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.

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.

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.

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.

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.

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.

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.

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.

Primary lateral sclerosis may occur within familial amyotrophic lateral sclerosis pedigrees.

Primary lateral sclerosis (PLS) is considered to be a specific sporadic motor neuron disorder, but some reports have shown familial history of motor neuron disorders that may comprise PLS cases. Here we report a novel pedigree highlighting an intrafamilial occurrence of PLS and amyotrophic lateral sclerosis (ALS) cases. These observations strengthen the hypothesis that PLS may represent an ALS phenotype with a long evolution and strongly suggest the involvement of common genetic factors that can lead to upper and lower motor neuron death.