Application of Clinical Genetics最新文献

{"title":"Ketogenic diet in ATAD3A mutation carriers may not improve cerebellar atrophy but some clinical features [Letter]","authors":"J. Finsterer","doi":"10.2147/TACG.S221407","DOIUrl":"https://doi.org/10.2147/TACG.S221407","url":null,"abstract":"Krankenanstalt Rudolfstiftung, Messerli Institute, Vienna, Austria Dear editor With interest I read the article by Madhoun et al about a 4.5-year-old female with multisystem mitochondrial disorder (MID) due to the variant c.251T>C in the ATAD3A gene. The patient was reported to have profited from the ketogenic diet (KD) by slowing the progression of cerebellar atrophy, and improving vitality, interaction, moaning, carrying, tremor, and weakness. I have the following comments and concerns. It is quite unlikely that the cerebellar volume increased upon application of the KD. More likely is that the increase in the relative sagittal length of the cerebellum was due to variability of repeated measurements or simply due to the growing cerebellum in this developing child. Potential volumetric changes can be only confirmed by investigating a series of patients but not by assessing a single case. The tremor in the patient was attributed to Parkinsonism most likely upon the phenotype as a hand pill rolling tremor. We should be informed about the DatScan results, if the tremor responded to L-DOPA, and if there were any other stigmata of Parkinsonism in this patient. More likely than Parkinson's tremor is a cerebellar tremor in the light of progressive cerebellar atrophy. A hand pill rolling tremor may also occur with a cerebellar syndrome. MRI in figure 1 suggests that there was also atrophy of the spinal cord. It is conceivable that muscle weakness in the described patient was attributable to involvement of the anterior horn cells. Were there any indications for neuronopathy in the presented patient? Though optic atrophy may be a feature of ATAD3A mutations, it was not reported as a feature of the index case. Optic atrophy may be subtle and not visible on ophthalmologic or imaging investigations but only on functional tests. Thus, we should be informed if latency and amplitude of visually evoked potentials were prolonged respectively reduced. We should be informed if muscle weakness was attributed to affection of the central nervous system or due to myopathy. It should be mentioned if deep tendon reflexes were reduced or exaggerated. A normal needle EMG does not exclude myopathy. Since seizures have been reported as a phenotypic feature of ATAD3A mutations, we should be informed about the history in this regards and the EEG findings. Correspondence: Josef Finsterer Krankenanstalt Rudolfstiftung, Messerli Institute, Postfach 20, 1180 Vienna, Austria Tel +43 1 711 657 2085 Fax +43 17 1165 Email fifigs1@yahoo.de The Application of Clinical Genetics Dovepress open access to scientific and medical research","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"12 1","pages":"161 - 162"},"PeriodicalIF":3.1,"publicationDate":"2019-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S221407","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44908136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polymorphisms of <i>CYP2C9*2, CYP2C9*3</i> and <i>VKORC1</i> genes related to time in therapeutic range in patients with atrial fibrillation using warfarin.","authors":"Maria Mariana Barros Melo da Silveira, Leiliandry de Araújo Melo, Filipe Maia Ferreira Gomes, Leonardo José de Cupertino Barreto da Rocha Andrade, Isabela Paulino Serur, Isabelle Cecília de Vasconcellos Piscoya, Raposo Marina Gueiros, Kleyton Palmeira do Ó, Raul Emídio de Lima, Victor Arthur Eulálio Brasileiro, Luydson Richardson Silva Vasconcelos, Dário Celestino Sobral Filho","doi":"10.2147/TACG.S197316","DOIUrl":"10.2147/TACG.S197316","url":null,"abstract":"<p><strong>Introduction: </strong>Warfarin continues to be the most widely used anticoagulant in clinical practice around the world for the prevention of thromboembolic events in patients with atrial fibrillation (AF). The evaluation of the quality of anticoagulation control, estimated by time in therapeutic range (TTR), is accepted as a good method to evaluate the quality of anticoagulation. The variability of TTR can be explained by the presence of variants of the <i>CYP2C9</i> and <i>VKORC1</i> genes.</p><p><strong>Methods: </strong>This study examined the association between polymorphisms of the <i>CYP2C9</i> and <i>VKORC1</i> genes and control of oral anticoagulation, through TTR, in patients with AF. A cross-sectional study was conducted within a cohort follow-up. The study comprised of 317 patients with AF, using warfarin, who were followed up for one year. The genotyping of genes <i>CYP2C9</i> (rs1057910), (rs1799853) and <i>VKORC1</i> (rs923231) was performed by PCR in real time, using TaqMan probes.</p><p><strong>Results: </strong>Patients who had variant genotypes for the <i>CYP2C9*3</i> gene (rs1057910) presented higher TTR (TTR 81-100%) when compared to when compared to the <45% and 46-60% TTR groups (<i>p</i>=0.005 and <i>p</i>=0.002, respectively). Regarding <i>VKORC1</i> (rs923231), patients who had the variant genotype for the <i>VKORC1</i> (rs923231) gene also presented a higher TTR (TTR 81-100%), when when compared to the <45% and 46-60% TTR groups (<i>p</i>=0.005 and <i>p</i>=0.004, respectively). In a multivariate model, <i>VKORC1</i> (rs923231) remained associated for comparisons with the TTR groups (<45% vs 81-100% groups, <i>p</i>=0.01; and 46-60% vs 81-100% groups, <i>p</i>=0.01).</p><p><strong>Conclusion: </strong>The genotypes of the <i>CYP2C9*3</i> (AA) and <i>VKORC1</i> -1639 (GG) genes were associated with the worst quality of anticoagulation control (TTR) in patients with AF using warfarin in the northeast of Brazil.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"12 ","pages":"151-159"},"PeriodicalIF":2.6,"publicationDate":"2019-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/08/84/tacg-12-151.PMC6684853.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41215365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ketogenic diet attenuates cerebellar atrophy progression in a subject with a biallelic variant at the ATAD3A locus [Response to Letter]","authors":"A. Al Madhoun, Fahad Alnaser, Motasem Melhem, R. Nizam, Tala Al-Dabbous, F. Al-Mulla","doi":"10.2147/TACG.S224520","DOIUrl":"https://doi.org/10.2147/TACG.S224520","url":null,"abstract":"Ashraf Al Madhoun Fahad Alnaser Motasem Melhem Rasheeba Nizam Tala Al-Dabbous Fahd Al-Mulla 1Genetics and Bioinformatics Department, Dasman Diabetes Institute, Dasman, 15462 Kuwait City, Kuwait; 2Animal and Imaging Core Facility Department, Dasman Diabetes Institute, Dasman, 15462 Kuwait City, Kuwait; 3Radiology Department, Ibn Sina Hospital, Ministry of Health, Kuwait City, Kuwait; 4Bayt Abdullah Children’s Hospice, NBK Children’s Cancer Hospital, Al-Adan ICU, Kuwait City, Kuwait Dear editor It is with great interest to read the comments of Dr. Josef Finsterer on our recent article, “Ketogenic diet attenuates cerebellar atrophy progression in a subject with a biallelic variant at the ATAD3A locus by Al Madhoun et al, 2019,” which has received a substantial article-level metrics and respond to the queries raised single nucleotide polymorphisms and deletion mutations within ATAD3 are lethal at embryonic stage or postnatally and the few survivors are living with low quality of life. Accordingly, ATAD3 genotyping enable prediction of genotype/phenotype relationship. Desai et al (2017) associated ATAD3 function with cholesterol homeostasis and maintenance of the mitochondrial genome stability. We thought that Ketogenic Diet (KD) may modulate mitochondrial biogenesis especially that it has proven efficacy in mitochondriopathies-mediated neurological disorders. Thus, it is not unrealistic to include KD treatment in a disease that is caused by ATAD3 gene mutations. The girl described in our paper is unique. She has been clinically evaluated extensively in Canada, but unfortunately, the family was not given a formal diagnosis. We diagnosed her with Harel-Yoon syndrome after discovering a novel pathogenic missense homozygous mutation in the ATAD3 gene (rs546711654 c.251C&gt;T; p.Thr84Met). Globally, the variant allele frequency of rs546711654 is 0.0002 (https://www.ncbi.nlm.nih.gov/clinvar/variation/452865/). This information means that the disease is rare and therefore it is not possible to study other children harboring the same mutation. In response to KD, we never claimed an increase in the relative sagittal length of the cerebellum. But rather, an obvious slowing of her cerebellar atrophy. The KD was applied between the 2nd and 3rd MRI examination at the age of 4 and 5.5 years old. It has been reported that KD lowers the blood pH, increases ATP by shifting from glucoseto ketone-based metabolism. Although all body tissues are influenced by KD, the most prominent effect is on the nervous system activities. Accordingly, we do not exclude a positive effect on the muscle function. KD increases mitochondrial biogenesis. We agree that a real-effect of KD can only be assessed reliably in double-blind randomized clinical trials, but this is Correspondence: Fahd Al-Mulla Head of Genetics and Bioinformatics Department, Dasman Diabetes Institute, Dasman, 15462 Kuwait City, Kuwait Tel +9 652 224 2999 Ext. 2211 Email fahd@al-mulla.org The Application of Clinical Gene","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"12 1","pages":"163 - 165"},"PeriodicalIF":3.1,"publicationDate":"2019-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S224520","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47382108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First report case with negative genetic study (array CGH, exome sequencing) in patients with vertical transmission of Zika virus infection and associated brain abnormalities","authors":"E. Candelo, G. Caicedo, F. Rosso, A. Ballesteros, Jaime Orrego, L. E. Escobar, P. Lapunzina, J. Nevado, H. Pachajoa","doi":"10.2147/TACG.S190661","DOIUrl":"https://doi.org/10.2147/TACG.S190661","url":null,"abstract":"Introduction Zika virus (ZIKV) is a little-known emerging mosquito-borne flavivirus. The perinatal ZIKV infection was associated with birth defects during the Brazilian outbreak. There was an increased risk of intrauterine transmission of the virus and a marked increase in the number of newborns with microcephaly. We report on two such cases. Case Report The first case was a 25-year-old pregnant woman from Colombia who became acutely ill with general symptoms during the tenth week of gestation, followed by severe generalized itching and maculopapular rash for approximately five days. This case was reported during the epidemic stage of the ZIKV infection in Colombia. At 23.3 gestational weeks, ultrasonography showed abnormal intracranial anatomy with cerebral ventriculomegaly, microcephaly, and parenchymal calcification. Given the grave prognosis, the patient elected to terminate the pregnancy at 25 gestational weeks. The second case was a 24-year-old pregnant woman who became acutely ill during the 17th week of gestation, which corresponded with the ZIKV epidemic in Colombia. At 30.5 gestational weeks, ultrasonography showed isolated fetal cerebral ventriculomegaly. We detected ZIKV in the amniotic fluid; however, the virus was not detected in the urine or serum of the mother or fetus. Tests for dengue virus, chikungunya virus, Toxoplasma gondii, rubella virus, cytomegalovirus, herpes simplex virus, HIV, hepatitis B and C, and parvovirus B19 were all negative. Different samples obtained from the placenta, amniotic liquid, and cerebrospinal fluid were positive for viral isolation of ZIKV RNA using TaqMan RT-PCR. Additionally, the parents and fetuses were tested for genetic diseases using whole exome sequencing and array CGH to rule out possible genetic syndromes that produce these congenital abnormalities. Conclusion These were the first cases in Colombia to show early vertical transmission of ZIKV and the first cases associated with congenital cerebral abnormalities in which molecular, infectious, and genomic tests were performed.","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"12 1","pages":"141 - 150"},"PeriodicalIF":3.1,"publicationDate":"2019-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S190661","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45975542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current understanding and treatment of cardiac and skeletal muscle pathology in laminin-α2 chain-deficient congenital muscular dystrophy","authors":"Q. Nguyen, K. Lim, T. Yokota","doi":"10.2147/TACG.S187481","DOIUrl":"https://doi.org/10.2147/TACG.S187481","url":null,"abstract":"Abstract Congenital muscular dystrophy (CMD) is a class of severe early-onset muscular dystrophies affecting skeletal/cardiac muscles as well as the central nervous system (CNS). Laminin-α2 chain-deficient congenital muscular dystrophy (LAMA2 MD), also known as merosin-deficient congenital muscular dystrophy type 1A (MDC1A), is an autosomal recessive CMD characterized by severe muscle weakness and degeneration apparent at birth or in the first 6 months of life. LAMA2 MD is the most common congenital muscular dystrophy, affecting approximately 4 in 500,000 children. The most common cause of death in early-onset LAMA2 MD is respiratory tract infection, with 30% of them dying within the first decade of life. LAMA2 MD is caused by loss-of-function mutations in the LAMA2 gene encoding for the laminin-α2 chain, one of the subunits of laminin-211. Laminin-211 is an extracellular matrix protein that functions to stabilize the basement membrane and muscle fibers during contraction. Since laminin-α2 is expressed in many tissue types including skeletal muscle, cardiac muscle, Schwann cells, and trophoblasts, patients with LAMA2 MD experience a multi-systemic clinical presentation depending on the extent of laminin-α2 chain deficiency. Cardiac manifestations are typically associated with a complete absence of laminin-α2; however, recent case reports highlight cardiac involvement in partial laminin-α2 chain deficiency. Laminin-211 is also expressed in the brain, and many patients have abnormalities on brain imaging; however, mental retardation and/or seizures are rarely seen. Currently, there is no cure for LAMA2 MD, but various therapies are being investigated in an effort to lessen the severity of LAMA2 MD. For example, antisense oligonucleotide-mediated exon skipping and CRISPR-Cas9 genome editing have efficiently restored the laminin-α2 chain in mouse models in vivo. This review consolidates information on the clinical presentation, genetic basis, pathology, and current treatment approaches for LAMA2 MD.","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"12 1","pages":"113 - 130"},"PeriodicalIF":3.1,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S187481","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43560479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacogenetics of alcohol addiction: current perspectives","authors":"M. Zastrozhin, V. Skryabin, S. S. Miroshkin, E. Bryun, D. Sychev","doi":"10.2147/TACG.S206745","DOIUrl":"https://doi.org/10.2147/TACG.S206745","url":null,"abstract":"Abstract Genetics of alcohol addiction is currently a contradictive and complex field, where data in the most studies reflect methods’ limitations rather than meaningful and complementary results. In our review, we focus on the genetics of alcohol addiction, leaving genetics of acute alcohol intoxication out of the scope. A review of the literature on pharmacogenetic biomarkers development for the pharmacotherapy personalization reveals that today the evidence base concerning these biomarkers is still insufficient. In particular, now the researches with the design of randomized controlled trials and meta-analysis investigating the effect of the SNPs as biomarkers on the therapy efficacy are available for naltrexone only. For other medications, there are only a few studies in small samples. It decreases the possibilities to implement the pharmacogenetic algorithms for the pharmacotherapy personalization in patients with alcohol use disorders (AUD). In view of the importance of the precision approaches development not in addiction medicine only, but in other fields of medicine also to increase the efficacy and safety of the therapy, studies on pharmacogenetic biomarkers development for the medications used in patients with AUD (eg, naltrexone, disulfiram, nalmefene, acamprosate, etc.) remain relevant to this day.","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"12 1","pages":"131 - 140"},"PeriodicalIF":3.1,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S206745","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42892515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in the management of erythropoietic protoporphyria - role of afamelanotide.","authors":"Ashley M Lane, Jerome T McKay, Herbert L Bonkovsky","doi":"10.2147/TACG.S122030","DOIUrl":"10.2147/TACG.S122030","url":null,"abstract":"<p><p>Erythropoietic protoporphyria (EPP) and the phenotypically similar disease X-linked protoporphyria (XLPP) are inherited cutaneous porphyrias characterized clinically by acute non-blistering photosensitivity, intolerance to sunlight, and significantly reduced quality of life. They are due to marked overproduction of protoporphyrin (PP) chiefly by erythroblasts and reticulocytes. In EPP, the underlying genetic defect is in the ferrochelatase gene, which encodes the final enzyme in the heme synthetic pathway. In XLPP, the genetic defect is a gain-of-function mutation, usually a four-base deletion, in the gene that encodes the enzyme 5-aminolevulinic acid synthase-2, the first and rate-controlling enzyme of heme synthesis in developing red blood cells. The excess PP causes acute and painful photosensitivity, being activated by light in the long ultraviolet to blue spectrum (380-420 nm, the Soret band). Although several treatments have been proposed, presently no very effective treatment exists for EPP or XLPP. Afamelanotide (Scenesse^®) is a first-in-class synthetic analog of α-melanocyte stimulating hormone. Afamelanotide mimics the naturally occurring hormone to increase skin pigmentation by increasing melanin production in melanocytes, resulting in increased sunlight tolerance in those with EPP/XLPP. Afamelanotide is currently approved for use in the European Union and Switzerland, and it is under review in the United States by the Food and Drug Administration for use in patients with EPP/XLPP. This paper provides a review of the clinical characteristics and current therapies for EPP/XLPP. We discuss the pharmacology, clinical efficacy, safety, and tolerability of afamelanotide and summarize the results of several key Phase II and III clinical trials. These data indicate that afamelanotide is a promising therapy for those with these debilitating diseases.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"9 1","pages":"179-189"},"PeriodicalIF":3.1,"publicationDate":"2016-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S122030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68481392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of binary responses with outcome-specific misclassification probability in genome-wide association studies.","authors":"Romdhane Rekaya, Shannon Smith, El Hamidi Hay, Nourhene Farhat, Samuel E Aggrey","doi":"10.2147/TACG.S122250","DOIUrl":"10.2147/TACG.S122250","url":null,"abstract":"<p><p>Errors in the binary status of some response traits are frequent in human, animal, and plant applications. These error rates tend to differ between cases and controls because diagnostic and screening tests have different sensitivity and specificity. This increases the inaccuracies of classifying individuals into correct groups, giving rise to both false-positive and false-negative cases. The analysis of these noisy binary responses due to misclassification will undoubtedly reduce the statistical power of genome-wide association studies (GWAS). A threshold model that accommodates varying diagnostic errors between cases and controls was investigated. A simulation study was carried out where several binary data sets (case-control) were generated with varying effects for the most influential single nucleotide polymorphisms (SNPs) and different diagnostic error rate for cases and controls. Each simulated data set consisted of 2000 individuals. Ignoring misclassification resulted in biased estimates of true influential SNP effects and inflated estimates for true noninfluential markers. A substantial reduction in bias and increase in accuracy ranging from 12% to 32% was observed when the misclassification procedure was invoked. In fact, the majority of influential SNPs that were not identified using the noisy data were captured using the proposed method. Additionally, truly misclassified binary records were identified with high probability using the proposed method. The superiority of the proposed method was maintained across different simulation parameters (misclassification rates and odds ratios) attesting to its robustness.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"9 ","pages":"169-177"},"PeriodicalIF":3.1,"publicationDate":"2016-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5138056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140289093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel treatment options for lysosomal acid lipase deficiency: critical appraisal of sebelipase alfa.","authors":"Kim Su, Emma Donaldson, Reena Sharma","doi":"10.2147/TACG.S86760","DOIUrl":"10.2147/TACG.S86760","url":null,"abstract":"<p><p>Lysosomal acid lipase deficiency (LAL-D) is a rare disorder of cholesterol metabolism with an autosomal recessive mode of inheritance. The absence or deficiency of the LAL enzyme gives rise to pathological accumulation of cholesterol esters in various tissues. A severe LAL-D phenotype manifesting in infancy is associated with adrenal calcification and liver and gastrointestinal involvement with characteristic early mortality. LAL-D presenting in childhood and adulthood is associated with hepatomegaly, liver fibrosis, cirrhosis, and premature atherosclerosis. There are currently no curative pharmacological treatments for this life-threatening condition. Supportive management with lipid-modifying agents does not ameliorate disease progression. Hematopoietic stem cell transplantation as a curative measure in infantile disease has mixed success and is associated with inherent risks and complications. Sebelipase alfa (Kanuma) is a recombinant human LAL protein and the first enzyme replacement therapy for the treatment of LAL-D. Clinical trials have been undertaken in infants with rapidly progressive LAL-D and in children and adults with later-onset LAL-D. Initial data have shown significant survival benefits in the infant group and improvements in biochemical parameters in the latter. Sebelipase alfa has received marketing authorization in the United States and Europe as long-term therapy for all affected individuals. The availability of enzyme replacement therapy for this rare and progressive disorder warrants greater recognition and awareness by physicians.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"9 1","pages":"157-167"},"PeriodicalIF":3.1,"publicationDate":"2016-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68482200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of the CFTR gene in Venezuelan cystic fibrosis patients, identification of six novel cystic fibrosis-causing genetic variants","authors":"Karen Sánchez, Elizabeth de Mendonca, Xiorama Matute, I. Chaustre, M. Villalón, Howard Takiff","doi":"10.2147/TACG.S78241","DOIUrl":"https://doi.org/10.2147/TACG.S78241","url":null,"abstract":"The mutations in the CFTR gene found in patients with cystic fibrosis (CF) have geographic differences, but there are scant data on their prevalence in Venezuelan patients. This study determined the frequency of common CFTR gene mutations in a group of Venezuelan patients with CF. The 27 exons of the CFTR gene from 110 Venezuelan patients in the National CF Program were amplified and sequenced. A total of 36 different mutations were identified, seven with frequencies greater than 1%: p.Phe508del (27.27%), p.Gly542* (3.18%), c.2988+1G>A (3.18%), p.Arg334Trp (1.36%), p.Arg1162* (1.36%), c.1-8G>C (1.36%), and p.[Gly628Arg;Ser1235Arg](1.36). In 40% of patients, all with a clinical diagnosis of CF, no mutations were found. This report represents the largest cohort of Venezuelan patients with CF ever examined, and includes a wider mutation panel than has been previously studied in this population. Mutations common in Southern European populations predominate, and several new mutations were discovered, but no mutations were found in 40% of the cohort.","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"9 1","pages":"33 - 38"},"PeriodicalIF":3.1,"publicationDate":"2016-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S78241","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68481858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}