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BACKGROUND AND PURPOSE: Late onset Pompe disease (LOPD) is a rare neuromuscular disorder caused by a deficit in acid alpha-glucosidase. Macroglossia and swallowing disorders have already been reported, but no study has focused yet on its frequency and functional impact on patients' daily life. METHODS: We reviewed 100 adult LOPD patients followed in 17 hospitals in France included in the French national Pompe disease registry. The Swallowing Quality of Life Questionnaire and the Sydney Swallow Questionnaire were completed by patients, and a specialist carried out a medical examination focused on swallowing and assigned a Salassa score to each patient. Respiratory and motor functions were also recorded. Subgroup analysis compared patients with and without swallowing difficulties based on Salassa score. RESULTS: Thirty-two percent of patients presented with swallowing difficulties, often mild but sometimes severe enough to require percutaneous endoscopic gastrostomy (1%). Daily dysphagia was reported for 20% of our patients and aspirations for 18%; 9.5% were unable to eat away from home. Macroglossia was described in 18% of our patients, and 11% had lingual atrophy. Only 15% of patients presenting with swallowing disorders were followed by a speech therapist. Swallowing difficulties were significantly associated with macroglossia (p = 0.015), longer duration of illness (p = 0.032), and a lower body mass index (p = 0.047). CONCLUSIONS: Swallowing difficulties in LOPD are common and have significant functional impact. Increased awareness by physicians of these symptoms with systematic examination of the tongue and questions about swallowing can lead to appropriate multidisciplinary care with a speech therapist and dietitian if needed.
ABSTRACT
INTRODUCTION: Late-onset Pompe disease (LOPD) is characterized by a progressive myopathy resulting from a deficiency of acid α-glucosidase enzyme activity. Enzyme replacement therapy has been shown to be effective, but long-term treatment results vary. Avalglucosidase alfa demonstrated non-inferiority to alglucosidase alfa in a phase 3 study, allowing in France compassionate access for advanced LOPD patients unresponsive to alglucosidase alfa. METHODS: Data from the French Pompe registry were analyzed for patients who benefited from a switch to avalglucosidase alfa with at least 1 year of follow-up. Respiratory (forced vital capacity [FVC]) and motor functions (Six-Minute Walk Test [6MWT]) were assessed before and 1 year after switching. Individual changes in FVC and 6MWT were expressed as slopes and statistical analyses were performed to compare values. RESULTS: Twenty-nine patients were included (mean age 56 years, 11 years of prior treatment). The FVC and 6MWT values remained stable. The individual analyses showed a stabilization of motor worsening: -1 m/year on the 6MWT after the switch versus -63 m/year the year before the switch (i.e., a worsening of 33%/year before vs. an improvement of 3%/year later). Respiratory data were not statistically different. DISCUSSION: At the group level, gait parameters improved slightly with a stabilization of previous worsening, but respiratory parameters showed limited changes. At the individual level, results were discordant, with some patients with a good motor or respiratory response and some with further worsening. CONCLUSION: Switching to avalglucosidase alfa demonstrated varied responses in advanced LOPD patients with failing alglucosidase alfa therapy, with a general improvement in motor stabilization.
Subject(s)
Enzyme Replacement Therapy , Glycogen Storage Disease Type II , alpha-Glucosidases , Humans , Glycogen Storage Disease Type II/drug therapy , Glycogen Storage Disease Type II/complications , Male , Middle Aged , Female , France , alpha-Glucosidases/therapeutic use , Enzyme Replacement Therapy/methods , Aged , Adult , Cohort Studies , Treatment Outcome , Registries , Disease Progression , Walk Test , Drug SubstitutionABSTRACT
BACKGROUND AND OBJECTIVES: The French Pompe disease registry was created in 2004 for study of the natural course of the disease in patients. It rapidly became a major tool for assessing the long-term efficacy of enzyme replacement therapy (ERT) after the market release of alglucosidase-alfa. METHODS: Approximately 10 years after publication of the baseline characteristics of the 126 initial patients of the French Late-Onset Pompe Disease registry, we provide here an update of the clinical and biological features of patients included in this registry. RESULTS: We describe 210 patients followed at 31 hospital-based French neuromuscular or metabolic centers. The median age at inclusion was 48.67 ± 14.91 years. The first symptom was progressive lower limb muscle weakness, either isolated (50%) or associated with respiratory symptoms (18%), at a median age of 38 ± 14.9 years. At inclusion, 64% of the patients were able to walk independently and 14% needed a wheelchair. Positive associations were found between motor function measure, manual motor test, and 6-minute walk test (6MWT) results, and these parameters were inversely associated with the time taken to sit up from a lying position at inclusion. Seventy-two patients had been followed for at least 10 years in the registry. Thirty-three patients remained untreated a median of 12 years after symptom onset. The standard ERT dose was administered for 177 patients. DISCUSSION: This update confirms previous findings for the adult population included in the French Pompe disease registry, but with a lower clinical severity at inclusion, suggesting that this rare disease is now diagnosed earlier; thanks to greater awareness among physicians. The 6MWT remains an important method for assessing motor performance and walking ability. The French Pompe disease registry provides an exhaustive, nationwide overview of Pompe disease and can be used to assess individual and global responses to future treatments.
Subject(s)
Glycogen Storage Disease Type II , Adult , Humans , Middle Aged , Young Adult , Glycogen Storage Disease Type II/drug therapy , Glycogen Storage Disease Type II/epidemiology , Glycogen Storage Disease Type II/diagnosis , alpha-Glucosidases/therapeutic use , Muscle Weakness/etiology , France/epidemiology , Registries , Walking , Enzyme Replacement Therapy/adverse effects , Enzyme Replacement Therapy/methodsABSTRACT
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
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
INTRODUCTION: IgG4 antibodies against neurofascin (Nfasc155 and Nfasc140/186), contactin (CNTN1) and contactin-associated protein (Caspr1) are described in specific subtypes of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Our objective was to assess, in a real-life practice, the incidence, the clinical features and the response to treatment of these forms of CIDP. METHODS: 1500 sera of patients suspected of having CIDP from France, Belgium and Switzerland were prospectively tested using a flow cytometry technique. The characteristics of patients with antibodies against the node of Ranvier were compared to 100 seronegative CIDP from our department. RESULTS: IgG4 antibodies against Nfasc155, CNTN1, and Caspr1 were, respectively, detected in 15 (prevalence 1%), 10 (0.7%) and 2 (0.2%) sera. Antibodies specific of the Nfasc140/186 were not detected. All subjects with antibodies against the node of Ranvier fulfilled diagnostic criteria for CIDP. CIDP with anti-Nfasc155 were younger, had more sensory ataxia and postural tremor than seronegative CIDP. CIDP with anti-CNTN1 had more frequent subacute onset and facial paralysis, commoner renal involvement with membranous glomerulonephritis and greater disability, than seronegative CIDP. CIDP with anti-Caspr1 had more frequent respiratory failure and cranial nerve involvement but not more neuropathic pain than seronegative CIDP. Intravenous immunoglobulins were ineffective in most seropositive patients. Rituximab produced dramatic improvement in disability and decreased antibodies titres in 13 seropositive patients (8 with anti-Nfasc155 and 5 with anti-CNTN1 antibodies). CONCLUSIONS: Although rare, anti-paranodal antibodies are clinically valuable, because they are associated with specific phenotypes and therapeutic response.
Subject(s)
Nerve Growth Factors , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating , Autoantibodies , Belgium , Cell Adhesion Molecules , France , Humans , Incidence , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/epidemiology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/therapy , Prospective Studies , Switzerland/epidemiologyABSTRACT
Cytoplasmic aggregation of TAR-DNA binding protein (TDP-43) in Amyotrophic Lateral Sclerosis (ALS) and fronto-temporal lobar dementia (FTLD) is associated with post-translational modifications (PTM) and delocalization. Studies on postmortem brains of ALS and FTLD patients showed the existence of TDP-43 fragments that end at position N291. We report a new heterozygous mutation p.N291H in a familial case of ALS. Expression of the mutant protein in cell lines and primary motor neurons induces aggregate formation in the cytoplasm and reduces cell viability. The discovery of mutations at cleavage sites in TDP-43 in patients, which we reviewed here, is valuable for understanding the true role of the various TDP-43 fragments identified in patients and thus, for developing effective targeted therapies for ALS and FTLD treatment.
Subject(s)
Amyotrophic Lateral Sclerosis , Amyotrophic Lateral Sclerosis/genetics , Brain/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Humans , Motor Neurons/metabolism , Mutation/geneticsABSTRACT
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, but its definitive diagnosis delays around 12 months. Although the research is highly active in the biomarker field, the absence of specific biomarkers for diagnosis contributes to this long delay. Another strategy of biomarker identification based on less specific but sensitive molecules may be of interest in clinical practice. For example, markers related to other neurodegenerative diseases such as Alzheimer's disease (AD) could be fully explored. Here, we compared baseline levels of amyloidß1-42 (Aß1-42), total Tau, and phosphorylated-Tau (phospho-Tau) protein in the cerebrospinal fluid (CSF) of ALS patients to controls and correlated it with clinical parameters of ALS progression collected over 12 months. We observed increased levels of Aß1-42 (controls: 992.9 ± 358.3 ng/L; ALS: 1277.0 ± 296.6 ng/L; p < 0.0001) and increased Aß1-42/phospho-Tau ratio and Innotest Amyloid Tau Index (IATI) (both p < 0.0001). IATI and the phospho-Tau/total Tau ratio correlated positively with ALSFRS-R and weight at baseline. Multivariate analysis revealed that baseline ALSFRS-R was associated with Aß1-42 and phospho-Tau/total Tau ratio (p = 0.0109 and p = 0.0013, respectively). Total Tau and phospho-Tau levels correlated negatively with ALSFRS-R variation at months 6 and 9, respectively (p = 0.02 and p = 0.04, respectively). Phospho-Tau/total Tau ratio correlated positively with ALSFRS-R variation at month 9 (p = 0.04). CSF levels of Aß1-42 could be used as a complementary tool to ALS diagnosis, and total Tau and phospho-Tau levels may help establishing the prognosis of ALS. Further studies merit exploring the pathophysiological mechanisms associated with these markers. Despite their lack of specificity, phospho-Tau/total Tau and Aß1-42 should be combined to other biological and clinical markers in order to improve ALS management.
Subject(s)
Amyloid beta-Peptides/cerebrospinal fluid , Amyotrophic Lateral Sclerosis/cerebrospinal fluid , Amyotrophic Lateral Sclerosis/diagnosis , Biomarkers , tau Proteins/cerebrospinal fluid , Aged , Aged, 80 and over , Case-Control Studies , Female , Humans , Male , Middle Aged , PrognosisABSTRACT
The availability of longitudinal clinical and biological data led us to wonder whether these parameters could be used to predict disturbances in body composition during ALS progression. Bioelectrical impedance analysis (BIA), as well as clinical and biological parameters (blood lipids and ferritin), were collected one year after diagnosis in ALS patients. The correlations were evaluated by the Spearman test. Performances to predict the evolution of BIA parameters during ALS evolution were evaluated by ROC analysis. Forty-two ALS patients were enrolled. Variations in FFM over one year were correlated to the variations in LDL-cholesterol (r = 0.53, p = 0.002) and ferritin (r = -0.58, p = 0.0002). To predict FFM loss, an increase in ferritin over 9 µg/L had a sensitivity of 90.0% and a specificity of 80.0% (p < 0.0001). Ferritine evolution would allow to easily follow the FFM without BIA during ALS. In addition, an adapted nutritional treatment based on this biological parameter might slow down ALS progression.
Subject(s)
Amyotrophic Lateral Sclerosis/blood , Amyotrophic Lateral Sclerosis/diagnosis , Body Composition/physiology , Cholesterol, LDL/blood , Electric Impedance , Ferritins/blood , Aged , Biomarkers/blood , Female , Follow-Up Studies , Humans , Longitudinal Studies , Male , Middle Aged , Retrospective StudiesABSTRACT
Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are two neurological disorders that seem, theoretically, completely divergent according to epidemiological, clinical, pathophysiological, and therapeutic data. However, some reports that have mentioned the occurrence of both conditions within the same patient underpin the suggestion that this co-occurrence might not be random. We report six co-occurrences of ALS and MS cases, focusing on epidemiological and clinical diseases findings. We then compare our cohort to those in the literature. Our cohort was composed of five females and one male. The age of onset for MS ranged from 27 to 54 years with either primary or secondary prominence while all being progressive. Both diseases occurred sequentially in all but one the cases. Concerning ALS, the age of onset ranged from 51 to 60 years and the site of onset was the legs in 5/6 cases. The disease lasted from four to 29 months. Although infrequent, this co-occurrence supports the hypothesis of common, pathophysiological mechanisms between ALS and MS. We discuss some arguments favoring a potential link between both conditions.
Subject(s)
Amyotrophic Lateral Sclerosis/complications , Amyotrophic Lateral Sclerosis/epidemiology , Multiple Sclerosis/complications , Multiple Sclerosis/epidemiology , Adult , Age of Onset , Amyotrophic Lateral Sclerosis/diagnostic imaging , Chi-Square Distribution , Databases, Bibliographic/statistics & numerical data , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis/diagnostic imagingABSTRACT
Although amyotrophic lateral sclerosis (ALS) typically occurs around 60 years, numerous publications report an onset of ALS before the age of 25 years that define juvenile ALS (jALS). Over the last decade, growing literature mentioned jALS with an aggressive evolution which are mainly linked to the FUS gene. We report here the case of a 25-year-old woman with a bulbar onset ALS that progressed in less than 12 months to invasive ventilation due to respiratory failure; Genetic screening identified a new mutation in the FUS gene that lies within the last codon. After reading the literature, it might be legitimate to consider that jALS linked to FUS mutations represent a specific entity different from both classical jALS and adult ALS linked to FUS gene. This should encourage clinician to firstly screen the FUS gene in the presence of a sporadic ALS that occurs before the age of 25 and with an aggressive profile of evolution.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , RNA-Binding Protein FUS/genetics , Adult , Amino Acid Sequence , Amyotrophic Lateral Sclerosis/pathology , Disease Progression , Female , Humans , Models, Molecular , Mutation/genetics , Neural Conduction , Respiratory Insufficiency/etiologyABSTRACT
Diagnosis of amyotrophic lateral. SCLEROSIS Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disorder in adult. In France, every day, 4 new cases are diagnosed. Although, ALS is currently considered easy to identify, in the presence of the combination of diffuse upper and lower motor neuron signs, the delay remains over 12 months for a disease with a median survival of 36 months. This finding strongly explains why clinicians feel uncomfortable for ascertaining the diagnosis especially during the early stages of the disease. Other explanations for such a delay might rely on the phenotypic heterogeneity of ALS and at least the absence of diagnostic marker that hampers the role of clinicians in their clinical practice.
Diagnostic de la sclérose latérale amyotrophique. La sclérose latérale amyotrophique est la plus fréquente des affections du motoneurone de l'adulte. Chaque jour, 4 nouveaux cas sont diagnostiqués en France. Si théoriquement le diagnostic est simple à porter devant une atteinte clinique du neurone moteur central et périphérique diffuse, le retard diagnostique est estimé à près de 12 mois pour une affection dont la médiane de survie est de 36 mois. Cet élément prouve la difficulté d'en faire le diagnostic notamment lors des stades précoces de la maladie. Le second élément expliquant ce retard est l'hétérogénéité clinique de la maladie. Enfin, l'absence de marqueur diagnostique complique aussi la tâche du clinicien.
Subject(s)
Amyotrophic Lateral Sclerosis , Adult , Amyotrophic Lateral Sclerosis/diagnosis , France , HumansABSTRACT
AIMS: Vitamin D deficiency has been associated with poorer prognosis in ALS. Better understanding of the role of vitamin D in ALS is needed to determine whether trials of systematic supplementation are justified. Our aim was to report vitamin D levels during the course of ALS and to evaluate its relationship with clinical parameters at diagnosis and with disease progression. METHODS: We prospectively collected vitamin D serum concentrations from 125 consecutive ALS patients. Cox proportional hazard models analyzed the relationship between vitamin D concentrations, clinical parameters, and survival. RESULTS: The mean vitamin D concentration was below our laboratory's lower limit of normal (P < 0.0001) and did not change during the course of the disease. The concentrations were higher in patients with bulbar onset (P = 0.003) and were negatively associated with body mass index (BMI) (P = 0.0095). Models with ALSFRS-R (ALS Functional Rating Scale-Revised) and BMI as a covariates showed that vitamin D concentrations predicted worse prognosis. CONCLUSION: The distribution of vitamin D concentrations in our cohort was consistent with previous reports. Surprisingly, we noted a negative effect of higher vitamin D levels on prognosis in ALS. More detailed research is warranted to determine whether manipulation of vitamin D could be beneficial to patients.