Fabry disease and multiple sclerosis misdiagnosis: the role of family history and neurological signs.
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ABSTRACT:
SUBMITTER: Colomba P
PROVIDER: S-EPMC5814255 | biostudies-other | 2018 Jan
REPOSITORIES: biostudies-other
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Project description:ObjectiveTo describe the clinical characteristics of encounters with patients misdiagnosed with multiple sclerosis (MS).MethodsA cross-sectional Internet-based physician survey of MS specialists was performed.ResultsThe response rate for the survey was 50.4%. Of those who responded, the majority (95%) reported having evaluated 1 or more patients who had been diagnosed with MS, but who they strongly felt did not have MS, within the last year. The majority of respondents (>90%) also reported the use of disease-modifying therapy in a proportion of these patients. Most respondents (94%) found clinical encounters with these patients equally or more challenging than giving a new diagnosis of MS. Fourteen percent of respondents reported that they did not always inform such patients of their opinion that they did not have MS.ConclusionsThe misdiagnosis of MS is common and has significant consequences for patient care and health care system costs. Caring for a patient with a misdiagnosis of MS is challenging, and at times honest disclosure of a misdiagnosis represents an important ethical concern for neurologists. More data are needed on this patient population to improve diagnostic acumen and the care of these patients.
| S-EPMC3369504 | biostudies-literature
Project description:Ocular signs in Fabry disease have generally been regarded to be primarily of diagnostic value. We explored whether ocular findings, alone or in particular in combination with the ?-galactosidase A gene mutation, have predictive value for disease severity. Data from the Fabry Outcome Survey (FOS), a large, global database sponsored by Shire, were selected for adult patients who had undergone ophthalmological examination. Three ocular signs were assessed: cornea verticillata, tortuous conjunctival and/or retinal vessels, and cataract. Fabry disease severity was measured using FOS Mainz Severity Score Index and modifications thereof. Ophthalmological data were available for 1203 (699 female, 504 male) adult patients with eye findings characteristic of Fabry disease in 55.1%. Cornea verticillata had a similar distribution in women (51.1%) and men (50.8%), whereas tortuous vessels and Fabry cataract were somewhat more frequent in men than in women. Patients with cornea verticillata, selected as the principal ocular sign for this study, had more severe disease (median score, 20.0) versus those without ocular signs (11.0; P<0.001). This finding could be confirmed by applying age adjusted severity scores. Moreover, the prevalence of cornea verticillata was significantly higher in patients with null (male, 76.9%; female, 64.5%) and missense (male, 79.2%; female, 67.4%) mutations versus mild missense (male, 17.1%; female, 23.1%) and the p.N215S (male, 15.0%; female, 15.6%) mutations (P<0.01). Our analyses show a correlation between the prevalence of ocular changes in Fabry disease and disease severity. Consequently, information on ocular findings and ?-galactosidase A gene mutation may help assess the risk for more severe Fabry disease. These observed findings are of notable clinical importance, as Fabry disease is characterized by high clinical course variability and only weak genotype-phenotype correlation at the individual patient level. Further confirmatory studies are needed.
| S-EPMC4363518 | biostudies-literature
Project description:Introduction: Cerebral autosomal dominant arteriopathy and subcortical infarct leukoencephalopathy (CADASIL) is the most common form of hereditary stroke caused by a mutation in the NOTCH3 gene located on the short arm of chromosome 19. A small number of published reports describe CADASIL patients who were initially diagnosed as multiple sclerosis. Although it was previously indicated that there was no association between NOTCH3 mutations and multiple sclerosis, the involvement of autoimmune mechanisms among patients with CADASIL has been hypothesized. Case Presentation: Case 1 is a middle-aged woman with initial diagnoses of multiple sclerosis (MS) and myelitis that continued to progress despite treatment with disease-modifying agents. She had occasional migraines, transient blurred vision, and multiple lacunar infarcts. She continued treatment for about 15 years with no significant alleviation and progressive changes on brain MRI; genetic testing was ordered which showed NOTCH3 mutation, and diagnosis was changed to CADASIL with subsequent revision of treatment course. However, the presence of myelitis in this patient is unusual and may raise the question of a concurrent autoimmune process. Case 2 is a woman presenting with vertigo and paresthesia and diagnosed with MS based on an initial brain MRI showing biventricular white matter hyperintensities; however, she was not started on any disease-modifying agents. Her symptoms were reevaluated by a neurologist, and genetic testing was performed for NOTCH 3. Case 3 is a young woman with a history of migraines who initially presented with numbness and gait ataxia which later progressed to speech difficulty and memory loss. A diagnosis of MS was established which was later changed to CADASIL. Conclusion: Since CADASIL is a rare disease, it is imperative to raise awareness of its unique clinical condition as well as variation in its clinical presentations. It is crucial that the overlapping symptoms between MS and CADASIL be thoroughly examined to avoid misdiagnosis and treatment complications. The involvement of autoimmune mechanisms in CADASIL and the role of NOTCH3 gene mutations in provoking an autoimmune process should be further investigated.
| S-EPMC7500095 | biostudies-literature
Project description:Fabry disease is a rare X linked lysosomal storage disorder resulting from deficiency of alpha-galactosidase A activity. Although the severity of clinical features in male patients is well described, only recently have studies reported the high prevalence of disabling clinical features in heterozygous females.This study sets out to examine the clinical features and natural history of Fabry disease in further detail in a large group of female patients.Data were obtained from 303 females enrolled in the Fabry Outcome Survey. Pain was assessed using the Brief Pain Inventory, and health related quality of life (HRQoL) was assessed using the European Quality of Life Questionnaire. A modified version of the Mainz Severity Score Index was also applied. Data on left ventricular mass (LVM) index, mean ventricular wall thickness, and glomerular filtration rate (GFR) were used to assess cardiac and renal involvement.The most commonly reported clinical features in females were neurological (77%) and cardiac (59%). A history of renal involvement was recorded in 40% of cases. Neurological features were the earliest to develop (mean age: 16 years), whereas cardiac (mean age: 33.5 years) and renal (mean age: 37.3 years) features developed later. LVM index increased exponentially with age. In addition, age was negatively correlated with estimated GFR and HRQoL.Females with Fabry disease report important age related clinical features and clinical investigation demonstrates evidence of disease progression. This study highlights the importance of careful and longitudinal assessment of female heterozygote patients with Fabry disease.
| S-EPMC2563231 | biostudies-literature
Project description:BackgroundIt is well known that axonal degeneration plays a role in disability in patients with multiple sclerosis, and synaptopathy has recently become an important issue.AimsTo investigate the possible roles of selected synaptic and presynaptic membrane protein genetic polymorphisms (VAMP2, SNAP-25, synaptotagmin, and syntaxin 1A) in patients with multiple sclerosis.Study designCase-control study.MethodsA total of 123 patients with multiple sclerosis and 192 healthy controls were included. The functional polymorphisms of specific SNARE complex proteins (VAMP2, synaptotagmin XI, syntaxin 1A, and SNAP-25) were analyzed by polymerase chain reaction.ResultsSignificant differences were detected in the genotype and allele distribution of 26-bp Ins/Del polymorphisms of VAMP2 between patients with multiple sclerosis and control subjects; Del/Del genotype and Del allele of VAMP2 were more frequent in patients with multiple sclerosis (p=0.011 and p=0.004, respectively). Similarly, Ddel polymorphism of SNAP-25 gene C/C genotype (p=0.059), syntaxin 1A T/C and C/C genotypes (p=0.005), and synaptotagmin XI gene C allele (p=0.001) were observed more frequently in patients with multiple sclerosis. CC, syntaxin rs1569061 1A gene for 33-bp promoter region TC haplotypes, and synaptotagmin XI gene were found to be associated with an increased risk for multiple sclerosis (p=0.012). Similarly, GC haplotype for rs3746544 of SNAP-25 gene and rs1051312 of SNAP-25 gene were associated with an increased risk for multiple sclerosis (p=0.022).ConclusionGenetic polymorphisms of SNARE complex proteins, which have critical roles in synaptic structure and communication, may play a role in the development of multiple sclerosis.
| S-EPMC6528533 | biostudies-literature
Project description:The discovery of disease biomarkers, along with the use of "liquid biopsies" as a minimally invasive source of biomarkers, continues to be of great interest. In inflammatory diseases of the central nervous system (CNS), cerebrospinal fluid (CSF) is the most obvious biofluid source. Extracellular vesicles (EVs) are also present in CSF and are thought to be potential "biomarker treasure chests". However, isolating these CSF-derived EVs remains challenging. This small-scale pilot study developed and tested a protocol to enrich for CSF-EVs, both in relapsing remitting multiple sclerosis (RRMS) CSF and controls. These were subsequently compared, using an aptamer based proteomics array, SOMAscan™. EVs were enriched from RRMS patient (n = 4) and non-demyelinating control (idiopathic intracranial hypertension (IIH) (n = 3)) CSF using precipitation and mini size-exclusion chromatography (SEC). EV-enriched fractions were selected using pre-defined EV characteristics, including increased levels of tetraspanins. EVs and paired CSF were analysed by SOMAscan™, providing relative abundance data for 1128 proteins. CSF-EVs were characterised, revealing exosome-like features: rich in tetraspanins CD9 and CD81, size ~100 nm, and exosome-like morphology by TEM. Sufficient quantities of, SOMAscan™ compatible, EV material was obtained from 5 ml CSF for proteomics analysis. Overall, 348 and 580 proteins were identified in CSF-EVs and CSF, respectively, of which 50 were found to be significantly (t-test) and exclusively enriched in RRMS CSF-EVs. Selected proteins, Plasma kallikrein and Apolipoprotein-E4, were further validated by western blot and appeared increased in CSF-EVs compared to CSF. Functional enrichment analysis of the 50 enriched proteins revealed strong associations with biological processes relating to MS pathology and also extracellular regions, consistent with EV enrichment. This pilot study demonstrates practicality for EV enrichment in CSF derived from patients with MS and controls, allowing detailed analysis of protein profiles that may offer opportunities to identify novel biomarkers and therapeutic approaches in CNS inflammatory diseases.
| S-EPMC5614217 | biostudies-literature
Project description:BackgroundSeveral studies have shown that when patients with functional neurological disorders are followed up, it is rare to find another neurological condition that better explains the initial symptoms in hindsight. No study has examined the reverse, studying patients with a range of neurological disease diagnoses with the aim of assessing how often a new diagnosis of functional disorder better explains the original symptoms.MethodsA prospective multi-centre cohort study of 2637 new neurology outpatient referrals from primary care in Scotland. Neurologists provided initial diagnoses and a rating of the extent to which their symptoms were explained by an 'organic' neurological disease. Patients were followed up 19 months later with a questionnaire to their primary care physician asking about diagnostic change, and when indicated also by discussion with the original assessing neurologist and review of secondary care records.ResultsValid responses were obtained for 2378 out of 2637 patients (90%) with symptoms 'largely' or 'completely' explained by organic disease at baseline. At follow-up, we found diagnostic errors in 48 patients. Of those, ten (0.4%) had a functional diagnosis and 38 patients (1.6%) had a different 'organic' diagnosis which better explained the original symptoms.ConclusionsPatients diagnosed with neurological disease sometimes have a functional diagnosis at follow-up which, with hindsight, better explains the original symptoms. This occurs at a frequency similar to the misdiagnosis of 'organic' neurological disease as functional disorder. Misdiagnosis can harm patients in either direction, especially as we enter an era of evidence-based treatment for functional neurological disorders.
| S-EPMC6647145 | biostudies-literature
Project description: Not available
| S-EPMC9527605 | biostudies-literature
Project description:Background: Women of child bearing age with multiple sclerosis (MS) must carefully consider treatments when planning a family, since disease modifying drugs (DMDs) are contraindicated during pregnancy. Objectives: This questionnaire-based study aimed to improve understanding of the effect of family planning on treatment decisions in female, Swiss MS patients. Methods: Female patients with MS (aged 18-55 years) participated in the 26-question survey between September 2014 and August 2015. Information captured included patient background, family planning status, treatment course, and previous pregnancies. Results: In total, 271 questionnaires distributed from 15 MS centres were returned for analysis. Of these, 250 (92.3%) participants received DMD therapy and 106 (39.1%) wanted children or were pregnant. Significantly more patients with a short-term plan to conceive within 2 years were treated with injectables (19/54) compared with those without a plan to conceive (19/108; p = 0.013). A proportionally greater number of women not planning to conceive took oral (34/108) or infusion therapies (41/108) compared with those with a short- (13/54 and 16/54, respectively) or medium-term (after 2 years or more; infusion therapy only, 14/44) plan to conceive. Conclusion: The study highlights that pregnancy remains an important yet unresolved concern in the treatment of MS patients. Nearly all women received DMD treatment, and type of DMD treatment was influenced by family planning, with significantly more women with a short-term plan to conceive using injectables.
| S-EPMC6191482 | biostudies-literature
Project description:Neurological diseases, such as MS, AD, PD and HD, are a major health concern of the elderly population, but still therapeutic options are limited. Recent advances in genomic sequencing and bioinformatics, present an opportunity to understand mechanisms of these diseases for identification of therapeutic targets. Several studies have shown association of immune dysfunction with immune system mediated neurological disease, MS, as well as neurodegenerative diseases (AD, PD and HD). However, similarities and differences in role of the immune system, immune pathways and immune cell types in these diseases remains unknown. In this study, immune cell type signature genes in gene networks associated with neurological diseases, MS, AD, PD and HD was investigated using meta-analysis and bioinformatics methods. Application of Weighted Gene Co-expression Network Analysis (WGCNA) on publicly available gene expression datasets (microarray and RNA-seq) revealed a ModArray_04 module (microarray) or ModRNAseq_06 module (RNA-seq), significantly associated with MS, AD, PD and HD. Hypergeometric enrichment test revealed significant enrichment of immune cell type genes in these neurological disease modules. This study demonstrates that immune system mediated neurological disease, MS and neurodegenerative diseases (AD, PD and HD), share a common gene network characterized by immune cell type signature genes (microglia, monocytes and macrophages) and are probable targets for therapeutic intervention. In summary, this work shows a connection between MS, a disease where the role of the immune system and inflammation is established, and neurodegenerative diseases (AD, PD and HD) where the role of inflammation is still a hypothesis.
| S-EPMC8649734 | biostudies-literature