Identification of eight novel coagulation factor XIII subunit A mutations: implied consequences for structure and function

Severe hereditary coagulation factor XIII deficiency is a rare homozygous bleeding disorder affecting one person in every two million individuals. In contrast, heterozygous factor XIII deficiency is more common, but usually not associated with severe hemorrhage such as intracranial bleeding or hemarthrosis. In most cases, the disease is caused by F13A gene mutations. Causative mutations associated with the F13B gene are rarer.

Preoperative mapping of arterial spinal supply using 3.0-T MR angiography with an intravasal contrast medium and high-spatial-resolution steady-state

Preoperative mapping of the arterial spinal supply prior to thoracoabdominal aortic aneurysm repair is highly relevant because of high risk for postoperative ischemic spinal cord injuries such as paraparesis or paraplegia.

Brain metabolite composition in relation to cognitive function and dystrophin mutations in boys with Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a hereditary X-linked recessive disorder affecting the synthesis of dystrophin, a protein essential for structural stability in muscle. Dystrophin also occurs in the central nervous system, particularly in the neocortex, hippocampus and cerebellum. Quantitative metabolic analysis by localized (1) H MRS was performed in the cerebellum (12 patients and 15 controls) and a temporo-parietal location (eight patients and 15 controls) in patients with DMD and healthy controls to investigate possible metabolic differences. In addition, the site of individual mutations on the dystrophin gene was analyzed and neuropsychological cognitive functions were examined. Cognitive deficits in the patient group were found in line with earlier investigations, mainly concerning verbal short-term memory, visuo-spatial long-term memory and verbal fluency, but also the full-scale IQ. Causal mutations were identified in all patients with DMD. Quantitative MRS showed consistent choline deficits, in both cerebellar white matter and temporo-parietal cortex, as well as small, but significant, metabolic abnormalities for glutamate and total N-acetyl compounds in the temporo-parietal region. Compartment water analysis did not reveal any abnormalities. In healthy subjects, choline levels were age related in the cerebellum. The choline deficit contrasts with earlier findings in DMD, where a surplus of choline was postulated for the cerebellum. In patients, total N-acetyl compounds in the temporo-parietal region were related to verbal IQ and verbal short-term memory. However, choline, the putative main metabolic abnormality, was not found to be associated with cognitive deficits. Furthermore, in contrast with the cognitive performance, the metabolic brain composition did not depend significantly on whether or not gene mutations concerned the expression of the dystrophin isoform Dp140, leading to the conclusion that the effect of the missing Dp140 isoform on cognitive performance is not mediated through the observed metabolite composition, or is caused by local effects beyond the resolution accessible to MRS investigations.

Factors influencing age at diagnosis of primary ciliary dyskinesia in European children

Primary ciliary dyskinesia (PCD) is a hereditary disorder of mucociliary clearance causing chronic upper and lower airways disease. We determined the number of patients with diagnosed PCD across Europe, described age at diagnosis and determined risk factors for late diagnosis. Centres treating children with PCD in Europe answered questionnaires and provided anonymous patient lists. In total, 223 centres from 26 countries reported 1,009 patients aged < 20 yrs. Reported cases per million children (for 5-14 yr olds) were highest in Cyprus (111), Switzerland (47) and Denmark (46). Overall, 57% were males and 48% had situs inversus. Median age at diagnosis was 5.3 yrs, lower in children with situs inversus (3.5 versus 5.8 yrs; p < 0.001) and in children treated in large centres (4.1 versus 4.8 yrs; p = 0.002). Adjusted age at diagnosis was 5.0 yrs in Western Europe, 4.8 yrs in the British Isles, 5.5 yrs in Northern Europe, 6.8 yrs in Eastern Europe and 6.5 yrs in Southern Europe (p < 0.001). This strongly correlated with general government expenditures on health (p < 0.001). This European survey suggests that PCD in children is under-diagnosed and diagnosed late, particularly in countries with low health expenditures. Prospective studies should assess the impact this delay might have on patient prognosis and on health economic costs across Europe.

Should intentional endovascular stent-graft coverage of the left subclavian artery be preceded by prophylactic revascularisation?

Thoracic endovascular aortic repair (TEVAR) has emerged as a promising therapeutic alternative to conventional open aortic replacement but it requires suitable proximal and distal landing zones for stent-graft anchoring. Many aortic pathologies affect in the immediate proximity of the left subclavian artery (LSA) limiting the proximal landing zone site without proximal vessel coverage. In patients in whom the distance between the LSA and aortic lesion is too short, extension of the landing zone can be obtained by covering the LSA's origin with the endovascular stent graft (ESG). This manoeuvre has the potential for immediate and delayed neurological and vascular symptoms. Some authors, therefore, propose prophylactic revascularisation of the LSA by transposition or bypass, while others suggest prophylactic revascularisation only under certain conditions, and still others see no requirement for prophylactic revascularisation in anticipation of LSA ostium coverage. In this review about LSA revascularisation in TEVAR patients with coverage of the LSA, we searched the electronic databases MEDLINE and EMBASE historically until the end date of May 2010 with the search terms left subclavian artery, covering, endovascular, revascularisation and thoracic aorta. We have gathered the most complete scientific evidence available used to support the various concepts to deal with this issue. After a review of the current available literature, 23 relevant articles were found, where we have identified and analysed three basic treatment concepts for LSA revascularisation in TEVAR patients (prophylactic, conditional prophylactic and no prophylactic LSA revascularisation). The available evidence supports prophylactic revascularisation of the LSA before ESG LSA coverage when preoperative imaging reveals abnormal supra-aortic vascular anatomy or pathology. We further conclude that elective patients undergoing planned coverage of the LSA during TEVAR should receive prophylactic LSA transposition or LSA-to-left-common-carotid-artery (LCCA) bypass surgery to prevent severe neurological complications, such as paraplegia or brain stem infarction.

Protective and risk factors in amateur equestrians and description of injury patterns: A retrospective data analysis and a case - control survey

Background In Switzerland there are about 150,000 equestrians. Horse related injuries, including head and spinal injuries, are frequently treated at our level I trauma centre. Objectives To analyse injury patterns, protective factors, and risk factors related to horse riding, and to define groups of safer riders and those at greater risk Methods We present a retrospective and a case-control survey at conducted a tertiary trauma centre in Bern, Switzerland. Injured equestrians from July 2000 - June 2006 were retrospectively classified by injury pattern and neurological symptoms. Injured equestrians from July-December 2008 were prospectively collected using a questionnaire with 17 variables. The same questionnaire was applied in non-injured controls. Multiple logistic regression was performed, and combined risk factors were calculated using inference trees. Results Retrospective survey A total of 528 injuries occured in 365 patients. The injury pattern revealed as follows: extremities (32%: upper 17%, lower 15%), head (24%), spine (14%), thorax (9%), face (9%), pelvis (7%) and abdomen (2%). Two injuries were fatal. One case resulted in quadriplegia, one in paraplegia. Case-control survey 61 patients and 102 controls (patients: 72% female, 28% male; controls: 63% female, 37% male) were included. Falls were most frequent (65%), followed by horse kicks (19%) and horse bites (2%). Variables statistically significant for the controls were: Older age (p = 0.015), male gender (p = 0.04) and holding a diploma in horse riding (p = 0.004). Inference trees revealed typical groups less and more likely to suffer injury. Conclusions Experience with riding and having passed a diploma in horse riding seem to be protective factors. Educational levels and injury risk should be graded within an educational level-injury risk index.

Monogenic forms of hypertension

Arterial hypertension in childhood is less frequent as compared to adulthood but is more likely to be secondary to an underlying disorder. After ruling out more obvious causes, some patients still present with strongly suspected secondary hypertension of yet unknown etiology. A number of these children have hypertension due to single gene mutations inherited in an autosomal dominant or recessive fashion. The finding of abnormal potassium levels (low or high) in the presence of suppressed renin secretion, and metabolic alkalosis or acidosis should prompt consideration of these familial diseases. However, mild hypertension and the absence of electrolyte abnormalities do not exclude hereditary conditions. In monogenic hypertensive disorders, three distinct mechanisms leading to the common final pathway of increased sodium reabsorption, volume expansion, and low plasma renin activity are documented. The first mechanism relates to gain-of-function mutations with a subsequent hyperactivity of renal sodium and chloride reabsorption leading to plasma volume expansion (e.g., Liddle's syndrome, Gordon's syndrome). The second mechanism involves deficiencies of enzymes that regulate adrenal steroid hormone synthesis and deactivation (e.g., subtypes of congenital adrenal hyperplasia, apparent mineralocorticoid excess (AME)). The third mechanism is characterized by excessive aldosterone synthesis that escapes normal regulatory mechanisms and leading to volume-dependent hypertension in the presence of suppressed renin release (glucocorticoid remediable aldosteronism). Hormonal studies coupled with genetic testing can help in the early diagnosis of these disorders.

Long-term outcome and adverse effects of selective dorsal rhizotomy in children with cerebral palsy: a systematic review

To assess the long-term outcome and adverse events of selective dorsal rhizotomy (SDR) in children with spastic cerebral palsy (CP).

A deletion in the N-myc downstream regulated gene 1 (NDRG1) gene in Greyhounds with polyneuropathy

The polyneuropathy of juvenile Greyhound show dogs shows clinical similarities to the genetically heterogeneous Charcot-Marie-Tooth (CMT) disease in humans. The pedigrees containing affected dogs suggest monogenic autosomal recessive inheritance and all affected dogs trace back to a single male. Here, we studied the neuropathology of this disease and identified a candidate causative mutation. Peripheral nerve biopsies from affected dogs were examined using semi-thin histology, nerve fibre teasing and electron microscopy. A severe chronic progressive mixed polyneuropathy was observed. Seven affected and 17 related control dogs were genotyped on the 50k canine SNP chip. This allowed us to localize the causative mutation to a 19.5 Mb interval on chromosome 13 by homozygosity mapping. The NDRG1 gene is located within this interval and NDRG1 mutations have been shown to cause hereditary motor and sensory neuropathy-Lom in humans (CMT4D). Therefore, we considered NDRG1 a positional and functional candidate gene and performed mutation analysis in affected and control Greyhounds. A 10 bp deletion in canine NDRG1 exon 15 (c.1080_1089delTCGCCTGGAC) was perfectly associated with the polyneuropathy phenotype of Greyhound show dogs. The deletion causes a frame shift (p.Arg361SerfsX60) which alters several amino acids before a stop codon is encountered. A reduced level of NDRG1 transcript could be detected by RT-PCR. Western blot analysis demonstrated an absence of NDRG1 protein in peripheral nerve biopsy of an affected Greyhound. We thus have identified a candidate causative mutation for polyneuropathy in Greyhounds and identified the first genetically characterized canine CMT model which offers an opportunity to gain further insights into the pathobiology and therapy of human NDRG1 associated CMT disease. Selection against this mutation can now be used to eliminate polyneuropathy from Greyhound show dogs.

Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura

The regulation of VWF multimer size is essential in preventing spontaneous microvascular platelet clumping, a central pathophysiologic finding in thrombotic thrombocytopenic purpura (TTP). In the majority of TTP patients, ADAMTS13, the principal regulator of VWF size, is severely deficient. Today, 2 forms of severe ADAMTS13 deficiency are recognized. The acquired form is caused by circulating autoantibodies inhibiting ADAMTS13 activity or increasing ADAMTS13 clearance. Pathogenic anti-ADAMTS13 Abs are mainly of the IgG class, predominantly of subclass IgG4, and inhibitory Abs recognize a defined epitope in the ADAMTS13 spacer domain. The reasons underlying the failure to maintain immunologic tolerance to ADAMTS13, however, are still poorly understood. Constitutional ADAMTS13 deficiency leading to hereditary TTP, also known as Upshaw-Schulman syndrome, is the result of homozygous or compound heterozygous ADAMTS13 gene mutations.

Icatibant , the bradykinin B2 receptor antagonist with target to the interconnected kinin systems

INTRODUCTION: HOE-140/ Icatibant is a selective, competitive antagonist to bradykinin (BK) against its binding to the kinin B2 receptor. Substitution of five non-proteogeneic amino acid analogues makes icatibant resistant to degradation by metalloproteases of kinin catabolism. Icatibant has clinical applications in inflammatory and vascular leakage conditions caused by an acute (non-controlled) production of kinins and their accumulation at the endothelium B2 receptor. The clinical manifestation of vascular leakage, called angioedema (AE), is characterized by edematous attacks of subcutaneous and submucosal tissues, which can cause painful intestinal consequences, and life-threatening complications if affecting the larynx. Icatibant is registered for the treatment of acute attacks of the hereditary BK-mediated AE, i.e., AE due to C1 inhibitor deficiency. AREAS COVERED: This review discusses emerging knowledge on the kinin system: kinin pharmacological properties, biochemical characteristics of the contact phase and kinin catabolism proteases. It underlines the responsibility of the kinins in AE initiation and the potency of icatibant to inhibit AE formation by kinin-receptor interactions. EXPERT OPINION: Icatibant antagonist properties protect BK-mediated AE patients against severe attacks, and could be developed for use in inflammatory conditions. More studies are required to confirm whether or not prolonged and frequent applications of icatibant could result in the impairment of the cardioprotective effect of BK.

A common variant of PNPLA3 (p.I148M) is not associated with alcoholic chronic pancreatitis

Background Chronic pancreatitis (CP) is an inflammatory disease that in some patients leads to exocrine and endocrine dysfunction. In industrialized countries the most common aetiology is chronic alcohol abuse. Descriptions of associated genetic alterations in alcoholic CP are rare. However, a common PNPLA3 variant (p.I148M) is associated with the development of alcoholic liver cirrhosis (ALC). Since, alcoholic CP and ALC share the same aetiology PNPLA3 variant (p.I148M) possibly influences the development of alcoholic CP. Methods Using melting curve analysis we genotyped the variant in 1510 patients with pancreatitis or liver disease (961 German and Dutch alcoholic CP patients, 414 German patients with idiopathic or hereditary CP, and 135 patients with ALC). In addition, we included in total 2781 healthy controls in the study. Results The previously published overrepresentation of GG-genotype was replicated in our cohort of ALC (p-value <0.0001, OR 2.3, 95% CI 1.6–3.3). Distributions of genotype and allele frequencies of the p.I148M variant were comparable in patients with alcoholic CP, idiopathic and hereditary CP and in healthy controls. Conclusions The absence of an association of PNPLA3 p.I148M with alcoholic CP seems not to point to a common pathway in the development of alcoholic CP and alcoholic liver cirrhosis.

Huntington's disease: new aspects on phenotype and genotype

Huntington's disease typically presents with involuntary movements, cognitive decline and behavioural abnormalities; however, new data show a greater spectrum and more complexity in the mode of presentation than previously appreciated. On one hand efforts are under way to better assess all aspects of the evolving phenotype over the course of the disease, on the other hand large cohorts have been prospectively followed-up and similar efforts are now being started in China. In this communication, we briefly review the most salient findings from the last couple of years. The recently established large cohorts allow the performance of accurate studies examining correlation of genetic polymorphisms with specific aspects of the phenotype thus allowing for some mechanistic insight into the causes of phenotypic variation. While Huntington's disease is the most frequent hereditary cause of chorea, other disorders with similar clinical phenotypes, including neuroacanthocytosis, are now better known, including a better understanding of the primary cause as well as the pathophysiology at the molecular level. Studies on the mechanisms of disease in these different disorders may shed light on the respective pathomechanisms and may open new approaches to a better understanding and additional treatment options for choreatiform neurodegenerative disorders.

Acute Encephalopathy with Unilateral Cortical-Subcortical Lesions in Two Unrelated Kindreds Treated with Glucocorticoids Prenatally for Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: Established Facts and Novel Insight

Background: Prenatal glucocorticoid (GC) treatment of the female fetus with 21-hydroxylase deficiency (21-OHD) may prevent genital virilization and androgen effects on the brain, but prenatal GC therapy is controversial because of possible adverse effects on fetal programming, the cardiovascular system and the brain. Case Reports: We report 2 patients with congenital adrenal hyperplasia (CAH) due to 21-OHD who were treated prenatally with dexamethasone, suffered from an acute encephalopathy and showed focal and multifocal cortical and subcortical diffusion restrictions in early MRI and signs of permanent alterations in the follow-up neuroimaging studies. Both patients recovered from the acute episode. Whereas the first patient recovered without neurological sequelae the second patient showed hemianopsia and spastic hemiplegia in the neurological follow-up examination. Conclusion: These are 2 children with CAH, both treated prenatally with high doses of dexamethasone to prevent virilization. The question arises whether prenatal high-dose GC treatment in patients with CAH might represent a risk factor for brain lesions in later life. Adverse effects/events should be reported systematically in patients undergoing prenatal GC treatment and long-term follow-up studies involving risk factors for cerebrovascular disease should be performed.

A clinical approach to arterial ischemic childhood stroke: increasing knowledge over the last decade

Childhood stroke is increasingly being recognized as an important burden not only for affected children and families, but also for socioeconomic reasons. A primary problem is delayed diagnosis, due to the many mimics of childhood stroke, and the variety of manifesting symptoms. The most important is hemiparesis (with/without dysphasia or facial palsy), but ataxia, seizures, and many more are also possible. Suspicion of stroke has to be ascertained by neuroimaging, gold standard being (diffusion weighted) magnetic resonance. Risk factors are multiple, but their presence might help to increase the suspicion of stroke. The most important factors are infectious/parainfectious etiologies, frequently possibly manifesting by transient focal cerebral arteriopathy (FCA). Cardiological underlying problems are the second most important. Arteriopathies can be detected in about half of the children, besides FCA and dissection and MoyaMoya disease are the most important. Hereditary coagulopathies increase the risk of stroke. There is still a controversy on best treatment in children: platelet antiaggregation and heparinization are used about equally. Thrombolysis is being discussed increasingly. Severity of symptoms at manifestation and on follow-up are not less significant in children than in young adults. About two-third of the children have significant residual neurological problems and a majority cognitive and behavior problems.