Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations. Mutations in the first subunit of the enzyme serine palmitoyltransferase (SPT) have been associated with HSAN-I. The SPT enzyme catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway. However, different studies suggest the implication of other genes in the pathology of HSAN-I. Therefore, we screened the two other known subunits of SPT, SPTLC2 and SPTLC3, in a cohort of 78 HSAN patients. No mutations were found in SPTLC3, but we identified three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families presenting with a typical HSAN-I phenotype. We demonstrate that these mutations result in a partial to complete loss of SPT activity in vitro and in vivo. Moreover, they cause the accumulation of the atypical and neurotoxic sphingoid metabolite 1-deoxy-sphinganine. Our findings extend the genetic heterogeneity in HSAN-I and enlarge the group of HSAN neuropathies associated with SPT defects. We further show that HSAN-I is consistently associated with an increased formation of the neurotoxic 1-deoxysphinganine, suggesting a common pathomechanism for HSAN-I.

Although numerous clinical, laboratory, and pharmacological variables have been reported as significant risk factors for critical illness polyneuromyopathy (CIPM), there is still no consensus on the aetiology of this condition. Objectives of the study were to assess the clinical and electrophysiological incidence and risk factors for CIPM.A cohort of critically ill patients was observed prospectively for a one-month period and the association between neuromuscular involvement and various potential risk factors was evaluated. Sixty one critically ill patients completed the follow-up (30 women, 31 men, median age 59 years).CIPM development was detected clinically in 17 patients (27.9 %) and electrophysiologically in 35 patients (57.4 %). CIPM was significantly associated with the presence and duration of systemic inflammatory response syndrome and the severity of multiple, respiratory, central nervous, and cardiovascular organ failures. The median duration of mechanical ventilation was significantly longer in patients with CIPM than in those without (16 vs 3 days, p<0.001). Independent predictors of CIPM obtainable within the 1(st) week of critical illness were the admission sequential organ failure assessment score (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.02-1.36), the 1(st) week total sequential organ failure assessment scores (OR, 1.14; 95 % CI, 1.06-1.46) and the 1(st) week duration of systemic inflammatory response syndrome (OR, 1.05; 95% CI, 1.01-1.15). They were able to correctly predict the development of CIPM at the end of the 1(st) week in about 80% of critically ill cases.In conclusion, the presence and duration of systemic inflammatory response syndrome and the severity of multiple and several organ failures are associated with increased risk of the development of CIPM.

Electrophysiological and histological examinations showed significant overlapping of several pathogenic components of neuromuscular involvement in critically ill patients, namely decreased muscle excitability, myopathy, axonal motor neuropathy and sensory neuropathy. The characterisation of the electrophysiological components of a complex polyneuromyopathy is preferred to the strict categorisation of abnormalities into critical illness myopathy and polyneuropathy.

Background: Publication of comprehensive clinical care guidelines for Duchenne muscular dystrophy (DMD) in 2010 was a milestone for DMD patient management. Our CARE-NMD survey investigates the neuromuscular, medical, and psychosocial care of DMD patients in Europe, and compares it to the guidelines.Methods: A cross-sectional survey of 1677 patients contacted via the TREAT-NMD patient registries was conducted using self-report questionnaires in seven European countries.Results: Survey respondents were 861 children and 201 adults. Data describe a European DMD population with mean age of 13.0 years (range 0.8–46.2) of whom 53% had lost ambulation (at 10.3 years of age, median). Corticosteroid medication raised the median age for ambulatory loss from 10.1 years in patients never medicated to 11.4 years in patients who received steroids (p < 0.0001). The majority of patients reported receiving care in line with guidelines, although we identified significant differences between countries and important shortcomings in prevention and treatment. Summarised, 35% of patients aged≥ nine years received no corticosteroid medication, 24% of all patients received no regular physiotherapy, echocardiograms were not performed regularly in 22% of patients, pulmonary function was not regularly assessed in 71% of non-ambulatory patients. Patients with regular follow-up by neuromuscular specialists were more likely to receive care according to guidelines, were better satisfied, and experienced shorter unplanned hospitalization periods.

This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90% to actual 53%. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300-400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects.