Lungworms (Metastrongylus spp.) demonstrated in domestic pigs with respiratory disease: was there a clinical relevance?

Background An outdoor pig herd was affected by severe respiratory disease in one out of three pastures. At necropsy, Mycoplasma hyopneumoniae and Pasteurella multocida were detected in the lungs, as well as the lung worm Metastrongylus apri. The life cycle of Metastrongylus spp. includes earthworms as intermediate hosts, and since domestic pigs mainly are reared indoors, lungworm infections have not been diagnosed in domestic pigs in Sweden for decades, not even in pigs reared outdoors. Therefore, this disease outbreak was scrutinised from the view of validating the impact of Metastrongylus spp. Results At the time of the disease outbreak, neither eggs of Metastrongylus spp., Trichuris suis nor Ascaris suum were detected in faeces of pigs aged ten weeks. In contrast, five-months-old pigs at the pasture with respiratory disease shed up to 3800 eggs per gram (Epg) of Ascaris suum and up to 1100 Epg of Trichuris suis, whereas eggs of these parasites were not demonstrated in healthy pigs aged six months at another pasture. Low numbers of eggs from Metastrongylus spp. (< 150 Epg) were seen in faecal samples from both these age categories. At slaughter, seven weeks later, ten normal weighted pigs in the preceding healthy batch were compared with ten normal weighted and five small pigs from the affected batch. Healing Mycoplasma-like pneumonic lesions were seen in all groups. All small pigs shed eggs of Ascaris suum in the faeces, compared to around 50% of the larger pigs. Metastrongylus spp. were demonstrated in 13 of the 25 pigs (52%), representing all groups included. Conclusion As Metastrongylus spp. were demonstrated regardless of health status, and also in another healthy outdoor herd, the impact of Metastrongylus spp. on the outbreak of respiratory disease was depreciated. Instead, a possible association with a high burden of Ascaris suum was suggested to have preceded the severe outbreak with respiratory disease in the affected herd. Further, it was concluded that Metastrongylus spp. will escape detection at routine meat inspections made at slaughterhouses, and as they appeared to generally not induce clinical signs of respiratory disease Metastrongylus spp. may be more common in outdoor production than previously believed

Update on the genetics of congenital myopathies

The congenital myopathies form a large clinically and genetically heterogeneous group of disorders. Currently mutations in at least 27 different genes have been reported to cause a congenital myopathy, but the number is expected to increase due to the accelerated use of next-generation sequencing methods. There is substantial overlap between the causative genes and the clinical and histopathologic features of the congenital myopathies. The mode of inheritance can be auto-somal recessive, autosomal dominant or X-linked. Both dominant and recessive mutations in the same gene can cause a similar disease phenotype, and the same clinical phenotype can also be caused by mutations in different genes. Clear genotype-phenotype correlations are few and far between. (C) 2019 Elsevier Inc. All rights reserved.Peer reviewe

Pregnancy and Delivery in Women With Congenital Myopathies

Reports on pregnancy and delivery issues in women with congenital myopathies are scarce. In this review, we summarize the medical literature along with updates of our own data. Included are patients with nemaline myopathy (n = 11), central core disease (n = 6), multi-minicore disease (n = 2), cytoplasmic body myopathy (n = 1), and congenital fiber-type disproportion (n = 1). Apart from 1 patient with nemaline myopathy, who had used a wheelchair from the age of 18 years, all other women were able to walk when becoming pregnant. In comparison with the general population, there were no increased pregnancy or delivery complications, apart from the fact that 38% elective Cesarean sections took place. Neonatal outcome was favorable. In cases where a possible influence of gestation on muscle function was assessed, a deterioration during or after pregnancy was not observed. Patients who wish to have children should be advised by a multidisciplinary team according to the specific diagnosis, severity, and distribution of muscle weakness. (C) 2019 Elsevier Inc. All rights reserved.Peer reviewe

Ethics in genetic counselling

Difficult ethical issues arise for patients and professionals in medical genetics, and often relate to the patient’s family or their social context. Tackling these issues requires sensitivity to nuances of communication and a commitment to clarity and consistency. It also benefits from an awareness of different approaches to ethical theory. Many of the ethical problems encountered in genetics relate to tensions between the wishes or interests of different people, sometimes even people who do not (yet) exist or exist as embryos, either in an established pregnancy or in vitro. Concern for the long-term welfare of a child or young person, or possible future children, or for other members of the family, may lead to tensions felt by the patient (client) in genetic counselling. Differences in perspective may also arise between the patient and professional when the latter recommends disclosure of information to relatives and the patient finds that too difficult, or when the professional considers the genetic testing of a child, sought by parents, to be inappropriate. The expectations of a patient’s community may also lead to the differences in perspective between patient and counsellor. Recent developments of genetic technology permit genome-wide investigations. These have generated additional and more complex data that amplify and exacerbate some pre-existing ethical problems, including those presented by incidental (additional sought and secondary) findings and the recognition of variants currently of uncertain significance, so that reports of genomic investigations may often be provisional rather than definitive. Experience is being gained with these problems but substantial challenges are likely to persist in the long term.Peer reviewe

Expansion of the clinical spectrum of frontometaphyseal dysplasia 2 caused by the recurrent mutation p.Pro485Leu in MAP3K7

Frontometaphyseal dysplasia 2 (FMD2) is a skeletal dysplasia with supraorbital hyperostosis combined with undermodeling of the bones, joint contractures and some extraskeletal features. It is caused by heterozygous mutations in MAP3K7, encoding the Mitogen-Activated Protein 3-Kinase 7. MAP3K7 is activated by TGF-beta and plays an important role in osteogenesis. Less than 20 patients with FMD2 and MAP3K7 mutations have been described thus far. The majority of the patients harbor a recurrent missense mutation, NM_003188.3: c.1454C > T [NP_003179.1: p.(Pro485Leu)], which leads to a more severe phenotype than mutations in other domains. Here we describe an additional patient with FMD2 caused by the recurrent c.1454C > T MAP3K7 mutation, identified as a de novo variant by whole-genome sequencing. The 17-year-old boy has the characteristic skeletal and facial features of FMD2. However, some novel features were also observed, including growth retardation and spina bifida occulta. In line with other patients harboring the same mutation he also showed keloid scars and had no intellectual disability. This report expands the clinical spectrum of FMD2 caused by the recurrent c.1454C > T [p.(Pro485Leu)] mutation in MAP3K7.Peer reviewe

Management practices related to the control of gastrointestinal parasites on Swedish pig farms

Background Internal parasites are common in pigs worldwide and may induce clinical disease or subclinical infections with negative effects such as poor weight gain and reduced welfare, which in turn affect productivity. Effective parasite control to reduce the negative impact of parasitic infections demands a combination of antiparasitic drugs as well as various hygiene and biosecurity practices. The aim of this study was to obtain information on current management practices and parasite control routines used on Swedish pig farms using an online questionnaire. Results Antiparasitic drugs were used on 69% of the farms routinely and were mainly administered to sows just prior to farrowing. Less than 5% of the herds conducted faecal analysis for parasites. Batchwise, age segregated rearing was common and overall, it was practiced for piglets, growers, and fatteners on 88, 80 and 75% of the farms, respectively. Large and medium sized farms appeared to apply stricter hygiene and biosecurity measures to the growing pigs compared to small farms. Dry sows were mainly housed in groups on deep litter straw beds and cleaning, as well as disinfection, between each group was less common compared to what was practiced for growing pigs. Outdoor access was rare and only occurred on organic and small farms. Most of the farms, 54, 74 and 82% of small, medium, and large sized herds respectively, reported to have less than 5% white spot lesions, caused by migrating A. suum larvae, registered at slaughter. Conclusion Several risk factors for parasite infections, such as bedding material, group housing and solid floors, are mandatory requirements by national law. However, it was evident from this study that although strategic hygiene and biosecurity practices appeared common, they were not practiced in all herds and less so for dry sows. Antiparasitic drugs were used frequently and mainly through routine prophylactic treatments without prior testing for parasites. A holistic approach is necessary when designing efficient parasite control programs, and it is essential that management factors and routine monitoring of parasites are given attention. This to achieve efficient parasite control and reduce the risk of unnecessary use of antiparasitic drugs

Clinically variable nemaline myopathy in a three-generation family caused by mutation of the skeletal muscle alpha-actin gene

We present here a Finnish nemaline myopathy family with a dominant mutation in the skeletal muscle alpha-actin gene, p.(Glu85Lys), segregating in three generations. The index patient, a 5-year-old boy, had the typical form of nemaline myopathy with congenital muscle weakness and motor milestones delayed but reached, while his mother never had sought medical attention for her very mild muscle weakness, and his maternal grandmother had been misdiagnosed as having myotonic dystrophy. This illustrates the clinical variability in nemaline myopathy. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

A novel MPLKIP-variant in three Finnish patients with non-photosensitive trichothiodystrophy type 4

Trichothiodystrophy is a group of multisystem neuroectodermal disorders with dysplastic hair as the cardinal symptom. We describe three patients from two Finnish families in whom whole-exome sequencing revealed a novel homozygous variant, c.26del, p.(Pro9Glnfs*144) in the MPLKIP-gene, confirming the diagnosis of non-photosensitive trichothiodystrophy type 4 (TTD4). The variant was confirmed by Sanger sequencing and inherited from unaffected carrier parents. This report adds to the literature by expanding the genetic and phenotypic spectra of MPLKIP-related trichothiodystrophy. We describe dysmorphic features in the patients and provide a comparison of clinical characteristics in patients with TTD4 reported to date.Peer reviewe

A custom ddPCR method for the detection of copy number variations in the nebulin triplicate region

The human genome contains repetitive regions, such as segmental duplications, known to be prone to copy number variation. Segmental duplications are highly identical and homologous sequences, posing a specific challenge for most mutation detection methods. The giant nebulin gene is expressed in skeletal muscle. It harbors a large segmental duplication region composed of eight exons repeated three times, the so-called triplicate region. Mutations in nebulin are known to cause nemaline myopathy and other congenital myopathies. Using our custom targeted Comparative Genomic Hybridization arrays, we have previously shown that copy number variations in the nebulin triplicate region are pathogenic when the copy number of the segmental duplication block deviates two or more copies from the normal number, which is three per allele. To complement our Comparative Genomic Hybridization arrays, we have established a custom Droplet Digital PCR method for the detection of copy number variations within the nebulin triplicate region. The custom Droplet Digital PCR assays allow sensitive, rapid, high-throughput, and cost-effective detection of copy number variations within this region and is ready for implementation a screening method for disease-causing copy number variations of the nebulin triplicate region. We suggest that Droplet Digital PCR may also be used in the study and diagnostics of other segmental duplication regions of the genome.Peer reviewe

An Extended Targeted Copy Number Variation Detection Array Including 187 Genes for the Diagnostics of Neuromuscular Disorders

Background: Our previous array, the Comparative Genomic Hybridisation design (CGH-array) for nemaline myopathy (NM), named the NM-CGH array, revealed pathogenic copy number variation (CNV) in the genes for nebulin (NEB) and tropomyosin 3 (TPM3), as well as recurrent CNVs in the segmental duplication (SD), i.e. triplicate, region of NEB (TRI, exons 82-89, 90-97, 98-105). In the light of this knowledge, we have designed and validated an extended CGH array, which includes a selection of 187 genes known to cause neuromuscular disorders (NMDs). Objective: Our aim was to develop a reliable method for CNV detection in genes related to neuromuscular disorders for routine mutation detection and analysis, as a much-needed complement to sequencing methods. Methods: We have developed a novel custom-made 4×180 k CGH array for the diagnostics of NMDs. It includes the same tiled ultra-high density coverage of the 12 known or putative NM genes as our 8×60 k NM-CGH-array but also comprises a selection of 175 additional genes associated with NMDs, including titin (TTN), at a high to very high coverage. The genes were divided into three coverage groups according to known and potential pathogenicity in neuromuscular disorders. Results: The array detected known and putative CNVs in all three gene coverage groups, including the repetitive regions of NEB and TTN. Conclusions: The targeted neuromuscular disorder 4×180 k array-CGH (NMD-CGH-array v1.0) design allows CNV detection for a broader spectrum of neuromuscular disorders at a high resolution. © 2018 - IOS Press and the authors. All rights reserved.Peer reviewe