Inhibition of autophagy prevents cardiac dysfunction at early stages of cardiomyopathy in Bag3-deficient hearts.

The HSP70 co-chaperone BAG3 targets unfolded proteins to degradation via chaperone assisted selective autophagy (CASA), thereby playing pivotal roles in the proteostasis of adult cardiomyocytes (CMs). However, the complex functions of BAG3 for regulating autophagy in cardiac disease are not completely understood. Here, we demonstrate that conditional inactivation of Bag3 in murine CMs leads to age-dependent dysregulation of autophagy, associated with progressive cardiomyopathy. Surprisingly, Bag3-deficient CMs show increased canonical and non-canonical autophagic flux in the juvenile period when first signs of cardiac dysfunction appear, but reduced autophagy during later stages of the disease. Juvenile Bag3-deficient CMs are characterized by decreased levels of soluble proteins involved in synchronous contraction of the heart, including the gap junction protein Connexin 43 (CX43). Reiterative administration of chloroquine (CQ), an inhibitor of canonical and non-canonical autophagy, but not inactivation of Atg5, restores normal concentrations of soluble cardiac proteins in juvenile Bag3-deficient CMs without an increase of detergent-insoluble proteins, leading to complete recovery of early-stage cardiac dysfunction in Bag3-deficient mice. We conclude that loss of Bag3 in CMs leads to age-dependent differences in autophagy and cardiac dysfunction. Increased non-canonical autophagic flux in the juvenile period removes soluble proteins involved in cardiac contraction, leading to early-stage cardiomyopathy, which is prevented by reiterative CQ treatment.

Associated Anomalies and Outcome in Patients with Prenatal Diagnosis of Aortic Arch Anomalies as Aberrant Right Subclavian Artery, Right Aortic Arch and Double Aortic Arch.

We aimed to evaluate retrospectively associated anomalies and outcome in prenatal aortic arch anomalies (AAAs). We included ninety patients with aberrant right subclavian artery (ARSA), right aortic arch (RAA) with mirror image branching (RAA-mirror) or aberrant left subclavian artery (RAA-ALSA) and double aortic arch (DAA) between 2011 and 2020. In total, 19/90 (21.1%) had chromosomal anomalies, the highest rate being within the ARSA subgroup (17/46, 37%). All (13/13) of the RAA-mirror subgroup, 10/27 (37.0%) of RAA-ALSA, 13/46 (28.3%) of ARSA and 0/4 within the DAA subgroup had additional intracardiac anomaly. The rate of extracardiac anomalies was 30.7% in RAA-mirror, 28.3% in ARSA, 25.0% in DAA and 22.2% in the RAA-ALSA subgroup. A total of 42/90 (46.7%) had isolated AAAs: three (7.1%) with chromosomal anomalies, all trisomy 21 (3/26, 11.5%) within the ARSA subgroup. Out of 90, 19 (21.1%) were lost to follow-up (FU). Two (2.2%) intrauterine deaths occurred, and six (6.7%) with chromosomal anomalies terminated their pregnancy. In total, 63 (70.0%) were liveborn, 3/63 (4.8%) with severe comorbidity had compassionate care and 3/60 (5.0%) were lost to FU. The survival rate in the intention-to-treat cohort was 53/57 (93%). Forty-one (77.4%) presented with vascular ring/sling, two (4.9%) with RAA-ALSA developed symptoms and one (2.4%) needed an operation. We conclude that intervention due to vascular ring is rarely necessary. NIPT could be useful in isolated ARSA cases without higher a priori risk for trisomy 21 and after exclusion of other anomalies.

PCYT2 deficiency in Saarlooswolfdogs with progressive retinal, central, and peripheral neurodegeneration.

We investigated a syndromic disease comprising blindness and neurodegeneration in 11 Saarlooswolfdogs. Clinical signs involved early adult onset retinal degeneration and adult-onset neurological deficits including gait abnormalities, hind limb weakness, tremors, ataxia, cognitive decline and behavioral changes such as aggression towards the owner. Histopathology in one affected dog demonstrated cataract, retinal degeneration, central and peripheral axonal degeneration, and severe astroglial hypertrophy and hyperplasia in the central nervous system. Pedigrees indicated autosomal recessive inheritance. We mapped the suspected genetic defect to a 15 Mb critical interval by combined linkage and autozygosity analysis. Whole genome sequencing revealed a private homozygous missense variant, PCYT2:c.4A>G, predicted to change the second amino acid of the encoded ethanolamine-phosphate cytidylyltransferase 2, XP_038402224.1:(p.Ile2Val). Genotyping of additional Saarlooswolfdogs confirmed the homozygous genotype in all eleven affected dogs and demonstrated an allele frequency of 9.9% in the population. This experiment also identified three additional homozygous mutant young dogs without overt clinical signs. Subsequent examination of one of these dogs revealed early-stage progressive retinal atrophy (PRA) and expansion of subarachnoid CSF spaces in MRI. Dogs homozygous for the pathogenic variant showed ether lipid accumulation, confirming a functional PCYT2 deficiency. The clinical and metabolic phenotype in affected dogs shows some parallels with human patients, in whom PCYT2 variants lead to a rare form of spastic paraplegia or axonal motor and sensory polyneuropathy. Our results demonstrate that PCYT2:c.4A>G in dogs cause PCYT2 deficiency. This canine model with histopathologically documented retinal, central, and peripheral neurodegeneration further deepens the knowledge of PCYT2 deficiency.

Relationship between magnetic resonance imaging findings and histological grade in spinal peripheral nerve sheath tumors in dogs.

BACKGROUND: Peripheral nerve sheath tumors (PNSTs) are a group of neoplasms originating from Schwann cells or pluripotent cell of the neural crest. Therapeutic options and prognosis are influenced by their degree of malignancy and location. HYPOTHESIS/OBJECTIVES: Identify magnetic resonance imaging (MRI) features predictive of PNST histologic grade. ANIMALS: Forty-four dogs with histopathological diagnosis of spinal PNSTs and previous MRI investigation. METHODS: A multicenter retrospective study including cases with (a) histopathologic diagnosis of PNST and (b) MRI studies available for review. Histologic slides were reviewed and graded by a board-certified pathologist according to a modified French system (FNCLCC) for grading soft tissue sarcomas. The MRI studies were reviewed by 2 board-certified radiologists blinded to the grade of the tumor and the final decision on the imaging characteristics was reached by consensus. Relationships between tumor grade and histological and MRI findings were assessed using statistical analysis. RESULTS: Forty-four cases met inclusion criteria; 16 patients were PNSTs Grade 1 (low-grade), 19 were PNSTs Grade 2 (medium-grade), and 9 were PNSTs Grade 3 (high-grade). Large volume (P = .03) and severe peripheral contrast enhancement (P = .04) were significantly associated with high tumor grade. Degree of muscle atrophy, heterogeneous signal and tumor growth into the vertebral canal were not associated with grade. CONCLUSIONS AND CLINICAL IMPORTANCE: Grade of malignancy was difficult to identify based on diagnostic imaging alone. However, some MRI features were predictive of high-grade PNSTs including tumor size and peripheral contrast enhancement.

Genetic Screening Reveals Heterogeneous Clinical Phenotypes in Patients with Dilated Cardiomyopathy and Troponin T2 Variants.

BACKGROUND: Cardiomyopathies (CMs) are a heterogeneous and severe group of diseases that shows a highly variable cardiac phenotype and an incidence of app. 1/100.000. Genetic screening of family members is not yet performed routinely. PATIENTS AND METHODS: Three families with dilated cardiomyopathy (DCM) and pathogenic variants in the troponin T2, Cardiac Type (TNNT2) gene were included. Pedigrees and clinical data of the patients were collected. The reported variants in the TNNT2 gene showed a high penetrance and a poor outcome, with 8 of 16 patients dying or receiving heart transplantation. The age of onset varied from the neonatal period to the age of 52. Acute heart failure and severe decompensation developed within a short period in some patients. CONCLUSION: Family screening of patients with DCM improves risk assessment, especially for individuals who are currently asymptomatic. Screening contributes to improved treatment by enabling practitioners to set appropriate control intervals and quickly begin interventional measures, such as heart failure medication or, in selected cases, pulmonary artery banding.

Cardiomyocyte hyperplasia and immaturity but not hypertrophy are characteristic features of patients with RASopathies.

AIMS: RASopathies are caused by mutations in genes that alter the MAP kinase pathway and are marked by several malformations with cardiovascular disorders as the predominant cause of mortality. Mechanistic insights in the underlying pathogenesis in affected cardiac tissue are rare. The aim of the study was to assess the impact of RASopathy causing mutations on the human heart. METHODS AND RESULTS: Using single cell approaches and histopathology we analyzed cardiac tissue from children with different RASopathy-associated mutations compared to age-matched dilated cardiomyopathy (DCM) and control hearts. The volume of cardiomyocytes was reduced in RASopathy conditions compared to controls and DCM patients, and the estimated number of cardiomyocytes per heart was ∼4-10 times higher. Single nuclei RNA sequencing of a 13-year-old RASopathy patient (carrying a PTPN11 c.1528C > G mutation) revealed that myocardial cell composition and transcriptional patterns were similar to <1 year old DCM hearts. Additionally, immaturity of cardiomyocytes is shown by an increased MYH6/MYH7 expression ratio and reduced expression of genes associated with fatty acid metabolism. In the patient with the PTPN11 mutation activation of the MAP kinase pathway was not evident in cardiomyocytes, whereas increased phosphorylation of PDK1 and its downstream kinase Akt was detected. CONCLUSION: In conclusion, an immature cardiomyocyte differentiation status appears to be preserved in juvenile RASopathy patients. The increased mass of the heart in such patients is due to an increase in cardiomyocyte number (hyperplasia) but not an enlargement of individual cardiomyocytes (hypertrophy).

Serum anti-GM2 and anti-GalNAc-GD1a ganglioside IgG antibodies are biomarkers for immune-mediated polyneuropathies in cats.

Recent work identified anti-GM2 and anti-GalNAc-GD1a IgG ganglioside antibodies as biomarkers in dogs clinically diagnosed with acute canine polyradiculoneuritis, in turn considered a canine equivalent of Guillain-Barré syndrome. This study aims to investigate the serum prevalence of similar antibodies in cats clinically diagnosed with immune-mediated polyneuropathies. The sera from 41 cats clinically diagnosed with immune-mediated polyneuropathies (IPN), 9 cats with other neurological or neuromuscular disorders (ONM) and 46 neurologically normal cats (CTRL) were examined for the presence of IgG antibodies against glycolipids GM1, GM2, GD1a, GD1b, GalNAc-GD1a, GA1, SGPG, LM1, galactocerebroside and sulphatide. A total of 29/41 IPN-cats had either anti-GM2 or anti-GalNAc-GD1a IgG antibodies, with 24/29 cats having both. Direct comparison of anti-GM2 (sensitivity: 70.7%; specificity: 78.2%) and anti-GalNAc-GD1a (sensitivity: 70.7%; specificity: 70.9%) antibodies narrowly showed anti-GM2 IgG antibodies to be the better marker for identifying IPN-cats when compared to the combined ONM and CTRL groups (P = .049). Anti-GA1 and/or anti-sulphatide IgG antibodies were ubiquitously present across all sample groups, whereas antibodies against GM1, GD1a, GD1b, SGPG, LM1 and galactocerebroside were overall only rarely observed. Anti-GM2 and anti-GalNAc-GD1a IgG antibodies may serve as serum biomarkers for immune-mediated polyneuropathies in cats, as previously observed in dogs and humans.

SLC25A12 Missense Variant in Nova Scotia Duck Tolling Retrievers Affected by Cerebellar Degeneration-Myositis Complex (CDMC).

We investigated two litters of distantly related Nova Scotia Duck Tolling Retrievers (NSDTR), of which four puppies were affected by cerebellar signs with or without neuromuscular weakness. The phenotype was termed cerebellar degeneration­myositis complex (CDMC). We suspected a heritable condition and initiated a genetic analysis. The genome of one affected dog was sequenced and compared to 565 control genomes. This search yielded a private protein-changing SLC25A12 variant in the affected dog, XM_038584842.1:c.1337C>T, predicted to result in the amino acid change XP_038440770.1:(p.Pro446Leu). The genotypes at the variant co-segregated with the phenotype as expected for a monogenic autosomal recessive mode of inheritance in both litters. Genotyping of 533 additional NSDTR revealed variant allele frequencies of 3.6% and 1.3% in a European and a North American cohort, respectively. The available clinical and biochemical data, together with current knowledge about SLC25A12 variants and their functional impact in humans, mice, and dogs, suggest the p.Pro446Leu variant is a candidate causative defect for the observed phenotype in the affected dogs.

Comparison of Dorsal-to-Ventral Ratios of the Cervical Paraspinal Musculature in French Bulldogs With and Without Cervical Intervertebral Disk Disease and Two Other Breeds Based on CT Scan Measurements.

Objective: To objectively assess the cervical paraspinal musculature of French bulldogs (FBs) using computed tomography (CT) scan-based measurements, outline differences in other breeds published in the literature, and investigate the potential influence of its cervical paraspinal musculature on predisposed sites for intervertebral disk disease. Animals: Thirty FBs that underwent CT scans of the cervical spine from the skull to C7/T1 were enrolled. Fifteen dogs were patients suffering from intervertebral disk herniation (IVDH group), and 15 dogs underwent CT scans due to brachycephalic obstructive airway syndrome (BOAS group). Methods: At the level of each cervical intervertebral disk from C2/C3 to C7/T1, measurements were performed and statistically analyzed. On the sagittal CT scan reconstruction, the height ratio of the dorsal to ventral paraspinal musculature and the angle of the disk axis to vertebral body length were assessed. On the transverse plane, the area ratio of the dorsal and ventral paraspinal musculature and the ratio of force moments were determined at each intervertebral disk level. Finally, ratios were compared to the values of Labrador retrievers and dachshunds published by Hartmann et al. (1). Results: Comparing the two FB groups, one significant difference was detected in the mean height ratio of the dorsal to ventral paraspinal musculature at the level of C5/C6 (P = 0.0092) and C6/C7 (P = 0.0076), with IVDH FBs having the more prominent dorsal paraspinal musculature. At the level of C3/C4, a significantly less prominent dorsal paraspinal musculature in FBs than in dachshunds (P = 0.0058) and a significantly steeper disk to vertebral body angulation were observed (P = 0.0005). Conclusion: Although some incidental differences were found, most parameters did not significantly differ between the BOAS and IVDH FBs. Significant conformational differences in the cervical paraspinal musculature and disk to vertebral body length angulation were found between FBs and two other breeds (chondrodystrophic and non-chondrodystrophic). This study's findings suggest that the paraspinal musculature is an additional biomechanical influencing factor on the preferential sites of IVDH in the cervical spine and that other major factors exist in IVDH development, especially in FBs.

Investigation of timing of surgery and other factors possibly influencing outcome in dogs with acute thoracolumbar disc extrusion: a retrospective study of 1501 cases.

BACKGROUND: Intervertebral disc extrusions in the thoracolumbar region are a common spinal neurologic disorder in dogs and usually considered a neurological emergency. Several factors, like timing of surgery, have previously been analysed in order to determine the effect on outcome and time of recovery. Most studies have investigated one defined population of dogs and the influence of a single factor on the overall outcome. In this retrospective study, a large cohort of dogs and the influence of one or combinations of several factors on outcome and time of recovery were analysed. RESULTS: The bivariate analysis demonstrated a significant association between the following variables and the time of recovery: the time span between the onset of clinical signs and surgery (Cramers Phi [Formula: see text] = 0.14; P = 0.003), the grade of severity ([Formula: see text] = 0.23; P < 0.001) and the implementation of physical rehabilitation ([Formula: see text] = 0.2; P < 0.001). However, the analysis of a multivariable regression model demonstrated that a significant correlation only exists between the time span between the onset of clinical signs and surgery and the overall outcome (P = 0.007), as well as between the grade of severity and the time of recovery (P < 0.001). The percentage of dogs with lacking deep pain perception (DPP) that had to be euthanised due to their neurological condition, decreased from 20.0 to 2.9% when physical rehabilitation was implemented. Additionally, the proportion of dogs (same group) that improved to reach an ambulatory status increased from 80.0 to 91.4%. CONCLUSION: The results of the bivariate analysis demonstrated several correlations between some variables and overall outcome or time of recovery, whereas the multivariable regression model demonstrated only two associations. The time span between the onset of clinical signs and surgery was significantly associated with the overall outcome. We therefore suggest that a surgical intervention should be performed without unreasonable delay. Due to the correlation between the grade of severity and time of recovery, owners of dogs with more severe neurological deficits prior to surgery should be informed about the presumably prolonged time of recovery.

Canine Lafora Disease: An Unstable Repeat Expansion Disorder.

Canine Lafora disease is a recessively inherited, rapidly progressing neurodegenerative disease caused by the accumulation of abnormally constructed insoluble glycogen Lafora bodies in the brain and other tissues due to the loss of NHL repeat containing E3 ubiquitin protein ligase 1 (NHLRC1). Dogs have a dodecamer repeat sequence within the NHLRC1 gene, which is prone to unstable (dynamic) expansion and loss of function. Progressive signs of Lafora disease include hypnic jerks, reflex and spontaneous myoclonus, seizures, vision loss, ataxia and decreased cognitive function. We studied five dogs (one Chihuahua, two French Bulldogs, one Griffon Bruxellois, one mixed breed) with clinical signs associated with canine Lafora disease. Identification of polyglucosan bodies (Lafora bodies) in myocytes supported diagnosis in the French Bulldogs; muscle areas close to the myotendinous junction and the myofascial union segment had the highest yield of inclusions. Postmortem examination of one of the French Bulldogs revealed brain Lafora bodies. Genetic testing for the known canine NHLRC1 mutation confirmed the presence of a homozygous mutation associated with canine Lafora disease. Our results show that Lafora disease extends beyond previous known breeds to the French Bulldog, Griffon Bruxellois and even mixed-breed dogs, emphasizing the likely species-wide nature of this genetic problem. It also establishes these breeds as animal models for the devastating human disease. Genetic testing should be used when designing breeding strategies to determine the frequency of the NHLRC1 mutation in affected breeds. Lafora diseases should be suspected in any older dog presenting with myoclonus, hypnic jerks or photoconvulsions.

The p.Ala2430Val mutation in filamin C causes a "hypertrophic myofibrillar cardiomyopathy".

Hypertrophic cardiomyopathy (HCM) often leads to heart failure. Mutations in sarcomeric proteins are most frequently the cause of HCM but in many patients the gene defect is not known. Here we report on a young man who was diagnosed with HCM shortly after birth. Whole exome sequencing revealed a mutation in the FLNC gene (c.7289C > T; p.Ala2430Val) that was previously shown to cause aggregation of the mutant protein in transfected cells. Myocardial tissue from patients with this mutation has not been analyzed before and thus, the underlying etiology is not well understood. Myocardial tissue of our patient obtained during myectomy at the age of 23 years was analyzed in detail by histochemistry, immunofluorescence staining, electron microscopy and western blot analysis. Cardiac histology showed a pathology typical for myofibrillar myopathy with myofibril disarray and abnormal protein aggregates containing BAG3, desmin, HSPB5 and filamin C. Analysis of sarcomeric and intercalated disc proteins showed focally reduced expression of the gap junction protein connexin43 and Xin-positive sarcomeric lesions in the cardiomyocytes of our patient. In addition, autophagy pathways were altered with upregulation of LC3-II, WIPI1 and HSPB5, 6, 7 and 8. We conclude that the p.Ala2430Val mutation in FLNC most probably is associated with HCM characterized by abnormal intercalated discs, disarray of myofibrils and aggregates containing Z-disc proteins similar to myofibrillar myopathy, which supports the pathological effect of the mutation.

Single Nuclei Sequencing Reveals Novel Insights Into the Regulation of Cellular Signatures in Children With Dilated Cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is a leading cause of death in children with heart failure. The outcome of pediatric heart failure treatment is inconsistent, and large cohort studies are lacking. Progress may be achieved through personalized therapy that takes age- and disease-related pathophysiology, pathology, and molecular fingerprints into account. We present single nuclei RNA sequencing from pediatric patients with DCM as the next step in identifying cellular signatures. METHODS: We performed single nuclei RNA sequencing with heart tissues from 6 children with DCM with an age of 0.5, 0.75, 5, 6, 12, and 13 years. Unsupervised clustering of 18 211 nuclei led to the identification of 14 distinct clusters with 6 major cell types. RESULTS: The number of nuclei in fibroblast clusters increased with age in patients with DCM, a finding that was confirmed by histological analysis and was consistent with an age-related increase in cardiac fibrosis quantified by cardiac magnetic resonance imaging. Fibroblasts of patients with DCM >6 years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans, switch in thrombospondin isoforms, and signatures of fibroblast activation. In addition, a population of cardiomyocytes with a high proregenerative profile was identified in infant patients with DCM but was absent in children >6 years of age. This cluster showed high expression of cell cycle activators such as cyclin D family members, increased glycolytic metabolism and antioxidative genes, and alterations in ß-adrenergic signaling genes. CONCLUSIONS: Novel insights into the cellular transcriptomes of hearts from pediatric patients with DCM provide remarkable age-dependent changes in the expression patterns of fibroblast and cardiomyocyte genes with less fibrotic but enriched proregenerative signatures in infants.

Aetiology and 30-Year Long-Term Outcome of Children with Cardiomyopathy Necessitating Heart Transplantation.

Studies assessing the long-term outcome after heart transplantation HTX in patients with cardiomyopathy (CM) in the paediatric age range are rare. The aim of this study was to determine the survival rate of children with CM undergoing HTX and to analyse how aetiology of cardiomyopathy influenced morbidity and mortality. We retrospectively analysed the medical records of children; who were transplanted in our centre between June 1988 and October 2019. 236 heart transplantations were performed since 1988 (9 re-transplants). 98 of 227 patients (43.2%) were transplanted because of CM. Survival rates were 93% after 1; 84% after 10 and 75% after 30 years. Overall; the aetiology of CM could be clearly identified in 37 subjects (37.7%). This rate increased up to 66.6% (12/19) by applying a comprehensive diagnostic workup since 2016. The survival rate was lower (p < 0.05) and neurocognitive deficits were more frequent (p = 0.001) in subjects with systemic diseases than in individuals with cardiac-specific conditions. These data indicate that the long-term survival rate of children with CM after HTX in experienced centers is high. A comprehensive diagnostic workup allows unraveling the basic defect in the majority of patients with CM undergoing HTX. Aetiology of CM affects morbidity and mortality in subjects necessitating HTX.

SLC19A3 Loss-of-Function Variant in Yorkshire Terriers with Leigh-Like Subacute Necrotizing Encephalopathy.

Sporadic occurrence of juvenile-onset necrotizing encephalopathy (SNE) has been previously reported in Yorkshire terriers. However, so far, no causative genetic variant has been found for this breed-specific form of suspected mitochondrial encephalomyopathy. Affected dogs showed gait abnormalities, central visual defects, and/or seizures. Histopathological analysis revealed the presence of major characteristics of human Leigh syndrome and SNE in Alaskan huskies. The aim of this study was to characterize the genetic etiology of SNE-affected purebred Yorkshire terriers. After SNP genotyping and subsequent homozygosity mapping, we identified a single loss-of-function variant by whole-genome sequencing in the canine SLC19A3 gene situated in a 1.7 Mb region of homozygosity on chromosome 25. All ten cases were homozygous carriers of a mutant allele, an indel variant in exon 2, that is predicted to lead to a frameshift and to truncate about 86% of the wild type coding sequence. This study reports a most likely pathogenic variant in SLC19A3 causing a form of SNE in Yorkshire terriers and enables selection against this fatal neurodegenerative recessive disorder. This is the second report of a pathogenic alteration of the SLC19A3 gene in dogs with SNE.

Fractures of the Second Cervical Vertebra in 66 Dogs and 3 Cats: A Retrospective Study.

BACKGROUND: In human medicine, fractures of the second cervical vertebra have been studied elaborately and categorized in detail. This is not the case in veterinary medicine where clinical decisions are often based on old studies focusing on the cervical spine in general. OBJECTIVES: The aim of this study was to describe the clinical features, fracture types, therapeutic options and outcome of dogs and cats with a fractured axis. STUDY DESIGN: The present study was a multi-institutional retrospective case series. RESULTS: Crossbreeds and Labrador Retrievers were the most represented dog breeds. Median age was 2 years. Motor vehicle accident was the most common inciting cause, followed by frontal collision. The most common neurological deficits ranged from cervical pain with or without mild ataxia (22/68) to tetraparesis (28/68) and tetraplegia (11/68). Concerning treatment, 37 of 69 patients underwent surgical fracture stabilization, 27/69 received conservative therapy and 5/69 were immediately euthanatized. Of all treated cases, 52/58 showed ambulatory recovery (23/25 of the conservatively treated and 29/33 of the surgically treated cases), whereby in 40/52 cases full recovery without persisting signs was achieved. CONCLUSIONS: Fractures of the axis commonly occur in young dogs. In many cases, neurological deficits are relatively mild. Generally, animals with a fractured axis have a very good prognosis for functional recovery. The risk of perioperative mortality is considerably lower than previously reported.

Genetic basis of hypertrophic cardiomyopathy in children.

BACKGROUND: Previous investigations assessing the genetic cause of pediatric hypertrophic cardiomyopathy (HCM) found underlying genetic mutations in 50-60% of cases. The purpose of our study was to analyze whether this number can be augmented by applying next-generation sequencing and directing further diagnostics by discussing unsolved cases in a multidisciplinary board. METHODS AND RESULTS: 42 patients with the diagnoses of HCM made before age 18 years were treated in our center from 2000 to 2016. Genetic analysis was performed in 36 subjects, a genetic defect was detected in 29 (78%) patients. 15 individuals (42%) had pathogenic variants in genes encoding sarcomere proteins, and 5 (14%) in genes coding for components of the RAS/MAPK signaling pathway. 4 subjects (11%) had mutations in the GAA gene (Pompe disease), and 3 (8%) had Frataxin repeat expansions (Friedreich's ataxia). One patient each showed a mutation in BAG3 and LMNA. Discussion of unsolved HCM cases after performing next-generation sequencing (28 genes) in an interdisciplinary board unraveled the genetic cause in 9 subjects (25%). CONCLUSION: A definite genetic diagnosis can be reached in nearly 80% with HCM of childhood onset. Next-generation sequencing in conjunction with a multidisciplinary cooperation can enhance the diagnostic yield substantially. This may be important for risk stratification, treatment planning and genetic counseling.

[Fibromyalgia Syndrome - Impact for Rehabilitation]. / Fibromyalgiesyndrom ­ Bedeutung für die Rehabilitation.

Fibromyalgia syndrome (FMS) is one of the most common chronic pain syndromes. In a representative survey, 2.1% of the German population was affected in 2013, whereby the diagnosis can only be made on the basis of subjective complaints. This article should provide concrete information on the disease concept, diagnosis, therapy, rehabilitation and socialmedical assessment at the FMS. The basis for this is the second update of the S3 guideline to the FMS adopted in 2017.