An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy.

The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 ± 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses

Early reoperation after laparoscopic fundoplication: The importance of routine postoperative contrast studies

Background: The necessity for routine postoperative contrast studies following laparoscopic fundoplication for either gastroesophageal reflux disease or paraesophageal hernia is unclear. Methods: To determine whether a routine contrast X-ray film influenced surgical decision making following laparoscopic fundoplication, we reviewed records from a prospective database of 1,894 patients who underwent a primary laparoscopic fundoplication for gastroesophageal reflux disease or paraesophageal hernia between October 1991 and June 2008, and identified those who underwent early reoperation. The value of early routine postoperative barium swallow examinations in the management of these patients was then determined. Results: The review showed that 53 patients (2.8%) underwent reoperative procedures within seven days of their original operation: 21 had originally undergone surgery for a paraesophageal hernia, and 32 for reflux. Of the 53 patients who underwent reoperaiton, 25 (47.2%) were treated for dysphagia, 17 (32.1%) for acute paraesophageal hernia, 6 (11.3%) for a gastrointestinal leak, and 5 (9.4%) for bleeding or peritonitis. Fifteen of the 17 patients who underwent repair of an acute hiatus hernia (0.8% of all patients) had no symptoms and underwent reoperative surgery because of radiological findings alone. Primary surgery for a large hiatus hernia was associated with a higher incidence of early reoperation (5.2 vs. 2.2%; P = 0.001). Conclusions: Approximately 1 in 125 patients who underwent laparoscopic surgery for reflux or a large hiatus hernia had an important finding on an early postoperative contrast swallow, and benefited from this investigation by undergoing early reoperative intervention.Shigeru Tsunoda, Glyn G. Jamieson, Peter G. Devitt, David I. Watson and Sarah K. Thompso