ABSTRACT
Background: Data from published studies about the effect of HFE polymorphisms on ALS risk, phenotype, and survival are still inconclusive. We aimed at evaluating whether the p.H63D polymorphism is a modifier of phenotype and survival in SOD1-mutated patients. Methods: We included 183 SOD1-mutated ALS patients. Mutations were classified as severe or mild according to the median survival of the study population. Patients were screened for the HFE p.H63D polymorphism. Survival was calculated using the Kaplan-Meier modeling, and differences were measured by the log-rank test. Multivariable analysis was performed with the Cox proportional hazards model (stepwise backward). Results: SOD1 severe mutation carriers show more frequent familial history for ALS and shorter survival compared to mild mutation carriers. Carriers and non-carriers of the p.H63D polymorphism did not differ in terms of sex ratio, frequency of positive familial history, age at onset, and bulbar/spinal ratio. In univariate and in Cox multivariable analysis using sex, age at onset, site of onset, family history, country of origin, and mutation severity as covariates, p.H63D carriers had a longer survival (p = 0.034 and p = 0.004). Conclusions: We found that SOD1-mutated ALS patients carrying the p.H63D HFE polymorphism have a longer survival compared to non-carriers, independently of sex, age and site of onset, family history, nation of origin, and severity of mutations, suggesting a possible role as disease progression modifier for the p.H63D HFE polymorphism in SOD1-ALS.
ABSTRACT
BACKGROUND: The objective of this study was to characterize the prototypical phenotype of patients with amyotrophic lateral sclerosis (ALS) associated with PFN1 mutations in profilin 1 (PFN1) and to determine clinical indications to test for mutations in this gene. MATERIAL AND METHODS: The phenotype of three relatives carrying the M114V PFN1 mutation are detailed here and are compared with those of patients with ALS linked to PFN1 previously reported in the literature. RESULTS: In this pedigree and in the literature, the main clinical findings which best describe familial ALS linked to PFN1 might be the following characteristics: pedigrees over five cases, age of onset around 50 years, site of onset systematically lower limbs and the absence of cognitive impairment. CONCLUSION: First, the infrequent incidence of patients with ALS linked to PFN1 mutation supports the pursuit of a precise characterization of the phenotype linked to PFN1 mutations. Then, the numerous similarities between the phenotype amongst patients linked to SOD1 and PFN1 mutations and between histological features amongst both mice models prompts a review of the current ALS classifications, taking into consideration both phenotype and genotype.
Subject(s)
Amyotrophic Lateral Sclerosis , Animals , Humans , Mice , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , Mutation/genetics , Profilins/genetics , Superoxide Dismutase-1/geneticsABSTRACT
Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS.
Subject(s)
Amyotrophic Lateral Sclerosis , Profilins , rab GTP-Binding Proteins , Amyotrophic Lateral Sclerosis/metabolism , Animals , Autophagy/genetics , Homeostasis , Humans , Mice , Mitochondria/metabolism , Mutation , Profilins/genetics , Profilins/metabolism , rab GTP-Binding Proteins/metabolismABSTRACT
BACKGROUND: The cause of the motor neuron (MN) death that drives terminal pathology in amyotrophic lateral sclerosis (ALS) remains unknown, and it is thought that the cellular environment of the MN may play a key role in MN survival. Several lines of evidence implicate vesicles in ALS, including that extracellular vesicles may carry toxic elements from astrocytes towards MNs, and that pathological proteins have been identified in circulating extracellular vesicles of sporadic ALS patients. Because MN degeneration at the neuromuscular junction is a feature of ALS, and muscle is a vesicle-secretory tissue, we hypothesized that muscle vesicles may be involved in ALS pathology. METHODS: Sporadic ALS patients were confirmed to be ALS according to El Escorial criteria and were genotyped to test for classic gene mutations associated with ALS, and physical function was assessed using the ALSFRS-R score. Muscle biopsies of either mildly affected deltoids of ALS patients (n = 27) or deltoids of aged-matched healthy subjects (n = 30) were used for extraction of muscle stem cells, to perform immunohistology, or for electron microscopy. Muscle stem cells were characterized by immunostaining, RT-qPCR, and transcriptomic analysis. Secreted muscle vesicles were characterized by proteomic analysis, Western blot, NanoSight, and electron microscopy. The effects of muscle vesicles isolated from the culture medium of ALS and healthy myotubes were tested on healthy human-derived iPSC MNs and on healthy human myotubes, with untreated cells used as controls. RESULTS: An accumulation of multivesicular bodies was observed in muscle biopsies of sporadic ALS patients by immunostaining and electron microscopy. Study of muscle biopsies and biopsy-derived denervation-naïve differentiated muscle stem cells (myotubes) revealed a consistent disease signature in ALS myotubes, including intracellular accumulation of exosome-like vesicles and disruption of RNA-processing. Compared with vesicles from healthy control myotubes, when administered to healthy MNs the vesicles of ALS myotubes induced shortened, less branched neurites, cell death, and disrupted localization of RNA and RNA-processing proteins. The RNA-processing protein FUS and a majority of its binding partners were present in ALS muscle vesicles, and toxicity was dependent on the expression level of FUS in recipient cells. Toxicity to recipient MNs was abolished by anti-CD63 immuno-blocking of vesicle uptake. CONCLUSIONS: ALS muscle vesicles are shown to be toxic to MNs, which establishes the skeletal muscle as a potential source of vesicle-mediated toxicity in ALS.
Subject(s)
Amyotrophic Lateral Sclerosis , Induced Pluripotent Stem Cells , Aged , Amyotrophic Lateral Sclerosis/genetics , Humans , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/pathology , Motor Neurons/metabolism , Muscle Cells/metabolism , ProteomicsABSTRACT
BACKGROUND: Interventional trials in amyotrophic lateral sclerosis (ALS) suffer from the heterogeneity of the disease as it considerably reduces statistical power. We asked if blood neurofilament light chains (NfL) could be used to anticipate disease progression and increase trial power. METHODS: In 125 patients with ALS from three independent prospective studies-one observational study and two interventional trials-we developed and externally validated a multivariate linear model for predicting disease progression, measured by the monthly decrease of the ALS Functional Rating Scale Revised (ALSFRS-R) score. We trained the prediction model in the observational study and tested the predictive value of the following parameters assessed at diagnosis: NfL levels, sex, age, site of onset, body mass index, disease duration, ALSFRS-R score, and monthly ALSFRS-R score decrease since disease onset. We then applied the resulting model in the other two study cohorts to assess the actual utility for interventional trials. We analyzed the impact on trial power in mixed-effects models and compared the performance of the NfL model with two currently used predictive approaches, which anticipate disease progression using the ALSFRS-R decrease during a three-month observational period (lead-in) or since disease onset (ΔFRS). RESULTS: Among the parameters provided, the NfL levels (P < 0.001) and the interaction with site of onset (P < 0.01) contributed significantly to the prediction, forming a robust NfL prediction model (R = 0.67). Model application in the trial cohorts confirmed its applicability and revealed superiority over lead-in and ΔFRS-based approaches. The NfL model improved statistical power by 61% and 22% (95% confidence intervals: 54%-66%, 7%-29%). CONCLUSION: The use of the NfL-based prediction model to compensate for clinical heterogeneity in ALS could significantly increase the trial power. NCT00868166, registered March 23, 2009; NCT02306590, registered December 2, 2014.
Subject(s)
Amyotrophic Lateral Sclerosis/blood , Amyotrophic Lateral Sclerosis/diagnosis , Disease Progression , Models, Neurological , Neurofilament Proteins/blood , Aged , Biomarkers/blood , Cohort Studies , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Prospective Studies , Reproducibility of ResultsABSTRACT
OBJECTIVE: Mutations in superoxide dismutase 1 gene (SOD1), encoding copper/zinc superoxide dismutase protein, are the second most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) motor neuron disease in populations of European descent. More than 200 missense variants are reported along the SOD1 protein. To limit the production of these aberrant and deleterious SOD1 species, antisense oligonucleotide approaches have recently emerged and showed promising effects in clinical trials. To offer the possibility to any patient with SOD1-ALS to benefit of such a gene therapy, it is necessary to ascertain whether any variant of unknown significance (VUS), detected for example in SOD1 non-coding sequences, is pathogenic. METHODS: We analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases. RESULTS: We identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358-10T>G nearsplice SOD1 variant was corroborated based on its high frequency (as the second most frequent SOD1 variant) in French fALS, the segregation analysis confirmed in eight affected members of a large pedigree, the typical SOD1-related phenotype observed (with lower limb onset and prominent lower motor neuron involvement), and findings on postmortem tissues showing SOD1 misaccumulation. CONCLUSIONS: Our results highlighted nearsplice/intronic mutations in SOD1 are responsible for a significant portion of French fALS and suggested the systematic analysis of the SOD1 mRNA sequence could become the method of choice for SOD1 screening, not to miss these specific cases.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Mutation , Pedigree , Superoxide Dismutase-1/genetics , Adult , Aged , Aged, 80 and over , DNA Mutational Analysis , Female , Genetic Testing , Genetic Therapy , Humans , Male , Middle Aged , PhenotypeABSTRACT
OBJECTIVES: To determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved. METHODS: We conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed. RESULTS: Regarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in C9orf72 was found in 98 cases as well as SOD1, TARBP or FUS mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in C9orf72 was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. SOD1 mutation involved all types of pedigrees. No TARDBP nor FUS mutation was present in monogenerational pedigrees. TARDBP mutation predominated in bigenerational pedigrees with at least three cases and FUS mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years. CONCLUSION: Our results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , C9orf72 Protein/genetics , Mutation , Aged , Cluster Analysis , DNA Mutational Analysis , DNA-Binding Proteins/genetics , Female , Genetic Testing , Genotype , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Pedigree , Phenotype , RNA-Binding Protein FUS/genetics , Superoxide Dismutase-1/geneticsABSTRACT
The objective of this study was to describe the care pathway of patients with amyotrophic lateral sclerosis (ALS) based on real-life textual data from a regional coordination network, the Ile-de-France ALS network. This coordination network provides care for 92% of patients diagnosed with ALS living in Ile-de-France. We developed a modular ontology (OntoPaRON) for the automatic processing of these unstructured textual data. OntoPaRON has different modules: the core, medical, socio-environmental, coordination, and consolidation modules. Our approach was unique in its creation of fully defined concepts at different levels of the modular ontology to address specific topics relating to healthcare trajectories. We also created a semantic annotation tool specific to the French language and the specificities of our corpus, the Ontology-Based Semantic Annotation Module (OnBaSAM), using the OntoPaRON ontology as a reference. We used these tools to annotate the records of 928 patients automatically. The semantic (qualitative) annotations of the concepts were transformed into quantitative data. By using these pipelines we were able to transform unstructured textual data into structured quantitative data. Based on data processing, semantic annotations, sociodemographic data for the patient and clinical variables, we found that the need and demand for human and technical assistance depend on the initial form of the disease, the motor state, and the patient age. The presence of exhaustion in care management, is related to the patient's motor and cognitive state.
Subject(s)
Amyotrophic Lateral Sclerosis/therapy , Delivery of Health Care , Natural Language Processing , France , Humans , LanguageABSTRACT
ANXA11 mutations have previously been discovered in amyotrophic lateral sclerosis (ALS) motor neuron disease. To confirm the contribution of ANXA11 mutations to ALS, a large exome data set obtained from 330 French patients, including 150 familial ALS index cases and 180 sporadic ALS cases, was analyzed, leading to the identification of 3 rare ANXA11 variants in 5 patients. The novel p.L254V variant was associated with early onset sporadic ALS. The novel p.D40Y mutation and the p.G38R variant concerned patients with predominant pyramidal tract involvement and cognitive decline. Neuropathologic findings in a p.G38R carrier associated the presence of ALS typical inclusions within the spinal cord, massive degeneration of the lateral tracts, and type A frontotemporal lobar degeneration. This mutant form of annexin A11 accumulated in various brain regions and in spinal cord motor neurons, although its stability was decreased in patients' lymphoblasts. Because most ANXA11 inclusions were not colocalized with transactive response DNA-binding protein 43 or p62 deposits, ANXA11 aggregation does not seem mandatory to trigger neurodegeneration with additional participants/partner proteins that could intervene.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Annexins/genetics , Genetic Association Studies , Mutation , Databases, Genetic , Datasets as Topic , Exome/genetics , Female , France , Frontotemporal Lobar Degeneration/genetics , Humans , MaleABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
To understand the home-based difficulties encountered in the health care pathways of patients with Amyotrophic Lateral Sclerosis (ALS), we must annotate a large amount of textual data, from a database created by the ALS Île de France coordination network. For this purpose, we have developed a modular ontology, consisting of four modules, and a semantic annotation tool integrating the created ontology. The specificity of our approach is the creation of equivalent classes at different levels of the ontology. These equivalent classes represent variables of interest allowing a statistical approach and a clinical analysis of comprehension of care pathways ruptures causing.
Subject(s)
Amyotrophic Lateral Sclerosis , Critical Pathways , Delivery of Health Care , Comprehension , France , Humans , SemanticsABSTRACT
Accurate patient stratification into prognostic categories and targeting Amyotrophic Lateral Sclerosis (ALS)-associated pathways may pave the way for promising trials. We evaluated blood-based prognostic indicators using an array of pathological markers. Plasma samples were collected as part of a large, phase III clinical trial (Mitotarget/TRO19622) at months 1, 6, 12 and 18. The ALSFRS-r score was used as a proxy of disease progression to assess the predictive value of candidate biological indicators. First, established clinical predictors were evaluated in all 512 patients. Subsequently, pathologic markers, such as proxies of neuronal integrity (Neurofilament light chain and phosphorylated heavy chain), DNA oxidation (8-oxo-2'-desoxyguanosine), lipid peroxidation (4-hydroxy-2-nonenal, isoprostane), inflammation (interleukin-6) and iron status (ferritin, hepcidin, transferrin) were assessed in a subset of 109 patients that represented the whole cohort. Markers of neuronal integrity, DNA and lipid oxidation, as well as iron status at baseline are accurate predictors of disability at 18-month follow-up. The composite scores of these markers in association with established clinical predictors enable the accurate forecasting of functional decline. The identified four biomarkers are all closely associated with 'ferroptosis', a recently discovered form of programmed cell death with promising therapeutic targets. The predictive potential of these pathophysiology-based indicators may offer superior patient stratification for future trials, individualised patient care and resource allocation.
Subject(s)
Amyotrophic Lateral Sclerosis/diagnosis , Biomarkers/blood , Neurons/pathology , 8-Hydroxy-2'-Deoxyguanosine/blood , Adult , Aldehydes/blood , Disease Progression , Female , Ferritins/blood , Ferroptosis , Follow-Up Studies , Humans , Iron/metabolism , Isoprostanes/blood , Lipid Peroxidation , Male , Middle Aged , Neurofilament Proteins/blood , Neurons/metabolism , Predictive Value of Tests , PrognosisABSTRACT
Spinal muscular atrophy (SMA) type III and IV are autosomal recessive, slowly progressive lower motor neuron syndromes. Nevertheless, wider cerebral involvement has been consistently reported in mouse models. The objective of this study is the characterisation of spinal and cerebral pathology in adult forms of SMA using multimodal quantitative imaging. METHODS: Twenty-five type III and IV adult SMA patients and 25 age-matched healthy controls were enrolled in a spinal cord and brain imaging study. Structural measures of grey and white matter involvement and diffusion parameters of white matter integrity were evaluated at each cervical spinal level. Whole-brain and region-of-interest analyses were also conducted in the brain to explore cortical thickness, grey matter density and tract-based white matter alterations. RESULTS: In the spinal cord, considerable grey matter atrophy was detected between C2-C6 vertebral levels. In the brain, increased grey matter density was detected in motor and extra-motor regions of SMA patients. No white matter pathology was identified neither at brain and spinal level. CONCLUSIONS: Adult forms of SMA are associated with selective grey matter degeneration in the spinal cord with preserved white matter integrity. The observed increased grey matter density in the motor cortex may represent adaptive reorganisation.
Subject(s)
Brain/pathology , Muscular Atrophy, Spinal/pathology , Spinal Cord/pathology , Spinal Muscular Atrophies of Childhood/pathology , Adolescent , Adult , Aged , Brain/diagnostic imaging , Diffusion Tensor Imaging , Female , Gray Matter/diagnostic imaging , Gray Matter/pathology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Muscular Atrophy, Spinal/diagnostic imaging , Spinal Cord/diagnostic imaging , Spinal Muscular Atrophies of Childhood/diagnostic imaging , White Matter/diagnostic imaging , White Matter/pathology , Young AdultABSTRACT
OBJECTIVE: Objective of this study is the comprehensive characterisation of motor unit (MU) loss in type III and IV Spinal Muscular Atrophy (SMA) using motor unit number index (MUNIX), and evaluation of compensatory mechanisms based on MU size indices (MUSIX). METHODS: Nineteen type III and IV SMA patients and 16 gender- and age-matched healthy controls were recruited. Neuromuscular performance was evaluated by muscle strength testing and functional scales. Compound motor action potential (CMAP), MUNIX and MUSIX were studied in the abductor pollicis brevis (APB), abductor digiti minimi (ADM), deltoid, tibialis anterior and trapezius muscles. A composite MUNIX score was also calculated. RESULTS: SMA patients exhibited significantly reduced MUNIX values (pâ¯<â¯0.05) in all muscles, while MUSIX was increased, suggesting active re-innervation. Significant correlations were identified between MUNIX/MUSIX and muscle strength. Similarly, composite MUNIX scores correlated with disability scores. Interestingly, in SMA patients MUNIX was much lower in the ADM than in the ABP, a pattern which is distinctly different from that observed in Amyotrophic Lateral Sclerosis. CONCLUSIONS: MUNIX is a sensitive measure of MU loss in adult forms of SMA and correlates with disability. SIGNIFICANCE: MUNIX evaluation is a promising candidate biomarker for longitudinal studies and pharmacological trials in adult SMA patients.
Subject(s)
Muscle, Skeletal/physiopathology , Recruitment, Neurophysiological , Spinal Muscular Atrophies of Childhood/pathology , Adult , Disability Evaluation , Female , Humans , Male , Middle Aged , Muscle Strength , Muscle, Skeletal/innervationABSTRACT
INTRODUCTION: Extrapyramidal deficits are poorly characterised in amyotrophic lateral sclerosis (ALS) despite their contribution to functional disability, increased fall risk and their quality-of-life implications. Given the concomitant pyramidal and cerebellar degeneration in ALS, the clinical assessment of extrapyramidal features is particularly challenging. OBJECTIVE: The comprehensive characterisation of postural instability in ALS using standardised clinical assessments, gait analyses and computational neuroimaging tools in a prospective study design. METHODS: Parameters of gait initiation in the anticipatory postural adjustment phase (APA) and execution phase (EP) were evaluated in ALS patients with and without postural instability and healthy controls. Clinical and gait analysis parameters were interpreted in the context of brain imaging findings. RESULTS: ALS patients with postural instability exhibit impaired gait initiation with an altered APA phase, poor dynamic postural control and significantly decreased braking index. Consistent with their clinical profile, "unsteady" ALS patients have reduced caudate and brain stem volumes compared to "steady" ALS patients. INTERPRETATION: Our findings highlight that the ALS functional rating scale (ALSFRS-r) does not account for extrapyramidal deficits, which are major contributors to gait impairment in a subset of ALS patients. Basal ganglia degeneration in ALS does not only contribute to cognitive and behavioural deficits, but also adds to the heterogeneity of motor disability.
Subject(s)
Amyotrophic Lateral Sclerosis/diagnostic imaging , Amyotrophic Lateral Sclerosis/physiopathology , Basal Ganglia/diagnostic imaging , Biomechanical Phenomena/physiology , Gait Disorders, Neurologic/physiopathology , Gray Matter/diagnostic imaging , Postural Balance/physiology , Aged , Amyotrophic Lateral Sclerosis/complications , Female , Gait Disorders, Neurologic/etiology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neuroimaging , Prospective StudiesABSTRACT
There is an urgent and unmet need for accurate biomarkers in Amyotrophic Lateral Sclerosis. A pharmaco-metabolomics study was conducted using plasma samples from the TRO19622 (olesoxime) trial to assess the link between early metabolomic profiles and clinical outcomes. Patients included in this trial were randomized into either Group O receiving olesoxime (n = 38) or Group P receiving placebo (n = 36). The metabolomic profile was assessed at time-point one (V1) and 12 months (V12) after the initiation of the treatment. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites (Biocrates® commercial kit). Multivariate analysis based on machine learning approaches (i.e. Biosigner algorithm) was performed. Metabolomic profiles at V1 and V12 and changes in metabolomic profiles between V1 and V12 accurately discriminated between Groups O and P (p<5×10-6), and identified glycine, kynurenine and citrulline/arginine as the best predictors of group membership. Changes in metabolomic profiles were closely linked to clinical progression, and correlated with glutamine levels in Group P and amino acids, lipids and spermidine levels in Group O. Multivariate models accurately predicted disease progression and highlighted the discriminant role of sphingomyelins (SM C22:3, SM C24:1, SM OH C22:2, SM C16:1). To predict SVC from SM C24:1 in group O and SVC from SM OH C22:2 and SM C16:1 in group P+O, we noted a median sensitivity between 67% and 100%, a specificity between 66.7 and 71.4%, a positive predictive value between 66 and 75% and a negative predictive value between 70% and 100% in the test sets. This proof-of-concept study demonstrates that the metabolomics has a role in evaluating the biological effect of an investigational drug and may be a candidate biomarker as a secondary outcome measure in clinical trials.
Subject(s)
Amyotrophic Lateral Sclerosis/diagnosis , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/metabolism , Biomarkers, Pharmacological/metabolism , Cholestenones/therapeutic use , Metabolomics/methods , Adult , Aged , Amyotrophic Lateral Sclerosis/pathology , Biomarkers, Pharmacological/analysis , Disease Progression , Double-Blind Method , Drug Resistance/drug effects , Female , Humans , Male , Metabolome/drug effects , Middle Aged , Placebos , PrognosisABSTRACT
This paper presents a modular ontology of health care in the context in Amyotrophic Lateral Sclerosis. 4 modules cover socio-environmental, medical, and care coordination aspects of the domain. They are organized by a core module. Its goal is to understand interruptions in health care provision in the context of a neurodegenerative disease.
Subject(s)
Amyotrophic Lateral Sclerosis/therapy , Communication , Disease Management , HumansABSTRACT
BACKGROUND: Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most frequent motor neuron disorders in adulthood and infancy, respectively. There is a growing literature supporting common pathophysiological patterns between those disorders. One important clinical issue for that is the co-occurrence of both diseases within a family. OBJECTIVES: To collect families in which ALS and SMA patients co-exist and describe the phenotype and the genotype of ALS patients. PATIENTS AND METHODS: Nine families with co-occurrence of SMA and ALS have been gathered over the last 15 years. Epidemiological, phenotype and genetic status were collected. RESULTS: Out of the nine families, six corresponded to the criteria of familial ALS (FALS). Clinical data were available for 11 patients out of the 15 ALS cases. Mean age of onset was 58.5 years, site of onset was lower limbs in nine cases (81.8%), median duration was 22 months. Four ALS patients carried a mutation: three mutations in SOD1 gene (G147N in two cases and one with E121G) and one repeat expansion in the C9ORF72 gene. Three patients had abnormal SMN1 copy numbers. CONCLUSIONS: While the high proportion of familial history of ALS cases in these ALS-SMA pedigrees could have suggested that these familial clusters of the two most frequent MND rely on a genetic background, we failed to exclude that this occurred by chance.
Subject(s)
Amyotrophic Lateral Sclerosis/complications , C9orf72 Protein/genetics , Family Health , Muscular Atrophy, Spinal/complications , Mutation/genetics , Superoxide Dismutase-1/genetics , Survival of Motor Neuron 1 Protein/genetics , Age of Onset , Aged , Amyotrophic Lateral Sclerosis/genetics , Female , Genotype , Humans , Male , Middle Aged , Muscular Atrophy, Spinal/genetics , PhenotypeABSTRACT
Mutations in UBQLN2 have been associated with rare cases of X-linked juvenile and adult forms of amyotrophic lateral sclerosis (ALS) and ALS linked to frontotemporal dementia (FTD). Here, we report 1 known (c.1489C>T, p.Pro497Ser, P497S) and 3 novel (c.1481C>T, p.Pro494Leu, P494L; c.1498C>T, p.Pro500Ser, P500S; and c.1516C>G, p.Pro506Ala, P506A) missense mutations in the PXX domain of UBQLN2 in familial motor neuron diseases including ALS and spastic paraplegia (SP). A novel missense mutation (c.1462G>A, p.Ala488Thr, A488T) adjacent to this hotspot UBQLN2 domain was identified in a sporadic case of ALS. These mutations are conserved in mammals, are absent from ExAC and gnomAD browsers, and are predicted to be deleterious by SIFT in silico analysis. Patient lymphoblasts carrying a UBQLN2 mutation showed absence of ubiquilin-2 accumulation, disrupted binding with HSP70, and impaired autophagic pathway. Our results confirm the role of PXX repeat in ALS pathogenesis, show that UBQLN2-linked disease can manifest like a SP phenotype, evidence a highly reduced disease penetrance in females carrying UBQLN2 mutations, which is important information for genetic counseling, and underline the pivotal role of ubiquilin-2 in proteolysis regulation pathways.