Effect of enzyme replacement therapy with alglucosidase alfa (Myozyme®) in 12 patients with advanced late-onset Pompe disease.

BACKGROUND: The efficacy of enzyme replacement therapy (ERT) in patients at an advanced stage of Pompe disease has only been addressed in a few studies. Our objective was to assess the long term effects of ERT in a cohort of patients with severe Pompe disease. METHODS: We identified patients from the French Pompe Registry with severe respiratory failure and permanent wheelchair use (assisted walk for a few meters was allowed) when starting ERT. Patients' medical records were collected and reviewed and respiratory and motor functions, before ERT initiation and upon last evaluation were compared. RESULTS: Twelve patients (7 males) were identified. Median age at symptom onset was 24years [IQR=15.5; 36.0]. At baseline ventilation was invasive in 11 patients and noninvasive in one, with a median ventilation time of 24h [IQR=21.88; 24.00] (min 20; max 24). ERT was initiated at a median age of 52.5years [IQR=35.75; 66.50]. Median treatment duration was 55months [IQR=39.5; 81.0]. During observational period no adverse reaction to ERT was recorded, five patients (41.67%) died, three decreased their ventilation time by 30, 60 and 90min and two increased their assisted walking distance, by 80 and 20m. CONCLUSION: Some patients at a very advanced stage of Pompe disease may show a mild benefit from ERT, in terms of increased time of autonomous ventilation and of enlarged distance in assisted walk. ERT can be initiated in these patients in order to retain their current level of independence and ability to perform daily life activities.

High incidence of obstructive sleep apnea syndrome in patients with late-onset epilepsy.

OBJECTIVES: The objective of the present study was to evaluate the prevalence of obstructive sleep apnea (OSA) in patients with late-onset epilepsy (LOE) who were considered at higher risk of cardiovascular disease. METHODS: Polysomnography was performed on 27 patients with LOE. Berlin questionnaires and Epworth sleepiness score were performed on all patients. We compared clinical, demographic and anthropometric characteristics, questionnaire scores on the patients with no or mild OSA (group 1) and the patients with moderate or severe OSA (group 2). Patients eligible for continuous positive airway pressure (CPAP) therapy were reviewed in consultation. RESULTS: Twenty-four patients (88.9%) had OSA and 55.6% had moderate or severe OSA. Patients in group 2 (n=15) were older than patients in group 1 (n=12). The two groups were similar in terms of body mass index (BMI), neck circumference, nocturnal seizure frequency, vascular cardiovascular risk factors and excessive daytime sleepiness. Leukoaraiosis in MRI was highly prevalent in our patients (40.7%), especially in group 2 patients. Eighty percent of the patients who had begun CPAP therapy experienced decreased seizure frequency. CONCLUSION: Patients with LOE should be screened for the presence of OSA and treated accordingly.

Adjunctive perampanel in refractory epilepsy: Experience at tertiary epilepsy care center in Tours.

PURPOSE: The purpose of this study was to evaluate the effectiveness and safety of PER as add-on treatment in patients with severe refractory epilepsy with a particular focus on patients with learning disability and/or psychiatric comorbidity. METHOD: We pooled retrospective data from adult patients with refractory epilepsy prescribed perampanel from a tertiary center in France between 1st May 2014 and 3rd June 2015. Data collection was done on February 2016. RESULTS: One hundred and one patients were included (mean age: 41.2years, 37.6% with learning disability and 49.5% with psychiatric comorbidity). Mean retention was 8.1months (range: 14days to 17months). On final evaluation, a >50% reduction in seizure frequency was reached in 41.6% of patients, and 7 patients (6.9%) became seizure-free. Sixty-three patients (62.4%) experienced adverse effects. The most common adverse effects were irritability, asthenia, aggression, and sedation. Efficacy, retention of treatment, and safety were equally similar in patients with learning disability or psychiatric comorbidity as for those without. The only significant difference was in percentage of seizure-free patients: 11.1% in the group without learning disability compared with 0% in the group with (p=0.043). CONCLUSION: Adjunctive PER can achieve clinically meaningful improvement, or even seizure freedom, in more than one-third of patients suffering from severe refractory epilepsies. It seems similarly safe and effective in the subgroup of these patients with learning disability or with psychiatric comorbidity. However, the rate of psychiatric side effects is high,; of note, we asked both patient and caregivers at each visit especially focusing on psychiatric side effects. Patients, caregivers, and families should be informed of potential psychiatric/behavioral risks associated with taking perampanel especially during the initial titration period.

Nutritional assessment of amyotrophic lateral sclerosis in routine practice: value of weighing and bioelectrical impedance analysis.

INTRODUCTION: We evaluated clinical and bioelectrical impedance (BIA) parameters at the time of diagnosis and during follow-up and associated these parameters with survival in amyotrophic lateral sclerosis (ALS) patients. METHODS: One hundred seventeen patients were enrolled and were evaluated prospectively every 3 months. All patients underwent at least 1 BIA-based assessment, and 73 underwent at least 2 assessments. Data regarding the site of onset, age at onset, weight, body mass index (BMI), amyotrophic lateral sclerosis functional rating scale score (ALSFRS), fat-free mass (FFM), fat mass (FM), and phase angle (PA) were collected. RESULTS: At the time of diagnosis, weight loss exceeding 5% of the premorbid weight and low PA were poor prognostic factors. During follow-up, a decrease of PA and FFM were associated with shorter survival, regardless of weight loss. CONCLUSIONS: These results confirm that BIA is useful to identify poor prognostic factors at the time of diagnosis and during follow-up and thus could be used to monitor patients during follow-up. Early identification of poor prognostic factors enables nutritional management and might improve patient survival.

Somatosensory evoked potentials in chronic inflammatory demyelinating polyradiculoneuropathy.

PURPOSE: Somatosensory evoked potentials (SEPs) offer complementary results to those of nerve conduction studies and contribute to the electrodiagnostic criteria of chronic inflammatory demyelinating polyradiculoneuropathy. METHODS: We performed nerve conduction studies and SEPs in patients with symmetrical motor weakness, areflexia, and/or sensory disturbances lasting for at least 8 weeks. We determined two groups according to the electrodiagnostic criteria of the European Federation of Neurological Societies. Group 1 included patients who met the definite or probable electrodiagnostic criteria, and group 2 included patients who met the possible electrodiagnostic criteria. We also compared SEPs results with those of controls (group of healthy subjects). RESULTS: Sixteen patients (14 men; mean age, 59 ± 17.3 years) were included in the study. The latencies of potentials N9, N13, N7, and N22 and the intervals N9-N13 and N7-N22 were significantly increased in patients compared with controls. The N9/iP14 amplitude ratio was significantly lower in patients. There was no significant difference in the latencies of SEPs between the two groups of patients. CONCLUSIONS: We confirm the contribution of SEPs as complementary information to nerve conduction studies in chronic inflammatory demyelinating polyradiculoneuropathy diagnosis. In addition to the usual abnormalities, a decrease in the N9/iP14 amplitude ratio could potentially be used as an electrodiagnostic criterion.

Association of a paraneoplastic motor neuron disease with anti-Ri antibodies and a novel SOD1 I18del mutation.

INTRODUCTION: Whether motor neuron diseases (MNDs) can be considered in some cases of paraneoplastic syndromes is controversial. We report a case of rapidly progressive motor neuronopathy following a diagnosis of breast carcinoma, with a presence of anti-Ri antibodies, and a novel SOD1 gene mutation. OBSERVATION: An 80-year-old woman with mucinous adenocarcinoma of the left breast for 4 years developed sub-acute quadriparesis. Myography revealed chronic denervation signs. The patient had serum anti-Ri onconeural antibodies. The diagnosis of paraneoplastic MND was established. Because of a familial history of ALS, a genetic analysis for familial ALS was performed. We identified a novel heterozygous mutation in SOD1 gene, SOD I18del. This mutation may reflect a genetic predisposition to develop a MND, inducing fragility of motor neurons. Neurological improvement was observed after three months of both intravenous gamma globulin and corticosteroids. CONCLUSION: The present observation supports the idea that MND can be considered as a paraneoplastic syndrome. A combination of anti-Ri onconeural antibodies and a particular SOD1 gene mutation, consisting in risk factor, might be in cause in the process of motor neuron death. When in doubt, paraneoplastic cause should be suspected in the differential diagnosis of MND. Immunotherapy treatment may lead to a favorable outcome.

Protein SUMOylation, an emerging pathway in amyotrophic lateral sclerosis.

The covalent attachment of SUMO proteins (small ubiquitin-like modifier) to specific proteins or SUMOylation regulates their functional properties in the nucleus and cytoplasm of neurons. Recent studies reported dysfunction of the SUMO pathway in molecular and cellular abnormalities associated with amyotrophic lateral sclerosis (ALS). Furthermore, several observations support a direct role for SUMOylation in diverse pathogenic mechanisms involved in ALS, such as response to hypoxia, oxidative stress, glutamate excitotoxicity and proteasome impairment. Recent results also suggest that SUMO modifications of superoxide dismutase 1, transactive response DNA-binding protein 43, CTE (COOH terminus of EAAT2) (proteolytic C-terminal fragment of the glutamate transporter excitatory amino acid transporter 2, EAAT2) and proteins regulating the turnover of ALS-related proteins can participate in the pathogenesis of ALS. Moreover, the fused in sarcoma (FUS) gene, mutated in ALS, encodes a protein with a SUMO E3 ligase activity. In this review, we summarize the functioning of the SUMO pathway in normal conditions and in response to stresses, its action on ALS-related proteins and discuss the need for further research on this pathway in ALS.

Myasthenia gravis in the elderly: a rare cause of undernutrition.

Myasthenia gravis is not a frequent disease in the elderly. The diagnosis of this neuromuscular junction disease in the elderly is difficult because of comorbidities and the broad differential diagnosis. We report here the case of a 86-year-old woman referred to hospital for loss of weight and difficulties in feeding. She was cachectic and had been suffering from dysphagia for several weeks. One week later, her clinical state worsened with the appearance of ptosis and oropharyngeal dysfunction, disturbing eating and talking. Myasthenia gravis was suspected and confirmed by a positive acetylcholine receptor antibody titer. The clinical state of the patient unfortunately worsened, with acute respiratory insufficiency, causing death. Myasthenia gravis must be suspected in a context of dysphagia, swallowing difficulties and loss of weight. This diagnosis leads to specific and symptomatic treatment and allows neuromuscular blockade-inducing drugs to be avoided.

Study of the HFE gene common polymorphisms in French patients with sporadic amyotrophic lateral sclerosis.

Our objective was to investigate whether the C282Y (p.Cys 282 Tyr) and H63D (p. His 63 Asp) HFE polymorphisms were associated with sporadic amyotrophic lateral sclerosis (SALS) in the French population. We searched for a relation of HFE polymorphisms with the clinical characteristics of the disease. The HFE polymorphisms were studied in 824 patients with SALS and 583 controls. We compared the frequency of the polymorphisms between SALS and controls groups by univariate and multivariate statistics, taking into account gender, site, age-at-onset and survival. We did not observe significant difference in the frequency of H63D polymorphism between SALS and control group. We observed a significant difference for C282Y between patients and controls with a low frequency of the Y allele in patients (3.2%) compared to our control group (5.9%). Disease duration, distribution of gender, site-of-onset, age-at-onset did not differ between groups taking into account genotypes of each polymorphism. Our results in this large cohort of ALS patients indicate that H63D polymorphism is not associated with SALS in the French population. This conclusion does not exclude a weak effect of the HFE gene polymorphisms in certain ALS populations, or an effect of other rare HFE gene variants.

Homozygous SMN2 deletion is a protective factor in the Swedish ALS population.

Abnormal survival motor neuron 1 (SMN1)-copy number has been associated with an increased risk of amyotrophic lateral sclerosis (ALS) in French and Dutch population studies. The aim of this study was to determine whether SMN gene copy number increases the risk of ALS or modulates its phenotype in a cohort of Swedish sporadic ALS (SALS) patients. In all, 502 Swedes with SALS and 502 Swedish controls matched for gender and age were enrolled. SMN1 and SMN2 gene copy numbers were studied by a semi-quantitative PCR method. A genotype-phenotype comparison was performed in order to determine whether SMN genes modulate the phenotype of ALS. The results were also compared with our previously reported French cohort of ALS patients. There was no difference between Swedish patients and controls in the frequency of SMN1 and SMN2 copy numbers. The frequency of SMN1 gene copies differed significantly between the French and Swedish ALS populations. The duration of the disease was significantly longer in the Swedish cohort with homozygous deletions of SMN2 when compared with the French cohort. Abnormal SMN1 gene copy number cannot be considered as a universal genetic susceptibility factor for SALS and this result underlines the importance of reproducing association gene studies in groups from different origins. We also suggest that SMN2 gene copy number might have different effects on ALS progression in disparate human populations.

Co-occurrence of progressive anarthria with an S393L TARDBP mutation and ALS within a family.

Progressive anarthria is usually classified as a tau pathology. We report an 87-year-old female with a family history of ALS and Parkinsonism, presenting with progressive anarthria. Molecular genetics analyses showed a heterozygous mutation S393L on exon 6 of the TARDBP gene. It has been previously reported in sporadic and familial amyotrophic lateral sclerosis. This case strengthens the hypothesis of a continuum between motor neuron disease and frontotemporal lobar degeneration among TDP-43 proteinopathies.

Molecular imaging of microglial activation in amyotrophic lateral sclerosis.

There is growing evidence of activated microglia and inflammatory processes in the cerebral cortex in amyotrophic lateral sclerosis (ALS). Activated microglia is characterized by increased expression of the 18 kDa translocator protein (TSPO) in the brain and may be a useful biomarker of inflammation. In this study, we evaluated neuroinflammation in ALS patients using a radioligand of TSPO, (18)F-DPA-714. Ten patients with probable or definite ALS (all right-handed, without dementia, and untreated by riluzole or other medication that might bias the binding on the TSPO), were enrolled prospectively and eight healthy controls matched for age underwent a PET study. Comparison of the distribution volume ratios between both groups were performed using a Mann-Whitney's test. Significant increase of distribution of volume ratios values corresponding to microglial activation was found in the ALS sample in primary motor, supplementary motor and temporal cortex (p = 0.009, p = 0.001 and p = 0.004, respectively). These results suggested that the cortical uptake of (18)F-DPA-714 was increased in ALS patients during the "time of diagnosis" phase of the disease. This finding might improve our understanding of the pathophysiology of ALS and might be a surrogate marker of efficacy of treatment on microglial activation.

Occurrence of eye movement disorders in motor neuron disease.

The diagnosis of amyotrophic lateral sclerosis (ALS) relies on symptoms and signs related to upper and lower motor neuron injury. Preservation of normal ocular motor movements is an important criterion for making this diagnosis as oculomotility pathways are classically spared in ALS. However, some authors report eye disturbances resulting from nuclear and supranuclear ophthalmoplegia in autopsy-proven ALS. Here, we report a case in which eye movement disorders were an early sign associated with a bulbar-onset ALS. The association of progressive ophthalmoplegia, dysexecutive syndrome and automatico-voluntary dissociation of eyelid occlusion suggested a 'progressive supranuclear palsy variant' of ALS caused by a disturbance in the descending frontal projections, even though morphological imaging was normal. Motor neuron disease with eye movement disorders must not be considered as a distinct clinical entity and must not exclude a diagnosis of ALS.

The high frequency of restless legs syndrome in patients with amyotrophic lateral sclerosis.

Restless legs syndrome (RLS) appears to be more frequent in certain neurodegenerative disorders. The aim of our study was to determine the frequency and the determinants of the association of RLS with amyotrophic lateral sclerosis (ALS) in a French cohort. Information on sex, age, age at onset, site of onset, body mass index, disease duration, ALS Functional Rating Scale-Revised and use of technical supports was obtained in a cohort of 69 ALS subjects (69.6 ± 9.7 years). RLS was diagnosed using the International RLS Study Group criteria. We compared our frequency rates by age with frequency rates of RLS in the French general population from literature. RLS was observed in 13 patients (18.8%). Frequency of RLS was higher (p = 0.007) in ALS patients older than 64 years than in the French general population of the same age group. There were no further demographic, clinical or biological differences between the patients with RLS and those without RLS, with the exception of a higher frequency of difficulty turning in bed and adjusting bedclothes (p = 0.023). In conclusion, RLS occurs frequently in ALS, and those affected should be identified and appropriately treated.

Association between divalent metal transport 1 encoding gene (SLC11A2) and disease duration in amyotrophic lateral sclerosis.

BACKGROUND: Dysregulation of iron homeostasis is one possible pathophysiological mechanism involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). SLC11A2 gene encodes the divalent metal transport 1 (DMT1) mediating iron transport in cerebral endosomal compartments. The objective of the study was to analyze DMT1 as a possible risk or modulating factor in sporadic ALS (SALS). METHODS: We performed a case-control association study on an intronic polymorphism (rs407135) previously analyzed in another neurodegenerative disease, Alzheimer's disease. This polymorphism was studied by DNA sequencing in 579 French patients with SALS and 517 healthy matched individuals. The clinical characteristics of patients were analyzed in relation to their genotypes. RESULTS: We observed that the C allele of rs407135 in SLC11A2 was associated with a shorter disease duration in SALS patients with onset in the legs [Hazard ratio: 1.5 [1.1-2.1] (p=0.02)]. These results are in line with previous observations suggesting that bulbar and spinal motor neurons have different metabolic regulation and gene expression profiles. CONCLUSIONS: Our findings support an implication for iron metabolism in ALS and suggest that the genotype of the SLC11A2 gene could modulate the duration of the disease in French SALS patients.

The P413L chromogranin B variation in French patients with sporadic amyotrophic lateral sclerosis.

Chromogranins interact with mutant forms of superoxide dismutase 1 (SOD1) responsible for a portion of familial amyotrophic lateral sclerosis (ALS). A particular variation (P413L) in the chromogranin B gene, CHGB, has been recently associated with an earlier age at onset in both familial and sporadic ALS. The aim of our study was to evaluate the P413L chromogranin variation in French patients with sporadic amyotrophic lateral sclerosis. We developed a High Resolution DNA Melting (HRM) protocol to analyse the P413L variation in the CHGB gene in 540 French patients with sporadic ALS and 504 controls. The clinical characteristics of patients were analysed in relation to their genotype. Results showed that our study on a large cohort of French-Caucasian patients with SALS and controls failed to confirm an increased frequency of the 413L variant in SALS patients. This frequency was 5.3% in the SALS population and 5.5% in the control group. Moreover, we did not observe a previous observation of a difference of age at onset between T-allele carriers and non-carriers (median age of onset 60.4 vs. 62.0 years of age, respectively). Thus, our findings do not support the 413L variant of rs742710 as a risk factor for sporadic ALS in the French population.

1H-NMR-based metabolomic profiling of CSF in early amyotrophic lateral sclerosis.

BACKGROUND: Pathophysiological mechanisms involved in amyotrophic lateral sclerosis (ALS) are complex and none has identified reliable markers useful in routine patient evaluation. The aim of this study was to analyze the CSF of patients with ALS by (1)H NMR (Nuclear Magnetic Resonance) spectroscopy in order to identify biomarkers in the early stages of the disease, and to evaluate the biochemical factors involved in ALS. METHODOLOGY: CSF samples were collected from patients with ALS at the time of diagnosis and from patients without neurodegenerative diseases. One and two-dimensional (1)H NMR analyses were performed and metabolites were quantified by the ERETIC method. We compared the concentrations of CSF metabolites between both groups. Finally, we performed principal component (PCA) and discriminant analyses. PRINCIPAL FINDINGS: Fifty CSF samples from ALS patients and 44 from controls were analyzed. We quantified 17 metabolites including amino-acids, organic acids, and ketone bodies. Quantitative analysis revealed significantly lower acetate concentrations (p = 0.0002) in ALS patients compared to controls. Concentration of acetone trended higher (p = 0.015), and those of pyruvate (p = 0.002) and ascorbate (p = 0.003) were higher in the ALS group. PCA demonstrated that the pattern of analyzed metabolites discriminated between groups. Discriminant analysis using an algorithm of 17 metabolites revealed that patients were accurately classified 81.6% of the time. CONCLUSION/SIGNIFICANCE: CSF screening by NMR spectroscopy could be a useful, simple and low cost tool to improve the early diagnosis of ALS. The results indicate a perturbation of glucose metabolism, and the need to further explore cerebral energetic metabolism.

Malnutrition at the time of diagnosis is associated with a shorter disease duration in ALS.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. During the course of the illness, malnutrition can occur and may shorten survival. The aim of our study was to determine whether clinical nutritional parameters that are used in daily practice are associated with prognosis and whether they can help guide therapeutic decisions. METHODS: We retrospectively reviewed a cohort of ALS patients in our institution between January 2002 and January 2006. Clinical and demographic outcomes were compiled. To evaluate predictors of survival, we analyzed several clinical nutritional parameters available in daily practice (body mass index, weight loss exceeding 10% of premorbid weight at the time of diagnosis and during the course of the disease and the use of technical supports such as percutaneous endoscopic gastrostomy (PEG) and non-invasive ventilation). RESULTS: Sixty-three patients were retrospectively studied. Thirteen patients had weight loss exceeding 10% of premorbid weight at the time of diagnosis and thirty patients had weight loss meeting this criterion at final examination. Weight loss exceeding 10% at the time of diagnosis was associated with a shorter duration of disease (17±6months versus 35±26months; p=0.002). A linear correlation was found between mean disease duration and time between onset and diagnosis (p<0.0001). The subgroup of patients with a PEG had a longer survival time than the other subgroup of patients (p=0.02). CONCLUSIONS: In ALS patients, early and marked weight loss significantly predicts a worse prognosis. The percentage of premorbid weight loss is a suitable and useful measure that can be used in daily practice to identify patients with a poor prognosis.