Monogenic Syndromes Research Articles

The Impact of Next-Generation Sequencing on the Diagnosis and Treatment of Epilepsy in Paediatric Patients

Next-generation sequencing (NGS) has contributed to the identification of many monogenic epilepsy syndromes and is favouring earlier and more accurate diagnosis in a subset of paediatric patients with epilepsy. The cumulative information emerging from NGS studies is rapidly changing our comprehension of the relations between early-onset severe epilepsy and the associated neurological impairment, progressively delineating specific entities previously gathered under the umbrella definition of epileptic encephalopathies, thereby influencing treatment choices and limiting the most aggressive drug regimens only to those conditions that are likely to actually benefit from them. Although ion channel genes represent the gene family most frequently causally related to epilepsy, other genes have gradually been associated with complex developmental epilepsy conditions, revealing the pathogenic role of mutations affecting diverse molecular pathways that regulate membrane excitability, synaptic plasticity, presynaptic neurotransmitter release, postsynaptic receptors, transporters, cell metabolism, and many formative steps in early brain development. Some of these discoveries are being followed by proof-of-concept laboratory studies that might open new pathways towards personalized treatment choices. No specific treatment is available for most of the monogenic disorders that can now be diagnosed early using NGS, and the main benefits of knowing the specific cause include etiological diagnosis, better prognostication and genetic counselling; however, for a limited number of disorders, timely treatment based on their known molecular pathology is already possible and sometimes decisive. Discovery of a causative gene defect associated with a non-progressive course may reduce the need for further diagnostic investigations in the search for a progressive disorder at the biochemical and imaging level. NGS has also improved the turnaround time for molecular diagnosis and allowed more timely and straightforward treatment choices for specific conditions as well as avoiding needless investigations and inappropriate or unnecessary treatment choices.

Genomics and Precision Medicine for Clinicians and Scientists in Hypertension.

In 1903, Sir William Osler wrote “the good physician treats the disease; the great physician treats the patient who has the disease.” These words ring very true in 2016 as we approach the era of precision or stratified medicine. The precision or stratified medicine (we are going to use these terms interchangeably) is based on identifying subgroups of patients with distinct mechanisms of disease and particular responses to treatments. This allows us to identify and develop treatments that are effective for particular groups of patients. Ultimately, precision medicine will ensure that the right patient gets the right treatment at the right time. The above definition broadly follows suggested definition published by the UK Medical Research Council (http://www.mrc.ac.uk/research/initiatives/stratified-medicine/). We can therefore summarize the promise of precision medicine as being able to remove nonresponders and toxic responders before prescribing medication and to treat with a given drug only responders and patients not predisposed to toxicity. Such approaches are very well developed in cancer medicine with several examples of successful precision medicine applications in breast, prostate, ovarian, colon, and pancreatic cancer,1–6 and this list is by no means complete. Cardiovascular medicine in general and hypertension in particular both lag behind oncology in this respect. However, there are examples from rare monogenic syndromes, where a single genetic mutation explains the entire pathophysiology of severe, early onset hypertension and dictating perfect pharmacogenetics-led prescription.7,8 These syndromes include the Glucocorticoid Remediable Aldosteronism, Liddle Syndrome, and pseudohypoaldosteronism type II to name just a few. In these syndromes, glucocorticoids, amiloride, and thiazide diuretics, …

High-throughput screen detects calcium signaling dysfunction in typical sporadic autism spectrum disorder

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders without any defined uniting pathophysiology. Ca2+ signaling is emerging as a potential node in the genetic architecture of the disorder. We previously reported decreased inositol trisphosphate (IP3)-mediated Ca2+ release from the endoplasmic reticulum in several rare monogenic syndromes highly comorbid with autism – fragile X and tuberous sclerosis types 1 and 2 syndromes. We now extend those findings to a cohort of subjects with sporadic ASD without any known mutations. We developed and applied a high throughput Fluorometric Imaging Plate Reader (FLIPR) assay to monitor agonist-evoked Ca2+ signals in human primary skin fibroblasts. Our results indicate that IP3 -mediated Ca2+ release from the endoplasmic reticulum in response to activation of purinergic receptors is significantly depressed in subjects with sporadic as well as rare syndromic forms of ASD. We propose that deficits in IP3-mediated Ca2+ signaling represent a convergent hub function shared across the spectrum of autistic disorders – whether caused by rare highly penetrant mutations or sporadic forms – and holds promise as a biomarker for diagnosis and novel drug discovery.

Dissecting Clinical Heterogeneity in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder in which affected children and adults are predisposed to the development of benign and malignant nervous system tumors. Caused by a germline mutation in the NF1 tumor suppressor gene, individuals with NF1 are prone to optic gliomas, malignant gliomas, neurofibromas, and malignant peripheral nerve sheath tumors, as well as behavioral, cognitive, motor, bone, cardiac, and pigmentary abnormalities. Although NF1 is a classic monogenic syndrome, the clinical features of the disorder and their impact on patient morbidity are variable, even within individuals who bear the same germline NF1 gene mutation. As such, NF1 affords unique opportunities to define the factors that contribute to disease heterogeneity and to develop therapies personalized to a given individual (precision medicine). This review highlights the clinical features of NF1 and the use of genetically engineered mouse models to define the molecular and cellular pathogenesis of NF1-associated nervous system tumors.

DUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure.

We describe a new syndrome characterized by early-onset diabetes associated with bone marrow failure, affecting mostly the erythrocytic lineage. Using whole-exome sequencing in a remotely consanguineous patient from a family with two affected siblings, we identified a single homozygous missense mutation (chr15.hg19:g.48,626,619A>G) located in the dUTPase (DUT) gene (National Center for Biotechnology Information Gene ID 1854), affecting both the mitochondrial (DUT-M p.Y142C) and the nuclear (DUT-N p.Y54C) isoforms. We found the same homozygous mutation in an unrelated consanguineous patient with diabetes and bone marrow aplasia from a family with two affected siblings, whereas none of the >60,000 subjects from the Exome Aggregation Consortium (ExAC) was homozygous for this mutation. This replicated observation probability was highly significant, thus confirming the role of this DUT mutation in this syndrome. DUT is a key enzyme for maintaining DNA integrity by preventing misincorporation of uracil into DNA, which results in DNA toxicity and cell death. We showed that DUT silencing in human and rat pancreatic β-cells results in apoptosis via the intrinsic cell death pathway. Our findings support the importance of tight control of DNA metabolism for β-cell integrity and warrant close metabolic monitoring of patients treated by drugs affecting dUTP balance.

Is obesity genetic disease?

Obesity is a complex disease that has unfavorable impacts for all ethnic populations in worldwide. Genetics, environment and lifestyle are among aetiological factors of this disease. Genetic contribution associated with this disease is generally classified into 2 types: monogenic syndromes that display severe obesity, and the polygenic model of common obesity. Single-gene mutations can cause severe obesity resulting from alteration in central and peripheral appetite control mechanisms. Candidate gene and genome-wide association studies have led to the identification of nine loci associated with Mendelian forms of obesity and 58 loci contributing to polygenic obesity. These loci explain a small fraction of the heritability for obesity and many genes remain to be identified. The interaction of several polymorphisms and epigenetic modifications open a new research field for common obesity. As a result, still remains to be a mystery.

DIAGNOSTIC SIGNIFICANCE OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN PATIENTS WITH PRIMARY MITRAL VALVE PROLAPSE

Aim. To evaluate diagnostic significance of the type A vascular endothelial growth factor (VEGF-A) and its receptors type 1 and 2 (VEGF-R1 and VEGF-R2) in primary mitral valve prolapse (MVP) patients. Material and methods. Totally, 83 MVP patients studied: 61 males, 22 females; mean age 21,93±4,22 y. o. The signs of systemic inflammation were assessed, as the grade of connective tissue involvement. Immune enzyme analysis was done for serum levels of VEGF-А, VEGF-R1 and VEGF-R2 (“Bender MedSystems GmbH”,Austria). Controls included 20 healthy volunteers — 14 males, 6 females, mean age 21,10±0,55 y. o. with no MVP and any other dysplastic features. Results. In the MVP group, the decreased levels of circulating VEGF-R1 were found, as the increase of cases number of high (42,17%) and low (32,53%) concentration of VEGF-А. In low levels of VEGF-A and VEGF-A/ VEGF-R1 prevalence of grade II mitral regurgitation increases 5,1 times comparing to the group of retained balance of VEGF-A and VEGF-R1 — 95% confidence interval (CI) 1,25-20,88, and the prevalence of clinically significant cardiac rhythm and conduction disorders increases 5,25 times in comparison to the cases with elevated VEGF-A and VEGF-R1 — 95% CI 1,33-20,76 and 4,09 times — comparing MVP patients with retained balance of VEGF-A and VEGF-R1 — 95% CI 1,18-14,17. Conclusion. In primary MVP patients, regardless clinical phenotype of monogenic hereditary syndromes, the heterogeneity of deviation and regulation of VEGF has been established. Highest number of II grade mitral regurgitation, significant rhythm disorders was found in the group with low VEGF-A and VEGF-A/VEGF-R1, that might be implemented as optimized risk stratification in heterogenic MVP patients population.

POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism.

ObjectiveMitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative disorders such as ataxia and Parkinson's disease. We describe an extended Belgian pedigree where seven individuals presented with adult‐onset cerebellar ataxia, axonal peripheral ataxic neuropathy, and tremor, in variable combination with parkinsonism, seizures, cognitive decline, and ophthalmoplegia. We sought to identify the underlying molecular etiology and characterize the mitochondrial pathophysiology of this neurological syndrome.MethodsClinical, neurophysiological, and neuroradiological evaluations were conducted. Patient muscle and cultured fibroblasts underwent extensive analyses to assess mitochondrial function. Genetic studies including genome‐wide sequencing were conducted.ResultsHallmarks of mitochondrial dysfunction were present in patients’ tissues including ultrastructural anomalies of mitochondria, mosaic cytochrome c oxidase deficiency, and multiple mtDNA deletions. We identified a splice acceptor variant in POLG2, c.970‐1G>C, segregating with disease in this family and associated with a concomitant decrease in levels of POLG2 protein in patient cells.InterpretationThis work extends the clinical spectrum of POLG2 deficiency to include an overwhelming, adult‐onset neurological syndrome that includes cerebellar syndrome, peripheral neuropathy, tremor, and parkinsonism. We therefore suggest to include POLG2 sequencing in the evaluation of ataxia and sensory neuropathy in adults, especially when it is accompanied by tremor or parkinsonism with white matter disease. The demonstration that deletions of mtDNA resulting from autosomal‐dominant POLG2 variant lead to a monogenic neurodegenerative multicomponent syndrome provides further evidence for a major role of mitochondrial dysfunction in the pathomechanism of nonsyndromic forms of the component neurodegenerative disorders.

Challenges in diagnosis and management of diabetes in the young.

The prevalence of diabetes in children and adolescents is increasing worldwide, with profound implications on the long-term health of individuals, societies, and nations. The diagnosis and management of diabetes in youth presents several unique challenges. Although type 1 diabetes is more common among children and adolescents, the incidence of type 2 diabetes in youth is also on the rise, particularly among certain ethnic groups. In addition, less common types of diabetes such as monogenic diabetes syndromes and diabetes secondary to pancreatopathy (in some parts of the world) need to be accurately identified to initiate the most appropriate treatment. A detailed patient history and physical examination usually provides clues to the diagnosis. However, specific laboratory and imaging tests are needed to confirm the diagnosis. The management of diabetes in children and adolescents is challenging in some cases due to age-specific issues and the more aggressive nature of the disease. Nonetheless, a patient-centered approach focusing on comprehensive risk factor reduction with the involvement of all concerned stakeholders (the patient, parents, peers and teachers) could help in ensuring the best possible level of diabetes control and prevention or delay of long-term complications.

Copy number variations in Saudi family with intellectual disability and epilepsy.

BackgroundEpilepsy is genetically complex but common brain disorder of the world affecting millions of people with almost of all age groups. Novel Copy number variations (CNVs) are considered as important reason for the numerous neurodevelopmental disorders along with intellectual disability and epilepsy. DNA array based studies contribute to explain a more severe clinical presentation of the disease but interoperation of many detected CNVs are still challenging.ResultsIn order to study novel CNVs with epilepsy related genes in Saudi family with six affected and two normal individuals with several forms of epileptic seizures, intellectual disability (ID), and minor dysmorphism, we performed the high density whole genome Agilent sure print G3 Hmn CGH 2x 400 K array-CGH chips analysis. Our results showed de novo deletions, duplications and deletion plus duplication on differential chromosomal regions in the affected individuals that were not shown in the normal fathe and normal kids by using Agilent CytoGenomics 3.0.6.6 softwear. Copy number gain were observed in the chromosome 1, 16 and 22 with LCE3C, HPR, GSTT2, GSTTP2, DDT and DDTL genes respectively whereas the deletions observed in the chromosomal regions 8p23-p21 (4303127–4337759) and the potential gene in this region is CSMD1 (OMIM: 612279). Moreover, the array CGH results deletions and duplication were also validated by using primer design of deleted regions utilizing the flanked SNPs using simple PCR and also by using quantitative real time PCR.ConclusionsWe found some of the de novo deletions and duplication in our study in Saudi family with intellectual disability and epilepsy. Our results suggest that array-CGH should be used as a first line of genetic test for epilepsy except there is a strong indication for a monogenic syndrome. The advanced high through put array-CGH technique used in this study aim to collect the data base and to identify new mechanisms describing epileptic disorder, may help to improve the clinical management of individual cases in decreasing the burden of epilepsy in Saudi Arabia.

Atypical Manifestation of LPS-Responsive Beige-Like Anchor Deficiency Syndrome as an Autoimmune Endocrine Disorder without Enteropathy and Immunodeficiency

Monogenic primary immunodeficiency syndromes can affect one or more endocrine organs by autoimmunity during childhood. Clinical manifestations include type 1 diabetes mellitus, hypothyroidism, adrenal insufficiency, and vitiligo. Lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA) deficiency was described in 2012 as a novel primary immunodeficiency, predominantly causing immune dysregulation and early onset enteropathy. We describe the heterogeneous clinical course of LRBA deficiency in two siblings, mimicking an autoimmune polyendocrine disorder in one of them in presence of the same underlying genetic mutation. The third child of consanguineous Egyptian parents (Patient 1) presented at 6 months of age with intractable enteropathy and failure to thrive. Later on, he developed symptoms of adrenal insufficiency, autoimmune hemolytic anemia, thrombocytopenia, and infectious complications due to immunosuppressive treatment. The severe enteropathy was non-responsive to the standard treatment and led to death at the age of 22 years. His younger sister (Patient 2) presented at the age of 12 to the endocrinology department with decompensated hypothyroidism, perioral vitiligo, delayed pubertal development, and growth failure without enteropathy and immunodeficiency. Using whole exome sequencing, we identified a homozygous frameshift mutation (c.6862delT, p.Y2288MfsX29) in the LRBA gene in both siblings. To our knowledge, our patient (Patient 2) is the first case of LRBA deficiency described with predominant endocrine phenotype without immunodeficiency and enteropathy. LRBA deficiency should be considered as underlying disease in pediatric patients presenting with autoimmune endocrine symptoms. The same genetic mutation can manifest with a broad phenotypic spectrum without genotype–phenotype correlation. The awareness for disease symptoms among non-immunologists might be a key to early diagnosis. Further functional studies in LRBA deficiency are necessary to provide detailed information on the origin of autoimmunity in order to develop reliable predictive biomarkers for affected patients.

Recent advances in genetics of chorea.

Chorea presenting in childhood and adulthood encompasses several neurological disorders, both degenerative and nonprogressive, often with a genetic basis. In this review, we discuss how modern genomic technologies are expanding our knowledge of monogenic choreic syndromes and advancing our insight into the molecular mechanisms responsible for chorea. A genome-wide association study in Huntington's disease identified genetic disease modifiers involved in controlling DNA repair mechanisms and stability of the HTT trinucleotide repeat expansion. Chorea is the cardinal feature of newly recognized genetic entities, ADCY5 and PDE10A-related choreas, with onset in infancy and childhood. A phenotypic overlap between chorea, ataxia, epilepsy, and neurodevelopmental disorders is becoming increasingly evident. The differential diagnosis of genetic conditions presenting with chorea has considerably widened, permitting a molecular diagnosis and an improved prognostic definition in an expanding number of cases. The identification of Huntington's disease genetic modifiers and new chorea-causing gene mutations has allowed the initial recognition of converging molecular pathways underlying medium spiny neurons degeneration and dysregulation of normal development and activity of basal ganglia circuits. Signalling downstream of dopamine receptors and control of cAMP levels represent a very promising target for the development of new aetiology-based treatments for chorea and other hyperkinetic disorders.

Genetics of osteoporosis: searching for candidate genes for bone fragility.

The pathogenesis of osteoporosis, a common disease with great morbidity and mortality, comprises environmental and genetic factors. As with other complex disorders, the genetic basis of osteoporosis has been difficult to identify. Nevertheless, several approaches have been undertaken in the past decades in order to identify candidate genes for bone fragility, including the study of rare monogenic syndromes with striking bone phenotypes (e.g. osteogenesis imperfecta and osteopetroses), the analysis of individuals or families with extreme osteoporotic phenotypes (e.g. idiopathic juvenile and pregnancy-related osteoporosis), and, chiefly, genome-wide association studies (GWAS) in large populations. Altogether, these efforts have greatly increased the understanding of molecular mechanisms behind bone remodelling, which has rapidly translated into the development of novel therapeutic strategies, exemplified by the tales of cathepsin K (CTSK) and sclerostin (SOST). Additional biological evidence of involvement in bone physiology still lacks for several candidate genes arisen from GWAS, opening an opportunity for the discovery of new mechanisms regulating bone strength, particularly with the advent of high-throughput genomic technologies. In this review, candidate genes for bone fragility will be presented in comprehensive tables and discussed with regard to how their association with osteoporosis emerged, highlighting key players such as LRP5, WNT1 and PLS3. Current limitations in our understanding of the genetic contribution to osteoporosis, such as yet unidentified genetic modifiers, may be overcome in the near future with better genotypic and phenotypic characterisation of large populations and the detailed study of candidate genes in informative individuals with marked phenotype.

DNA demethylation of inflammasome-associated genes is enhanced in patients with cryopyrin-associated periodic syndromes

Inflammasomes are cytosolic multiprotein complexes in macrophages. They assemble after infection- or stress-associated stimuli, activating both caspase-1-mediated inflammatory cytokine secretion and pyroptosis. Increased inflammasome activity resulting from gene mutations is related to monogenic autoinflammatory syndromes. However, variable penetrance among patients with the same gene mutations suggests involvement of additional mechanisms associated with inflammasome gene regulation. We sought to investigate the role of DNA demethylation in activating inflammasome genes during macrophage differentiation and monocyte activation in healthy control subjects and patients with autoinflammatory syndrome. Inflammasome-related genes were tested for DNA methylation and mRNA levels by using bisulfite pyrosequencing and quantitative RT-PCR in monocytes invitro differentiated to macrophages and exposed to inflammatory conditions. The contribution of Tet methylcytosine dioxygenase 2 (TET2) and nuclear factor κB to DNA demethylation was tested by using chromatin immunoprecipitation, small interfering RNA-mediated downregulation, and pharmacologic inhibition. We observed that inflammasome-related genes are rapidly demethylated in both monocyte-to-macrophage differentiation and on monocyte activation. Demethylation associates with increased gene expression, and both mechanisms are impaired when TET2 and nuclear factor κB are downregulated. We analyzed DNA methylation levels of inflammasome-related genes in patients with cryopyrin-associated periodic syndromes (CAPS) and familial Mediterranean fever, 2 archetypical monogenic autoinflammatory syndromes. Under the above conditions, monocytes from untreated patients with CAPS undergo more efficient DNA demethylation than those of healthy subjects. Interestingly, patients with CAPS treated with anti-IL-1 drugs display methylation levels similar to those of healthy control subjects. Our study is the first to demonstrate the involvement of DNA methylation-associated alterations in patients with monogenic autoinflammatory disease and opens up possibilities for novel clinical markers.

Epigenetic regulation of TGF-β1 signalling in dilative aortopathy of the thoracic ascending aorta.

The term 'epigenetics' refers to heritable, reversible DNA or histone modifications that affect gene expression without modifying the DNA sequence. Epigenetic modulation of gene expression also includes the RNA interference mechanism. Epigenetic regulation of gene expression is fundamental during development and throughout life, also playing a central role in disease progression. The transforming growth factor β1 (TGF-β1) and its downstream effectors are key players in tissue repair and fibrosis, extracellular matrix remodelling, inflammation, cell proliferation and migration. TGF-β1 can also induce cell switch in epithelial-to-mesenchymal transition, leading to myofibroblast transdifferentiation. Cellular pathways triggered by TGF-β1 in thoracic ascending aorta dilatation have relevant roles to play in remodelling of the vascular wall by virtue of their association with monogenic syndromes that implicate an aortic aneurysm, including Loeys-Dietz and Marfan's syndromes. Several studies and reviews have focused on the progression of aneurysms in the abdominal aorta, but research efforts are now increasingly being focused on pathogenic mechanisms of thoracic ascending aorta dilatation. The present review summarizes the most recent findings concerning the epigenetic regulation of effectors of TGF-β1 pathways, triggered by sporadic dilative aortopathy of the thoracic ascending aorta in the presence of a tricuspid or bicuspid aortic valve, a congenital malformation occurring in 0.5-2% of the general population. A more in-depth comprehension of the epigenetic alterations associated with TGF-β1 canonical and non-canonical pathways in dilatation of the ascending aorta could be helpful to clarify its pathogenesis, identify early potential biomarkers of disease, and, possibly, develop preventive and therapeutic strategies.

Rare variants, autoimmune disease, and arthritis.

We review select studies of newly discovered rare variants in autoimmune diseases with a focus on newly described monogenic disorders, rheumatoid arthritis, and systemic lupus erythematosus. Two new monogenic syndromes of inflammatory arthritis were discovered using whole exome sequencing: the coatomer subunit alpha syndrome because of rare mutations in coatomer subunit alpha and haploinsufficiency of A20 resulting from rare mutations in TNFAIP3. Targeted exon sequencing identified rare variants in IL2RA and IL2RB associated with rheumatoid arthritis. Rare variants in TREX1 and other genes associated with monogenic interferonopathies are also associated with systemic lupus erythematosus. Rare genetic variants contribute to the heritability of autoimmunity and provide key insight into both novel and previously implicated immunological pathways that are disrupted in autoimmune diseases.

Zespoły gorączek okresowych u dzieci w praktyce oddziału pediatryczno-zakaźnego – doświadczenia ośrodka wrocławskiego

IntroductionFever is one of the top reasons for pediatric visits. Periodic fever syndroms (PFSs) are rare but increasingly recognized disorders and represent a new challenge for Polish doctors. The aimTo evaluate clinical picture, treatment results, disease outcome and its’ impact on the quality of life of patients with PFSs, based on a 10-year single center experience. Materials and MethodsFifty-five patients diagnosed with PFSs in 2006–2015 were included in the study. Diagnostic and therapeutic algorithms, definitions of treatment response and remission were established. The patients were followed up via hospital and outpatient visits, and telephone consultations. ResultsPeriodic fever, aphtous stomatitis, pharyngitis and adenitis (PFAPA) syndrome was diagnosed in 47 and monogenic periodic fever syndromes (MPFSs) in 8 patients.: In PFAPA syndrome, the most common symptoms accompanying fever were pharyngitis, cervical adenitis and aphtous stomatitis, in MPFSs: abdominal pain and diarrhea. In 80% of cases, ibuprofen was more effective than paracetamol in symptomatic treatment of febrile episodes. Steroids aborted PFAPA flares in 90.9% of the treated patients, tonsillectomy was effective in all operated children. Full remission (≥12 months) was reached by 14 PFAPA patients and 1 patient with MPFS, who was the only one to receive biological treatment. In most cases, after the diagnosis of a PFS, the use of antibiotics, number of hospitalizations and blood draws and the level of general parental fear about the child's health have decreased. ConclusionsPolish doctors’ readiness to recognize periodic fever syndromes allows avoidance of unnecessary antibiotic use and has a positive impact on the quality of life of patients and their families. While PFAPA syndrome is a mild, self-limiting disease, PFSs are chronic conditions that require effective prevention of amyloidosis.

Advanced non-alcoholic fatty liver disease and adipose tissue fibrosis in patients with Alström syndrome.

Alström syndrome (AS) is a recessive monogenic syndrome characterized by obesity, extreme insulin resistance and multi-organ fibrosis. Despite phenotypically being high risk of non-alcoholic fatty liver disease (NAFLD), there is a lack of data on the extent of fibrosis in the liver and its close links to adipose in patients with AS. Our aim was to characterize the hepatic and adipose phenotype in patients with AS. Observational cohort study with comprehensive assessment of metabolic liver phenotype including liver elastography (Fibroscan® ), serum Enhanced Liver Fibrosis (ELF) Panel and liver histology. In addition, abdominal adipose histology and gene expression was assessed. We recruited 30 patients from the UK national AS clinic. A subset of six patients underwent adipose biopsies which was compared with control tissue from nine healthy participants. Patients were overweight/obese (BMI 29.3 (25.95-34.05) kg/m2 ). A total of 80% (24/30) were diabetic; 74% (20/27) had liver ultrasound scanning suggestive of NAFLD. As judged by the ELF panel, 96% (24/25) were categorized as having fibrosis and 10/21 (48%) had liver elastography consistent with advanced liver fibrosis/cirrhosis. In 7/8 selected cases, there was evidence of advanced NAFLD on liver histology. Adipose tissue histology showed marked fibrosis as well as disordered pro-inflammatory and fibrotic gene expression profiles. NAFLD and adipose dysfunction are common in patients with AS. The severity of liver disease in our cohort supports the need for screening of liver fibrosis in AS.

Monogenic signs of susceptibility to ischemic stroke: literature review

Genetic factors are the important chain in the complex conditions determining the development of ischemic stroke. Mutations have different significance for the risk of its development. Monogenic syndromes define clearly determined type of stroke. These syndromes include: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, mutation in the NOTCH3 gene); cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL, mutation in the HTRA1 gene); Fabry disease (FD, GLA D313Y mutation); COL4A1-related brain small vessel disease associated with mutation in the gene encoding IVα1 collagen; Ehlers Danlos syndrome (EDS) caused by mutation in the COL3A1 gene; hereditary endotheliopathy with retinopathy, nephropathy and stroke (HERNS, mutation in the TREX1 gene); sickle cell disease (SCD, mutation in the beta-globin gene); homocystinuria - hereditary metabolic disorder associated with mutations in the MTHFR, MTRR, MTR CBS genes of the folate cycle; neurofibromatosis type 1 (NF1, mutation in the gene NF1); hereditary hemorrhagic telangiectasia (HHT, mutations in the ENG, ALK1 or SMAD4 genes); hereditary cerebral amyloid angiopathy (CAA, mutation in the APP gene); cerebral cavernous malformations (CCM, mutations in the CCM1, CCM2 or CCM3 genes); mithochondrial encephalopathy lactic acidosis and strokelike episodes (MELAS, mutations in the MT-ND1, MT-ND5, MT-TH, MT-TL1, MT-TV genes).The study of the genetic profile permits to personify medical tactics in ischemic stroke.

Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability

Genetic studies of intellectual disability and identification of monogenic causes of obesity in humans have made immense contribution toward the understanding of the brain and control of body mass. The leptin > melanocortin > SIM1 pathway is dysregulated in multiple monogenic human obesity syndromes but its downstream targets are still unknown. In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia. The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families, and there was dramatic phenotypic overlap among affected individuals who were independently ascertained without bias from clinical features. Analysis of the deletions revealed a ∼350 kb critical region on chromosome 6q16.1 that encompasses a gene for proneuronal transcription factor POU3F2, which is important for hypothalamic development and function. Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area. We show that this finding is consistent with the expression patterns of POU3F2 and related genes in the human brain. Our work helps to further delineate the neuro-endocrine control of energy balance/body mass and demonstrates that this molecular pathway is conserved across multiple species.