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Extra Quality Download Charcot Marie Tooth Disease Subtypes Pdf

There are many different types of Charcot-Marie-Tooth disease (CMT), which are classified according to the gene mutation that causes the disease. The main types (CMT1, CMT2, CMT3, CMT4 and CMTX) and the related subtypes are described in more detail below.

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To investigate the prevalence of fatigue, daytime sleepiness, reduced sleep quality, and restless legs syndrome (RLS) in a large cohort of patients with Charcot-Marie-Tooth disease (CMT) and their impact on health-related quality of life (HRQoL). Participants of a web-based survey answered the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, the Multidimensional Fatigue Inventory, and, if the diagnostic criteria of RLS were met, the International RLS Severity Scale. Diagnosis of RLS was affirmed in screen-positive patients by means of a standardized telephone interview. HRQoL was assessed by using the SF-36 questionnaire. Age- and sex-matched control subjects were recruited from waiting relatives of surgical outpatients. 227 adult self-reported CMT patients answered the above questionnaires, 42.9% were male, and 57.1% were female. Age ranged from 18 to 78 years. Compared to controls (n = 234), CMT patients reported significantly higher fatigue, a higher extent and prevalence of daytime sleepiness and worse sleep quality. Prevalence of RLS was 18.1% in CMT patients and 5.6% in controls (p = 0.001). RLS severity was correlated with worse sleep quality and reduced HRQoL. Women with CMT were affected more often and more severely by RLS than male patients. With regard to fatigue, sleep quality, daytime sleepiness, RLS prevalence, RLS severity, and HRQoL, we did not find significant differences between genetically distinct subtypes of CMT. HRQoL is reduced in CMT patients which may be due to fatigue, sleep-related symptoms, and RLS in particular. Since causative treatment for CMT is not available, sleep-related symptoms should be recognized and treated in order to improve quality of life.

It is a limitation of our study that objective clinical data on neurological impairment were not available. This fact is inherent to the survey approach we chose, and it makes it impossible to support the assumption that sleep-related symptoms are correlated with disease severity in CMT, as we showed before in a small group of CMT1A patients with OSA [10]. For this purpose, standardized scoring tools such as the CMT neuropathy scale should be applied in future studies [40]. For the benefit of a large study population, we put up with the fact that the genetic diagnosis of participants could not be verified. The unexpected small number of individuals with CMTX indicates that self-reported data on genetic diagnoses have to be interpreted carefully, making it difficult to ascertain differences between CMT subgroups. However, the percentage of participants who reported having CMT1 or CMT2 appears to be in accordance with the estimated prevalence of the most common CMT subtypes [1]. Keeping these aspects in mind, it is the quintessence of our survey that HRQoL is markedly reduced in CMT patients, which is in keeping with previous reports [41, 42]. This may be due to excessive daytime sleepiness, substantial fatigue, poor sleep, and the presence of RLS in particular. Since causative treatment for CMT is not available, therapy should not be restricted to physiotherapy, walking aids and proper foot care. Patients should be asked for sleep-related symptoms and fatigue in order to identify treatable conditions. Apnea screening is appropriate in patients with at least moderate disability, and PSG should initially be performed if severe RLS, PLMS or nocturnal hypoventilation are suspected.

There are several ways that phosphorylation could cause aggregation. First, it could alter ionic interactions among the subunits to create aberrant intermediates that are prone to aggregation or drive assembly over disassembly [66, 67]. Second, hyper-phosphorylation could alter the association of NF subunits with molecular motors and disrupt their transport, leading to their aggregation; NF mutants that mimic permanent phosphorylation states display lower rates of transport, and premature phosphorylation sequesters NF subunits within the cell soma [68, 69]. Third, phosphorylation could protect NFs from proteolytic cleavage, which could enhance their biochemical stability and trigger aggregation through the imbalance in the tight stoichiometry among the different subunits that is required for correct filament formation [70, 71]. There is evidence to support this stoichiometric model too (Table 2): transgenic mice overexpressing wild type NF subtypes can mimic strategic mutant versions that impair NF assembly in their ability to develop abnormal neurofilamentous axonal swellings and progressive neuropathy that are highly reminiscent of those found in ALS [72, 76, 84]. Moreover, these data supported a causal role for NF aggregates in causing neurodegeneration [90]. In the absence of disease-causing mutations, however, these experiments did not prompt inquiry into possible roles of NFs in the pathophysiology of bona fide neurodegenerative diseases.

Overexpressing wild type gigaxonin rapidly clears NF aggregates and rescues mitochondrial motility and metabolic defects. Since E3 ligase adaptors have multiple substrates, which also appears to be the case with gigaxonin [119, 120], it is still not entirely clear the extent to which NF aggregates contribute to pathology. Some aspects of the disease could well stem from derangements in other cellular processes. This would explain why GAN pathology is more severe and affects more neuronal subtypes that those affected in the CMT disorders. Even with this shortcoming in our knowledge, gigaxonin promises to become a tool to study NF degradation and clearance. The therapeutic potential of gigaxonin is also being tested in clinical trials where viral vectors are being used to deliver gigaxonin to the nervous system of GAN patients [121].

For decades, the role of NF accumulation in many neurological disorders has been neglected. But with the discovery of Mendelian diseases affecting NF proteins or those involved in their metabolism, we are beginning to gain novel insights into the role of NFs in disease. But GAN is not the only disease caused by mutations in factors directly involved in NF metabolism. There are a few other recently discovered disorders that feature NF aggregation and promise to shed light on NF quality control mechanisms (Table 3). These include diseases such as giant axonal neuropathy 2 (GAN2), a disease also characterized by enlarged neurons, but in which the pathology is due to loss of function mutations in another E3 ligase adaptor named DDB1 and CUL4 associated factor 8 (DCAF8), which interacts with Cullin4 (instead of Cullin3) [95]. Others are due to pathological mutations in molecular chaperones that help nascent NFs acquire a correct tertiary structure: this is the case with CMT2F and CMT2L, two CMT subtypes due to dominant mutations in the heat shock protein (HSP)-encoding genes HSPB1 and HSPB8, respectively [97, 98]. There is also myofibrillar myopathy 6 (MFM6), a severe neuromuscular disorder caused by mutations in BCL2 associated athanogene 3 (BAG3), a gene encoding a factor that regulates the HSP70 protein family [99].

These five subtypes should neither be taken as exclusive nor absolute since overlap of these patterns is not uncommon. For instance, some patients with a hereditary neuropathy (i.e., ATTRv amyloidosis) present with a rapidly progressive disease course, and are often misdiagnosed as CIDP. On the other hand, also CIDP patients occasionally present with a slowly progressive disease course. 041b061a72

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