Abe et al [] reported a child with severe CMT and compound heterozygosity for complete deletion of PMP22 on one allele and deletion of PMP22 exon 5 on the other allele. Taioli et al [] have reported two sibs with early onset demyelinating CMT both heterozygous for a p. Heterozygosity for de novo autosomal dominant single-nucleotide variants in both PMP22 and MPZ and homozygosity for PMP22 pathogenic variants have been found in individuals with severe childhood-onset disease. Thirteen heterozygous missense variants in PMP22 are associated with this phenotype.
Three missense variants at codon 72 of PMP22 are associated with this phenotype , suggesting that codon 72 pathogenic variants lead to a severe phenotype [ Nelis et al a ]. Pathogenic variants in EGR2 may also cause the severe early-onset phenotype [ Boerkoel et al ]. Persons with pathogenic variants in two different neuropathy-causing genes may have a DSS phenotype [ Hodapp et al ]. Prevalence The overall prevalence of hereditary neuropathies is estimated at approximately Other phenotypes associated with mutation of PMP The very rare autosomal recessive neuropathy CMT4 is caused by homozygosity for single-nucleotide variants in PMP22 [ Parman et al , Numakura et al ].
In one family, sibs homozygous for a PMP22 single-nucleotide variant c. Differential Diagnosis Acquired causes of neuropathy and other inherited neuropathies need to be considered see CMT Overview. Five types are recognized to date: The phenotype is a classic, mild to moderately severe Charcot-Marie-Tooth hereditary neuropathy that often includes pes cavus foot deformity, depressed tendon reflexes, distal muscle weakness and atrophy, and sensory loss.
Soong et al [] reported heterozygous pathogenic variants in GNB4 in a family previously reported by Lee et al [] and a de novo case. NCV varied widely from slow to normal. Management Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 1 CMT1 , the following evaluations are recommended: Physical examination to determine extent of weakness and atrophy, pes cavus , gait stability, and sensory loss.
Treatment is symptomatic and may include the following: Exercise within the individual's capability; many remain physically active.
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Exercise is not detrimental to persons with CMT [ Piscosquito et al ]. Serial night casting to help increase ankle flexibility [ Rose et al ]. Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [ Carter et al ]. Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin. Interventions designed to improve leg cramps, tremor, agility, endurance, and ankle flexibility, thereby improving quality of life; see Burns et al [] study of children with CMT1A. Prevention of Secondary Complications Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.
Surveillance Individuals should be evaluated regularly by a team comprising physiatrists, neurologists, and physical and occupational therapists to determine neurologic status and functional disability. Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Genetic Counseling Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions.
Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include neurologic examination and molecular genetic testing. The risk to the sibs depends on the genetic status of the proband 's parents. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. If the pathogenic variant cannot be detected in leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism [ Fabrizi et al a ]. The risk to other family members depends on the status of the proband 's parents.
If a parent has the pathogenic variant , his or her family members are at risk. Related Genetic Counseling Issues Testing of at-risk asymptomatic adult relatives of individuals with CMT1 is possible after molecular genetic testing has identified the specific pathogenic variant in the family. Family planning The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling including discussion of potential risks to offspring and reproductive options to young adults who are affected or at risk. Charcot Marie Tooth disease. Charcot-Marie-Tooth Neuropathy Type 1: The molecular defect in CMT1A is a 1.
This duplication results from unequal crossing over of homologous chromosomes at regions of repetitive elements that flank the duplicated region. Variant designation that does not conform to current naming conventions. Ethical and policy issues in genetic testing and screening of children. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions.
Fibulin-5 mutations link inherited neuropathies, age-related macular degeneration and hyperelastic skin. PMC ] [ PubMed: Pregnancy course and outcome in women with hereditary neuromuscular disorders: Genetic spectrum of hereditary neuropathies with onset in the first year of life. Recent advances in Charcot-Marie-Tooth disease.
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Effect of an R69C mutation in the myelin protein zero gene on myelination and ion channel subtypes. Clinical progression in Charcot-Marie-Tooth disease type 1A duplication: Two amino-acid substitutions in the myelin protein zero gene of a case of Charcot-Marie-Tooth disease associated with light-near dissociation. Late onset axonal Charcot-Marie-Tooth phenotype caused by a novel myelin protein zero mutation. J Neurol Neurosurg Psychiatry.
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Impotence associated with the Charcot-Marie-Tooth syndrome. Sleep disorders in Charcot-Marie-Tooth disease type 1. Charcot-Marie-Tooth disease and related neuropathies: Minimally invasive early operative treatment of progressive foot and ankle deformity associated with Charcot-Marie-Tooth disease. J Foot Ankle Surg. Clinical and in silico evidence for and against pathogenicity of 11 new mutations in the MPZ gene. Meeting of the Peripheral Nerve Society. Determinants of reduced health-related quality of life in pediatric inherited neuropathies.
Rehabilitation management in neuromuscular disease. Neuropathic pain in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil. Charcot-Marie-Tooth disease type 1A: J Peripher Nerv Syst. Autosomal dominant optic atrophy with asymptomatic peripheral neuropathy.
Introduction
Central nervous system abnormalities in patients with PMP22 gene mutations: Axonal phenotype of Charcot-Marie-Tooth disease associated with a mutation in the myelin protein zero gene. Clinical spectrum and gender differences in a large cohort of Charcot-Marie-Tooth type 1A patients.
Charcot-Marie-Tooth disease and related peripheral neuropathies. Charcot-Marie-Tooth disease and sleep apnoea syndrome: Hereditary motor and sensory neuropathy with spastic paraplegia and optic atrophy: Steroid responsive polyneuropathy in a family with a novel myelin protein zero mutation. Prednisone-responsive hereditary motor and sensory neuropathy.
Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton. Gene dosage sensitivity of a novel mutation in the intracellular domain of P0 associated with Charcot-Marie-Tooth disease type 1B. PMP22 related congenital hypomyelination neuropathy. Gait pattern classification in children with Charcot-Marie-Tooth disease type 1A. Novel C59T leader peptide mutation in the MPZ gene associated with late-onset, axonal, sensorimotor polyneuropathy. Soluble neuregulin-1 modulates disease pathogenesis in rodent models of Charcot-Marie-Tooth disease 1A.
Gene dosage effects in hereditary peripheral neuropathy. Expression of peripheral myelin protein 22 in Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies nerve biopsies. Charcot-Marie-Tooth disease type 1A duplication: Charcot-Marie-Tooth disease type 1A with 17p duplication in infancy and early childhood: Sensory manifestations in Charcot-Marie-Tooth disease.
Distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a Pmp22 point mutation. Coexistent hereditary and inflammatory neuropathy. Grandis M, Shy ME.
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Curr Treat Options Neurol. Different cellular and molecular mechanisms for early and late-onset myelin protein zero mutations. The pathogenesis and surgical management of foot deformity in Charcot-Marie-Tooth disease. Double trouble in hereditary neuropathy: Pregnancies and deliveries in patients with Charcot-Marie-Tooth disease.
Houlden H, Reilly MM. Molecular genetics of autosomal-dominant demyelinating Charcot-Marie-Tooth disease. Charcot-Marie-Tooth caused by a copy number variation in myelin protein zero. Eur J Med Genet. Dejerine-Sottas syndrome and vestibular loss due to a point mutation in the PMP22 gene. Quality-of-life in Charcot-Marie-Tooth disease: Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy.
Four novel mutations of the myelin protein zero gene presenting as a mild and late-onset polyneuropathy. Genetic testing in inherited peripheral neuropathies. Application of whole exome sequencing in undiagnosed inherited polyneuropathies. How to assess the pathogenicity of mutations in Charcot-Marie-Tooth disease and other diseases? Early onset Charcot-Marie-Tooth type 1B disease caused by a novel Leufs mutation in the myelin protein zero gene.
Eur J Paediatr Neurol. Charcot-Marie-Tooth disease with sensorineural hearing loss--an autosomal dominant trait. Birth Defects Orig Artic Ser. Anticipation in a unique family with Charcot-Marie-Tooth syndrome and deafness: Am J Med Genet. Am J Hum Genet. Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A.
Preimplantation genetic diagnosis for Charcot-Marie-Tooth disease. Clin Exp Reprod Med. Clinical characterization and genetic analysis of a possible novel type of dominant Charcot-Marie-Tooth disease. Myelin protein zero gene mutations in Taiwanese patients with Charcot-Marie-Tooth disease type 1. High-dosage ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A: Connexin 31 GJB3 is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment. Nerve ultrasound in patients with CMT1C: Description of three cases. Clinical features and molecular modelling of novel MPZ mutations in demyelinating and axonal neuropathies.
Eur J Hum Genet. Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene. Peripheral myelin protein 22 gene duplication with atypical presentations: McGann R, Gurd A. The association between Charcot-Marie-Tooth disease and developmental dysplasia of the hip. Early onset neuropathy in a compound form of Charcot-Marie-Tooth disease. Antiprogesterone therapy uncouples axonal loss from demyelination in a transgenic rat model of CMT1A neuropathy. Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies.
Molecular genetics and biology of inherited peripheral neuropathies: Nicholson G, Myers S. Intermediate forms of Charcot-Marie-Tooth neuropathy: Hemizygous mutation of the peripheral myelin protein 22 gene associated with Charcot-Marie-Tooth disease type 1.
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Despite streamlined, appropriate implementation of spirometry, differential diagnosis in COPD is challenging. In particular, differentiation between asthma and COPD can be difficult for clinicians due to substantial overlap in disease presentation and symptoms. Indeed the possibility of both disorders coexisting is likely more common than expected and can influence management strategies. Due to the aforementioned challenges of diagnosis, various analyses report diagnosis primarily in later stages of the disease.
Patients who fall into these later stages of COPD before diagnosis classically exhibit less response to treatment modalities. In addition, while pulmonary function decline is slower in earlier stages of COPD, it becomes more rapid in more advanced disease. As well as enhancing the frequency and efficiency of spirometry screening, population screening tools have emerged as options to facilitate earlier diagnosis of COPD.
These tools attempt to simplify identification of COPD in the general population by providing a straightforward means for individuals to discuss their respiratory symptoms with a clinician. The self-scored COPD population screener questionnaire COPD-PS is one such tool that attempts to encompass a broad group of individuals for screening regardless of smoking history, previous diagnosis, or other clinical information.
A key future component of effective COPD disease management includes an appropriate assessment of disease severity through symptom evaluation to guide therapy. Although spirometry is essential for diagnosis, its role seems to be less well defined in regard to ongoing disease state management. While some sources still promote spirometry use in bronchodilator reversibility testing, this test is no longer recommended due to lack of efficacy as a tool to predict treatment response.
These tools present a format for assessing the impact of COPD on quality of life indicators to help guide clinicians to properly select appropriate, guideline-recommended treatment strategies. A recent randomized controlled study indicates that the CAT is a disease-specific instrument that significantly improves the assessment of COPD severity of illness.
Pulmonary imaging has become an area of interest that may play a more significant role in COPD assessment and care in the future. Quantitative pulmonary imaging can provide greater insight into lung structure and function in comparison with spirometry which can only assess disease severity. Significant weaknesses of these imaging studies include the need for both CT and MRI studies for appropriate lung assessment, availability, and cost. Smoking is the single most influential factor in the natural history of COPD.
It must be the first step in modifying the clinical course of COPD and reducing the rate of decline in lung function. Although the most important strategy, smoking cessation may prove especially challenging in these patients, and should be approached utilizing both behavioral and pharmacological therapy when appropriate. Although controversial due to low quality evidence, long-term oxygen therapy has been shown to decrease mortality in patients with severe resting hypoxemia.
Despite the need for additional studies to illustrate the benefits of long-term oxygen therapy, ethical constraints of withholding oxygen therapy will likely be a limiting factor in future prospective studies. The anti-inflammatory and immunomodulatory effects of macrolide antibiotics as described in the literature, 43 along with increased rates of early clinical response with their use, have increased their use in patients with acute infectious COPD exacerbations.
Modest improvements in time to acute exacerbations, frequency of exacerbations, quality of life, 45 and also number of moderate to severe exacerbations 46 have all been reported with the use of macrolide prophylaxis in patients with COPD. As described previously, any reduction in acute exacerbations has the potential to translate into significant economic savings. However, it is important to note that none of these studies have indicated a mortality benefit, and significant adverse effects and collateral damage from year-long use of macrolide therapy should be seriously considered.
Recently, the US Food and Drug Administration issued a Drug Safety Communication on the widespread use of azithromycin, and the risk of potentially fatal heart arrhythmias. Perhaps of even greater concern, the spread of antibiotic resistant isolates poses a threat to both macrolides and various other antimicrobials that exhibit similar mechanisms of action, and are thus affected by similar resistance gene mutations.
The primary goal of chronic COPD management is stabilization of chronic disease and prevention of exacerbations. Exacerbations not only incur significant morbidity and mortality, but also negatively impact the natural history of the disease causing a progression in disease severity. Treatment guidelines on selection and escalation of therapy are available. Some direction is given on the appropriate order of agent initiation, but much is left to clinical judgment.
Bronchodilators are the mainstay of COPD management. Other options include a combination of SABA and SAMA or a long-acting bronchodilator; however, data for the combination of short-acting agents are limited 49 , 50 and evidence for long-acting agents is focused on patients with more severe disease.
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Progression of symptoms, and possible decline in FEV 1 , warrant the use of long-acting bronchodilators over short-acting agents. Selecting either a long-acting beta 2 -agonist LABA or long-acting muscarinic antagonist LAMA should be based on patient response, preference, and affordability as limited data exist defining the best initial treatment. Some evidence suggests benefit of selecting tiotropium as the initial agent over a LABA, 53 — 56 but data are limited. Indacaterol is currently the only LABA available that is dosed once daily, compared with formoterol and salmeterol which are dosed twice daily.
Patients with severe symptoms that persist despite treatment with a single long-acting bronchodilator can be considered for combination bronchodilator therapy. Studies evaluating the combination of tiotropium and LABAs have shown improvement in lung function and dyspnea compared with either agent alone. These agents would offer an option to patients who need combination therapy to control their symptoms, without increasing the burden of additional devices and the need for more than once daily dosing.
Unfortunately, diminishing the number of delivery devices does not necessarily correlate to diminishing price, and therefore may not be the ideal option for all patients. Theophylline may be considered as an option if inhaled bronchodilator therapy is unavailable or unaffordable, but it is less effective and less well tolerated than inhaled bronchodilators.
For patients with frequent exacerbations with or without consistent symptoms, inhaled corticosteroids should be considered. Reduction in COPD exacerbations 54 — 57 , 59 — 61 , Despite less clear data in patients on ICS, roflumilast has been shown to be effective in reducing exacerbations in patients treated with long-acting bronchodilators.
With over 50 new medications in the pipeline for the treatment of COPD, optimal management will continue to evolve and grow more complex with balancing benefits of therapy with the limitations and needs of each patient. In addition to pharmacologic therapies, a few non-pharmacologic therapies may also be considered for the treatment of COPD. Pulmonary rehabilitation is recommended to reduce dyspnea, improve health-related quality of life, and reduce hospital days and other measures of health-care utilization.
Various surgical interventions are available for consideration in the management of medically refractory, advanced stage COPD. Lung volume reduction surgery involves an excision of emphysematous lung tissue to decrease lung volume and reduce hyperinflation. Lung transplantation is an additional alternative surgical option which can completely replace malfunctioning lung, but typically a waiting period is required, it is a more invasive surgical procedure, and transplantation carries serious risks such as organ rejection and the need for lifelong immunosuppressive therapy.
COPD is a complex, multifactorial, and progressive disease associated with significant morbidity and mortality in the USA. The rising economic burden of COPD correlates with increases in disease severity, and hospital admissions and readmissions account for a significant bulk of cost across all stages of COPD.
Early, appropriate behavioral and pharmacotherapy options to reduce COPD exacerbations are essential for slowing disease progression, increasing patient quality of life, and subsequently reducing the overall cost burden of this disease state. Despite the known clinical and economic devastation this disease causes, a great deal remains unknown about optimal therapy.
Specifically, more conclusive evidence is needed concerning ideal therapy selection and appropriate sequencing of therapy. Additionally, the role of screening tools in facilitating early diagnosis of COPD and the impact of early treatment on cost and patient outcomes need further delineation.
Fortunately, a renewed interest in identifying new drug targets and novel pharmacotherapy for the management of COPD is being observed. It is imperative that the role these new agents play in the management of this disease is clearly elucidated. The anticipated high cost of these new therapies will ultimately have to be balanced with their overall benefit in disease state management and the specific medical and financial needs of the individual patient. No financial support was received for this manuscript. The authors report no conflicts of interest in this work.
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Journal List Clinicoecon Outcomes Res v. Published online Jun Author information Copyright and License information Disclaimer. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. This article has been cited by other articles in PMC.