatic brain injury, pesticide exposure, coffee intake, and reduced smoking, are thought to be associated with an increased risk of developing PD. However, in the last decade, the role of genetic factors has become increasingly evident, even in sporadic cases [5]. More than 10 autosomal recessive and 5 autosomal dominant genetic mutations play a significant role in at least 10% of the family lines [5]. Whole-gene and genome-wide studies as well as well-designed family studies have led to a progressive increase in the number of genetic susceptibility loci identified. These findings have provided valuable insights to explore the pathogenesis of PD, including common molecular pathways involved in protein misfolding and aggregation; in addition to facilitating the establishment of new animal models [5]. Since 1978, various studies targeting neuroprotective or disease-modifying therapies have been conducted to slow disease progression in PD. one of the largest and most recent studies published in 2015 was the NET-PD study, a double-blind, placebo-controlled, NIH-funded trial of creatine therapy that enrolled 1,741 patients [6]. Like previous PD disease-modifying therapy trials, the NET-PD trial was unsuccessful, perhaps because the pathology of the study cohort had progressed to the point of no benefit. Interventions for individuals at risk for PD could lead to improved disease modifying treatment strategies in the future. New insights into pre-symptomatic and early symptomatic PD and HD HD is an autosomal dominant, slowly progressive neurodegenerative disorder characterized by chorea and psychiatric cognitive changes. Unlike PD, the disease has a clear etiology and is caused by an increase in the CAG trinucleotide repeat of the HTT gene on chromosome 4. The typical patient has a mid-life onset, but the age of onset can occur from early childhood to old age and is determined by the number of trinucleotide repeats, and the rate of disease progression is also determined by the number of repeats. As in PD, pathological changes appear in the pre-symptomatic period, and abnormal Huntington protein deposits in neurons have been found in the fetal brain. The aim of the multinational TRACK-HD study was to clarify the natural history of pre-symptomatic and early symptomatic HD, which was collected over 36 months, and the results were published in 2013 [7]. The identification of asymptomatic HTT carriers allows investigators to make long-term observations and thus objectively identify biomarkers of disease onset, progression, and development. dynamic images from the TRACK-HD study several years before the patient became symptomatic can show atrophy of the basal ganglia area, cortical and white matter, and loss of structural connections between the basal ganglia and gray matter. Disease-associated proteins identified in the cerebrospinal fluid can serve as markers of disease progression and facilitate the development of disease-modifying therapies. Developments in gene therapy include silencing of HTT mutant genes and mRNA activity, involving zinc finger proteins, antisense oligonucleotides and mRNA interference techniques, which have been shown to be effective in animal models, and disease modifying treatments may be successful in the near future [8]. Genotyping has improved disease typing and understanding of genetic and phenotypic heterogeneity relative to other hyperactivity disorders. For example, mutations in the SLC2A1 gene lead to GLUT1 deficiency syndrome, which can result in paroxysmal dyskinesia, classic developmental delay syndrome, and convulsions [9]. Trinucleotide repeats associated with spinal cerebellar ataxia type 2 can lead to ataxia, levodopa-responsive Parkinson’s syndrome or amyotrophic lateral sclerosis. Some recently identified autoimmune factors, such as anti-N-methyl-D aspartate receptor antibodies, can lead to paroxysmal [2] and non-paroxysmal movement disorders [10]. In conclusion, the diagnosis of movement disorders [3] has improved and expanded in the last decade with the identification of genetic and environmental factors and has led to the further development of new classifications, grading scales and biomarkers to assess disease progression [4]. In particular, new insights into the pre-symptomatic and early symptomatic stages of PD and HD [5] have facilitated the discovery of early intervention strategies for these disorders [6]. Animal models have led to a better understanding of the pathophysiology of movement disorders and have made it possible to develop new therapeutic approaches. We are optimistic that these advances will lead to better disease modifications and therapeutic outcomes in the near future [7].