Identification of potential non-invasive biomarkers in diastrophic dysplasia.

Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by pathogenic variants in the SLC26A2 gene encoding for a cell membrane sulfate/chloride antiporter crucial for sulfate uptake and glycosaminoglycan (GAG) sulfation. Research on a DTD animal model has suggested possible pharmacological treatment approaches. In view of future clinical trials, the identification of non-invasive biomarkers is crucial to assess the efficacy of treatments. Urinary GAG composition has been analyzed in several metabolic disorders including mucopolysaccharidoses. Moreover, the N-terminal fragment of collagen X, known as collagen X marker (CXM), is considered a real-time marker of endochondral ossification and growth velocity and was studied in individuals with achondroplasia and osteogenesis imperfecta. In this work, urinary GAG sulfation and blood CXM levels were investigated as potential biomarkers for individuals affected by DTD. Chondroitin sulfate disaccharide analysis was performed on GAGs isolated from urine by HPLC after GAG digestion with chondroitinase ABC and ACII, while CXM was assessed in dried blood spots. Results from DTD patients were compared with an age-matched control population. Undersulfation of urinary GAGs was observed in DTD patients with some relationship to the clinical severity and underlying SLC26A2 variants. Lower than normal CXM levels were observed in most patients, even if the marker did not show a clear pattern in our small patient cohort because CXM values are highly dependent on age, gender and growth velocity. In summary, both non-invasive biomarkers are promising assays targeting various aspects of the disorder including overall metabolism of sulfated GAGs and endochondral ossification

Family history of neurodegenerative and vascular diseases in ALS: a population-based study

Item does not contain fulltextOBJECTIVE: To determine whether the frequency of Parkinson disease (PD), dementia, and vascular diseases in relatives of patients with amyotrophic lateral sclerosis (ALS) differs from the frequency of those diseases in relatives of controls, providing further information about the association between these diseases. METHODS: We studied the occurrence of neurodegenerative and vascular diseases in families of patients with ALS in a prospective, population-based, case-control study in the Netherlands between 2006 and 2009, using the recurrence risk lambda. Family history data were obtained by asking participants to fill in questionnaires. RESULTS: A total of 635 patients and 1,616 controls were included. The frequency of dementia was mildly increased only among parents and siblings of patients with sporadic ALS (lambda1.32; 95 confidence interval [CI] 1.10-1.59), not among grandparents, or aunts and uncles. The risk of PD was not elevated (any relative: lambda 0.91; 95% CI 0.70-1.17). Among relatives of patients with familial ALS, no significantly increased risk of neurodegenerative diseases was found. A reduced risk of vascular diseases was found in relatives of patients with sporadic ALS (stroke: lambda 0.90; 95% CI 0.80-1.01 and myocardial infarction: lambda 0.86; 95% CI 0.79-0.94), and in relatives of patients with familial ALS (stroke: lambda 0.88; 95% CI 0.61-1.27 and myocardial infarction: lambda 0.61; 95% CI 0.43-0.86). CONCLUSIONS: This large, prospective, population-based study showed that familial aggregation of ALS, dementia, and PD is substantially lower than previously thought. The lowered risk of vascular diseases in relatives of patients with ALS supports the view that a beneficial vascular risk profile increases ALS susceptibility

Mutations in the TRPV4 gene are not associated with sporadic progressive muscular atrophy.

Item does not contain fulltext1 juni 201

UBQLN2 in familial amyotrophic lateral sclerosis in The Netherlands.

Item does not contain fulltextRecently it was discovered that mutations in the UBQLN2 gene were a cause of an X-linked dominant type of familial amyotrophic lateral sclerosis (ALS). We investigated the frequency of mutations in this gene in a cohort of 92 families with ALS in the Netherlands. Eight families were excluded because of male-to-male transmission. In the remaining 84 familial ALS cases no mutations were discovered in UBQLN2. Hence, UBQLN2 was not found to be a cause of familial ALS in the Netherlands.1 september 201

The Lambert-Eaton myasthenic syndrome 1988-2008: a clinical picture in 97 patients.

Contains fulltext : 70850.pdf (publisher's version ) (Closed access)BACKGROUND: Neuromuscular symptoms in patients with Lambert-Eaton myasthenic syndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in LEMS patients without a SCLC. We studied how this clinical information, which is readily available at the first consultation, can be used to predict the presence of SCLC. PATIENTS AND METHODS: In our study we included 52 LEMS patients with SCLC and 45 non-tumor patients (NT-LEMS). We interviewed patients using a structured checklist and reviewed their clinical records. We compared frequency and onset of symptoms during the course of LEMS. RESULTS: In the first six months, over half the SCLC-LEMS patients had developed seven separate symptoms, while NT-LEMS patients developed only two symptoms. Proximal leg weakness and dry mouth were early symptoms in both groups. Rapid involvement of proximal arm muscles (p=0.0001), distal arm muscles (p=0.0037), distal leg muscles (p=0.0002), dysartria (p=0.0091) and the presence of erectile dysfunction (p=0.007) were found significantly more often in SCLC-LEMS patients in both cohorts. Cerebellar symptoms, although present in 9% of LEMS patients, were almost exclusively related to SCLC-LEMS. CONCLUSION: A rapidly progressive course of disease from onset in LEMS patients should raise a high suspicion of SCLC. Special attention should be paid to involvement of upper extremities, involvement of distal arm and distal leg muscles, to erectile dysfunction and probably ataxia in order to discriminate between SCLC-LEMS and NT-LEMS

Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial.

Item does not contain fulltextOBJECTIVES: To determine the safety and efficacy of lithium for the treatment of amyotrophic lateral sclerosis (ALS) in a randomised, placebo controlled, double blind, sequential trial. METHODS: Between November 2008 and June 2011, 133 patients were randomised to receive lithium carbonate (target blood level 0.4-0.8 mEq/l) or placebo as add-on treatment with riluzole. The primary endpoint was survival, defined as death, tracheostomal ventilation or non-invasive ventilation for more than 16 h/day. Secondary outcome measures consisted of the revised ALS Functional Rating Scale and forced vital capacity. Analysis was by intention to treat and according to a sequential trial design. RESULTS: 61 patients reached a primary endpoint, 33 of 66 in the lithium group and 28 of 67 patients in the placebo group. Lithium did not significantly affect survival (cumulative survival probability of 0.73 in the lithium group (95% CI 0.63 to 0.86) vs 0.75 in the placebo group (95% CI 0.65 to 0.87) at 12 months and 0.62 in the lithium group (95% CI 0.50 to 0.76) vs 0.67 in the placebo group (95% CI 0.56 to 0.81) at 16 months). Secondary outcome measures did not differ between treatment groups. No major safety concerns were encountered. CONCLUSIONS: This trial, designed to detect a modest effect of lithium, did not demonstrate any beneficial effect on either survival or functional decline in patients with ALS. TRIAL REGISTRATION NUMBER: NTR1448. Name of trial registry: Lithium trial in ALS.1 mei 201