Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an important subgroup of ALS. We recently reported specific SPTLC1 variants resulting in sphingolipid overproduction as a cause for juvenile ALS. Here, we report six patients from six independent families with a recurrent, de novo, heterozygous variant in SPTLC2 c.778G>A [p.Glu260Lys] manifesting with juvenile ALS. METHODS: Clinical examination of the patients along with ancillary and genetic testing, followed by biochemical investigation of patients' blood and fibroblasts, was performed. RESULTS: All patients presented with early-childhood-onset progressive weakness, with signs and symptoms of upper and lower motor neuron degeneration in multiple myotomes, without sensory neuropathy. These findings were supported on ancillary testing including nerve conduction studies and electromyography, muscle biopsies and muscle ultrasound studies. Biochemical investigations in plasma and fibroblasts showed elevated levels of ceramides and unrestrained de novo sphingolipid synthesis. Our studies indicate that SPTLC2 variant [c.778G>A, p.Glu260Lys] acts distinctly from hereditary sensory and autonomic neuropathy (HSAN)-causing SPTLC2 variants by causing excess canonical sphingolipid biosynthesis, similar to the recently reported SPTLC1 ALS associated pathogenic variants. Our studies also indicate that serine supplementation, which is a therapeutic in SPTLC1 and SPTCL2-associated HSAN, is expected to exacerbate the excess sphingolipid synthesis in serine palmitoyltransferase (SPT)-associated ALS. CONCLUSIONS: SPTLC2 is the second SPT-associated gene that underlies monogenic, juvenile ALS and further establishes alterations of sphingolipid metabolism in motor neuron disease pathogenesis. Our findings also have important therapeutic implications: serine supplementation must be avoided in SPT-associated ALS, as it is expected to drive pathogenesis further

A cohort of 17 patients with kyphoscoliotic Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history.

PurposeIn 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and hyperelastic skin. FKBP14 is an ER-resident protein belonging to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases); it catalyzes the folding of type III collagen and interacts with type III, type VI, and type X collagens. Only nine affected individuals have been reported to date.MethodsWe report on a cohort of 17 individuals with FKBP14-kEDS and the follow-up of three previously reported patients, and provide an extensive overview of the disorder and its natural history based on clinical, biochemical, and molecular genetics data.ResultsBased on the frequency of the clinical features of 23 patients from the present and previous cohorts, we define major and minor features of FKBP14-kEDS. We show that myopathy is confirmed by histology and muscle imaging only in some patients, and that hearing impairment is predominantly sensorineural and may not be present in all individuals.ConclusionOur data further support the extensive clinical overlap with PLOD1-kEDS and show that vascular complications are rare manifestations of FKBP14-kEDS

A case of chylous fistula after axillary dissection in breast-conserving treatment for breast cancer

Chyle fistula is not a well-known complication of axillary dissection in patients with breast cancer. Although rare, this complication can occur as a result of anatomic variation of the thoracic duct and its venous anastomosis. Injury to the lateral terminating branches or lymphatic trunk, leading to retrograde chyle flow, is more likely than direct injury to the duct. We report a case of chylous fistula after axillary dissection in a patient with breast cancer, review the literature, and discuss the management of this rare complicatio

Recruitment challenges to the i CARE study: A randomised trial on general practitioner-led colon cancer survivorship care

Objectives The I CARE study (Improving Care After colon canceR treatment in the Netherlands) aims to compare surgeon-led to general practitioner (GP)-led colon cancer survivorship care. Recruitment to the trial took longer than expected. In this descriptive study, recruitment is critically reviewed. Setting Patients were recruited from eight Dutch medical centres. Participants Patients treated with curative intent for stages I-III colon cancer. Target patient sample size was calculated at 300. Interventions Patients were randomised to surgeon-led (usual) versus GP-led care, with or without access to an eHealth application (Oncokompas). Outcome measures Baseline characteristics of (non-)participants, reasons for non-participation and strategies to improve recruitment were reviewed. Results Out of 1238 eligible patients, 353 patients were included. Of these, 50 patients dropped out shortly after randomisation and before start of the intervention, resulting in a participation rate of 25%. Participants were on average slightly younger (68.1 years vs 69.3 years) and more often male (67% vs 50%) in comparison to non-participants. A total of 806 patients declined participation for reasons most often relating to research (57%), including the wish to remain in specialist care (31%) and too much effort to participate (12%). Some patients mentioned health (9%) and confrontation with the disease (5%) as a reason. In 43 cases, GPs declined participation, often related to the study objective, need for financial compensation and time restraints. The generally low participation rate led to concerns about reaching the target sample size. Methods to overcome recruitment challenges included changes to the original recruitment procedure and the addition of new study centres. Conclusions Challenges were faced in the recruitment to a randomised trial on GP-led colon cancer survivorship care. Research on the transition of care requires sufficient time, funding and support base among patients and healthcare professionals. These findings will help inform researchers and policy-makers on the development of future practices. Trial registration number NTR4860

Efficacy of Antibiotic Agents after Spill of Bile and Gallstones during Laparoscopic Cholecystectomy

Background: Perforation of the gallbladder during laparoscopic cholecystectomy (LC) results in spill of bile or gallstones in the abdominal cavity. The aim of this study was to assess whether antibiotic agents after spill have an effect on post-operative and infectious complications. Patients and Methods: Operative reports and clinical data of patients undergoing LC between 2012 and 2016 in three hospitals were screened retrospectively for spill of bile and spill of gallstones. Included patients were divided into two groups: Patients who were treated with antibiotic agents (either prophylactic or a single administration during or directly post-operatively because of spill) and patients who did not receive any antibiotic agents. Patients were also categorized as to uncomplicated or complicated gallstone disease. Multi-variable logistic regression was used to assess risk factors for overall and infectious complications after spill. Results: Spill was reported in 14.7% (481 of 3,262). The infectious complication rate was 8.7% (42/481). Of 481 patients, 295 (61.3%) had uncomplicated gallstone disease and 239 (49.7%) received antibiotic treatment. Rates of infectious complications were comparable among patients receiving antibiotic agents or no antibiotic agents (8% vs. 9%, respectively; p = 0.779); also when analysis only included patients with complicated gallstone disease (11% vs. 10% respectively, p = 0.861). Spill of stones was the only independent risk factor associated with post-operative complications (odds ratio 2.55, 95% confidence interval 1.23-5.29, p = 0.012). Conclusion: Antibiotic agents (prophylaxis or intra-operative) after spill of bile and spill of gallstones do not reduce the risk of overall and infectious complications. Spill of stones is associated independently with post-operative complications. The present study sample may leave small differences in complication rates undetected

Single and Combined Diagnostic Value of Clinical Features and Laboratory Tests in Acute Appendicitis

Objectives: The objective was to evaluate the diagnostic accuracy of clinical features and laboratory test results in detecting acute appendicitis. Methods: Clinical features and laboratory test results were prospectively recorded in a consecutive series of 1,101 patients presenting with abdominal pain at the emergency department (ED) in six hospitals. Likelihood ratios (LRs) and the areas under the receiver operating characteristic curve (AUC) were calculated for the individual features. Variants of clinical presentation, based on different combinations of clinical features, were investigated and the accuracies of combinations of clinical features were evaluated. Results: The discriminative power (AUC) of the individual features in patients with suspected appendicitis ranged from 0.50 to 0.65. For five of the 23 predictor sets, the accuracy for appendicitis was more than 85%. This accuracy was only found in male patients. The relative frequency of these predictor sets ranged from 2% to 13% of patients with suspected appendicitis. A combination of the clinical features migration of pain to the right lower quadrant (RLQ), and direct tenderness in the RLQ, was present in only 28% (120/422) of clinically suspected patients, of whom no more than 85 patients had appendicitis (71%). A "classical" presentation (combination of migration of pain to the RLQ, tenderness in the RLQ, and rigidity) occurred in only 6% (25/422) of patients with suspected appendicitis and yielded an accuracy of 100% in males but only 46% in females. Conclusions: The discriminative power (AUC) of individual clinical features and laboratory test results for appendicitis was weak in patients with suspected appendicitis. Combinations of clinical features and laboratory tests with high diagnostic accuracy are relatively infrequent in patients with suspected appendiciti

Restrictive strategy versus usual care for cholecystectomy in patients with gallstones and abdominal pain (SECURE): a multicentre, randomised, parallel-arm, non-inferiority trial

Contains fulltext : 204615.pdf (publisher's version ) (Closed access

Novel SPEG mutations in congenital myopathies:Genotype-phenotype correlations

Introduction: Centronuclear myopathies (CNMs) are a subtype of congenital myopathies (CMs) characterized by muscle weakness, predominant type 1 fibers, and increased central nuclei. SPEG (striated preferentially expressed protein kinase) mutations have recently been identified in 7 CM patients (6 with CNMs). We report 2 additional patients with SPEG mutations expanding the phenotype and evaluate genotype-phenotype correlations associated with SPEG mutations. Methods: Using whole exome/genome sequencing in CM families, we identified novel recessive SPEG mutations in 2 patients. Results: Patient 1, with severe muscle weakness requiring respiratory support, dilated cardiomyopathy, ophthalmoplegia, and findings of nonspecific CM on muscle biopsy carried a homozygous SPEG mutation (p.Val3062del). Patient 2, with milder muscle weakness, ophthalmoplegia, and CNM carried compound heterozygous mutations (p.Leu728Argfs*82) and (p.Val2997Glyfs*52). Conclusions: The 2 patients add insight into genotype-phenotype correlations of SPEG-associated CMs. Clinicians should consider evaluating a CM patient for SPEG mutations even in the absence of CNM features. Muscle Nerve 59:357-362, 201