The Application of Clinical Genetics最新文献

{"title":"A Homozygous Truncating Mutation in <i>NALCN</i> Causing IHPRF1: Detailed Clinical Manifestations and a Review of Literature.","authors":"Amir Hossein Karimi,&nbsp;Mohammad Reza Karimi,&nbsp;Poopak Farnia,&nbsp;Farshid Parvini,&nbsp;Majid Foroutan","doi":"10.2147/TACG.S261781","DOIUrl":"https://doi.org/10.2147/TACG.S261781","url":null,"abstract":"<p><p>Infantile hypotonia, with psychomotor retardation and characteristic facies 1 (IHPRF1), is a rare disorder characterized by global developmental delay and dysmorphic features. This syndrome is caused by genetic anomalies within the <i>NALCN</i> gene. The current report examines a 9-year-old female IHPRF1 patient. Our objective was to contribute to the delineation of the underlying factors influencing this rare condition. Whole exome sequencing (WES) was utilized to identify the disease-causing mutation in the affected individual. Subsequently, Sanger sequencing was performed for the patient, her parents, and two close relatives in order to confirm the detected mutation. Moreover, detailed clinical examinations including EEG, echocardiography, and biochemical/physical tests were carried out to elucidate the effects of the mutation. WES identified a homozygous nonsense mutation in the <i>NALCN</i> gene (c.2563C>T p.R855X). This mutation was confirmed by Sanger sequencing in the patient and her family members and segregated with the autosomal recessive inheritance pattern of IHPRF1. Moreover, genotype-phenotype correlation analysis confirmed the disease-causing nature of this mutation. The current report provides the first detailed description of a patient with this homozygous nonsense mutation (c.2563C>T p.R855X) and expands the clinical spectrum of IHPRF1 disease. Possible influences of sex and other factors on this disease are discussed and a review of the literature is also provided.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"13 ","pages":"151-157"},"PeriodicalIF":3.1,"publicationDate":"2020-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S261781","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38391009","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":"The Influence of <i>IL-1B</i> Gene Polymorphisms on <i>H. pylori</i> Infection and Triple Treatment Response Among Jordanian Population.","authors":"Muhamad Ali K Shakhatreh,&nbsp;Omar F Khabour,&nbsp;Karem H Alzoubi,&nbsp;Mohammed N BaniHani,&nbsp;Ahmed Abu-Siniyeh,&nbsp;Nabil A Bashir,&nbsp;Salsabeel H Sabi,&nbsp;Mahmoud Mahafdah","doi":"10.2147/TACG.S253778","DOIUrl":"https://doi.org/10.2147/TACG.S253778","url":null,"abstract":"<p><strong>Background: </strong><i>Helicobacter pylori</i> (<i>H. pylori</i>) is considered the main cause of gastritis, peptic ulcer and gastric carcinoma in the human populations. <i>H. pylori</i> infection influences the secretion level of several proinflammatory cytokines including IL-1β, which encoded by the <i>IL-1B</i> gene.</p><p><strong>Objective: </strong>The current study aimed to investigate whether <i>IL-1B</i> gene polymorphisms are associated with <i>H. pylori</i> infection among the Jordanian population and responses to triple therapy.</p><p><strong>Subjects and methods: </strong>The gastroscopic examination was performed on 412 subjects for <i>H. pylori</i> infection diagnosis, 257 subjects were found to be infected by <i>H. Pylori</i> (positive cases), whereas 155 subjects were uninfected (negative controls). The <i>IL-1B</i> gene T-31C and C3954T polymorphisms were genotyped by PCR-RFLP.</p><p><strong>Results: </strong>It was found that the T-31C polymorphism has a significant association with <i>H. pylori</i> infection (<i>P</i><0.05), and the TT genotype frequency was significantly higher in infected subjects (50.2%) compared to controls (38.7%). On the other hand, no significant association was detected between C3954T SNPs and <i>H. pylori</i> infection among the Jordanian population. In addition, none of the examined polymorphisms were found to influence the responses to triple therapy.</p><p><strong>Conclusion: </strong>The <i>IL-1B</i> gene T-31C SNP might be associated with an enhanced risk of <i>H. pylori</i> infection among the Jordanian population.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"13 ","pages":"139-145"},"PeriodicalIF":3.1,"publicationDate":"2020-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S253778","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38158521","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":"The Impact of the Genetic Polymorphism in DNA Repair Pathways on Increased Risk of Glioblastoma Multiforme in the Arab Jordanian Population: A Case-Control Study.","authors":"Sohaib M Al-Khatib,&nbsp;Nour Abdo,&nbsp;Laith N Al-Eitan,&nbsp;Abdel-Hameed W Al-Mistarehi,&nbsp;Deeb Jamil Zahran,&nbsp;Marwan Al Ajlouni,&nbsp;Tariq Zuheir Kewan","doi":"10.2147/TACG.S248994","DOIUrl":"https://doi.org/10.2147/TACG.S248994","url":null,"abstract":"<p><strong>Introduction: </strong>Among the Jordanian population, brain tumors are the tenth most common type of cancers in both males and females, comprising 2.8% of all newly diagnosed neoplasms. Diffuse gliomas are the most prevalent and the most aggressive primary brain tumors in adults. The incidence of diffuse gliomas varies among different populations; this variation is partially linked to genetic polymorphisms. The purpose of the study is to examine the association between (BRCA1 rs799917G>A, rs1799966T>C, EXO1 rs1047840G>A, EME1 rs12450550T>C, ERCC2 rs13181T>G, rs1799793C>T, and XRCC1 rs1799782G>A) DNA repair gene polymorphisms and glioblastoma multiforme (GBM) susceptibility, and survival in the Jordanian Arab population.</p><p><strong>Methods: </strong>Eighty-four patients diagnosed with glioblastoma multiforme at the King Abdullah University Hospital (KAUH) between 2013 and 2018 and 225 healthy cancer-free control subjects with similar geographic and ethnic backgrounds to the patients were included in the study. Genomic DNA was extracted from the formalin-fixed paraffin-embedded tissues of the subjects. The Sequenom MassARRAY^® sequencer system (iPLEX GOLD) was used. The analyses included assessments of population variability and survival.</p><p><strong>Results: </strong>This study is the first to address the relationship between BRCA1 rs1799966 and rs799917 SNP, and the risk of GBM among the Arab Jordanian population. The findings of the study show that BRCA1 rs799917 is associated with decreased risk of GBM in the recessive model (AA vs G/G-A/G: OR, 0.46, 95% CI, 0.26-0.82, p=0.01) and the same SNP is associated with increased risk of GBM in the overdominant model (AG vs G/G-A/A: OR, 1.72, 95% CI, 1.02-2.89, p=0.04).</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"13 ","pages":"115-126"},"PeriodicalIF":3.1,"publicationDate":"2020-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S248994","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38109327","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":"Association of Cholinergic Muscarinic M4 Receptor Gene Polymorphism with Schizophrenia.","authors":"Ivan V Pozhidaev,&nbsp;Anastasiia S Boiko,&nbsp;Anton J M Loonen,&nbsp;Diana Z Paderina,&nbsp;Olga Yu Fedorenko,&nbsp;Gennadiy Tenin,&nbsp;Elena G Kornetova,&nbsp;Arkadiy V Semke,&nbsp;Nikolay A Bokhan,&nbsp;Bob Wilffert,&nbsp;Svetlana A Ivanova","doi":"10.2147/TACG.S247174","DOIUrl":"https://doi.org/10.2147/TACG.S247174","url":null,"abstract":"<p><strong>Background: </strong>Previous studies have linked muscarinic M4 receptors (CHRM4) to schizophrenia. Specifically, the rs2067482 polymorphism was found to be highly associated with this disease.</p><p><strong>Purpose: </strong>To test whether rs2067482 and rs72910092 are potential risk factors for schizophrenia and/or pharmacogenetic markers for antipsychotic-induced tardive dyskinesia.</p><p><strong>Patients and methods: </strong>We genotyped DNA of 449 patients with schizophrenia and 134 healthy controls for rs2067482 and rs72910092 polymorphisms of the <i>CHRM4</i> gene with the use of the MassARRAY^® System by Agena Bioscience. Mann-Whitney test was used to compare qualitative traits and <i>χ</i> ² test was used for categorical traits.</p><p><strong>Results: </strong>The frequency of genotypes and alleles of rs72910092 did not differ between patients with schizophrenia and control subjects. We did not reveal any statistical differences for both rs2067482 and rs72910092 between schizophrenia patients with and without tardive dyskinesia. The frequency of the C allele of the polymorphic variant rs2067482 was significantly higher in healthy persons compared to patients with schizophrenia (OR=0.51, 95% CI [0.33-0.80]; p=0.003). Accordingly, the CC genotype was found significantly more often in healthy persons compared to patients with schizophrenia (OR=0.49, 95% CI [0.31-0.80]; p=0.010).</p><p><strong>Conclusion: </strong>Our study found the presence of the minor allele (T) of rs2067482 variant being associated with schizophrenia. We argue that the association of rs2067482 with schizophrenia may be via its regulatory effect on some other gene with protein kinase C and casein Kknase substrate in neurons 3 (<i>PACSIN3</i>) as a possible candidate. Neither rs2067482 nor rs72910092 is associated with tardive dyskinesia.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"13 ","pages":"97-105"},"PeriodicalIF":3.1,"publicationDate":"2020-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S247174","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37900447","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":"Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide.","authors":"Rafael Loch Batista,&nbsp;Berenice Bilharinho Mendonca","doi":"10.2147/TACG.S198178","DOIUrl":"https://doi.org/10.2147/TACG.S198178","url":null,"abstract":"<p><strong>Introduction: </strong>The conversion of testosterone into dihydrotestosterone is catalyzed by the 5α-reductase type 2 enzyme which plays a crucial role in the external genitalia virilization. It is encoded by the <i>SRD5A2</i> gene. Allelic variants in this gene cause a 46,XY DSD with no genotype-phenotype relationship. It was firstly reported in the early 70s from isolated clusters. Since then, several cases have been reported. Putting together, it will expand the knowledge on the molecular bases of androgen milieu.</p><p><strong>Methods: </strong>We searched for SRD5A2 allelic variants (AV) in the literature (PubMed, Embase, MEDLINE) and websites (ensembl, HGMD, ClinVar). Only cases with AV in both alleles, either in homozygous or compound heterozygous were included. The included cases were analyzed according to ethnicity, exon, domain, aminoacid (aa) conservation, age at diagnosis, sex assignment, gender reassignment, external genitalia virilization and functional studies. External genitalia virilization was scored using Sinnecker scale. Conservation analysis was carried out using the CONSURF platform. For categorical variables, we used X2 test and Cramer's V. Continuous variables were analyzed by <i>t</i> test or ANOVA. Concordance was estimated by Kappa.</p><p><strong>Results: </strong>We identified 434 cases of 5ARD2 deficiencies from 44 countries. Most came from Turkey (23%), China (17%), Italy (9%), and Brazil (7%). Sixty-nine percent were assigned as female. There were 70% of homozygous allelic variants and 30% compound heterozygous. Most were missense variants (76%). However, small indels (11%), splicing (5%) and large deletions (4%) were all reported. They were distributed along with all exons with exon 1 (33%) and exon 4 (25%) predominance. Allelic variants in the exon 4 (NADPH-binding domain) resulted in lower virilization (p<0.0001). The codons 55, 65, 196, 235 and 246 are hotspots making up 25% of all allelic variants. Most of them (76%) were located at conserved aa. However, allelic variants at non-conserved aa were more frequently indels (28% vs 6%; p<0.01). The overall rate of gender change from female to male ranged from 16% to 70%. The lowest rate of gender change from female to male occurred in Turkey and the highest in Brazil. External genitalia virilization was similar between those who changed and those who kept their assigned gender. The gender change rate was significantly different across the countries (V=0.44; p<0.001) even with similar virilization scores.</p><p><strong>Conclusion: </strong>5ARD2 deficiency has a worldwide distribution. Allelic variants at the NADPH-ligand region cause lower virilization. Genitalia virilization influenced sex assignment but not gender change which was influenced by cultural aspects across the countries. Molecular diagnosis influenced on sex assignment, favoring male sex assignment in newborns with 5α-reductase type 2 deficiency.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"13 ","pages":"83-96"},"PeriodicalIF":3.1,"publicationDate":"2020-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S198178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37882103","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":"Alternating Hemiplegia of Childhood: Understanding the Genotype-Phenotype Relationship of ATP1A3 Variations.","authors":"Alessandro Capuano,&nbsp;Giacomo Garone,&nbsp;Giuseppe Tiralongo,&nbsp;Federica Graziola","doi":"10.2147/TACG.S210325","DOIUrl":"https://doi.org/10.2147/TACG.S210325","url":null,"abstract":"<p><p>Alternating hemiplegia of childhood (AHC) is a rare neurological disorder affecting children with an onset before 18 months. Diagnostic clues include transient episodes of hemiplegia alternating in the laterality or quadriparesis, nystagmus and other paroxysmal attacks as tonic and dystonic spells. Epilepsy is also a common feature. In the past, a great effort has been done to understand the genetic basis of the disease leading to the discovery of mutations in the ATP1A3 gene encoding for the alpha3 subunit of Na⁺/K⁺ATPase, a protein already related to another disease named Rapid Onset Dystonia Parkinsonism (RDP). ATP1A3 mutations account for more than 70% of cases of AHC. In particular, three hotspot mutations account for about 60% of all cases, and these data have been confirmed in large population studies. Specifically, the p.Asp801Asn variant has been found to cause 30-43% of all cases, p.Glu815Lys is responsible for 16-35% of cases and p.Gly947Arg accounts for 8-15%. These three mutations are associated with different clinical phenotype in terms of symptoms, severity and prognosis. In vitro and in vivo models reveal that a crucial role of Na⁺/K⁺ATPase pump activity emerges in maintaining a correct membrane potential, survival and homeostasis of neurons. Herein, we attempt to summarize all clinical, genetic and molecular aspects of AHC considering ATP1A3 as its primary disease-causing determinant.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"13 ","pages":"71-81"},"PeriodicalIF":3.1,"publicationDate":"2020-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S210325","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37826530","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":"A Novel <i>APOC2</i> Mutation in a Colombian Patient with Recurrent Hypertriglyceridemic Pancreatitis.","authors":"Gabriel D Pinilla-Monsalve,&nbsp;Juliana Lores,&nbsp;Harry Pachajoa,&nbsp;Juan D López-Ponce de León,&nbsp;Alejandro López,&nbsp;Lisa X Rodríguez-Rojas,&nbsp;José A Nastasi-Catanese","doi":"10.2147/TACG.S243148","DOIUrl":"https://doi.org/10.2147/TACG.S243148","url":null,"abstract":"<p><p>Hypertriglyceridemia is a common disease with only 2% of cases exhibiting monogenic mutations. Familial chylomicronemia syndrome (FCS) is a rare genetic condition associated with recurrent and severe episodes of pancreatitis and is mainly caused by mutations in the LPL gene, with few cases related to abnormal function of apolipoprotein C-II. This is a 50-year-old female with a past medical history of arterial hypertension, miscarriage and recurrent pancreatitis. In the last four years, her triglycerides and lipase concentration reached >3000 mg/dL and >700 U/L, respectively. The patient was not responsive to statins, fibrates, or tetrahydrolipstatin. A novel homozygous frameshift mutation on exon 3 of the <i>APOC2</i> gene was detected, c.133_134delTC. Subsequent Sanger sequencing confirmed that three first-degree relatives were carriers of the same mutation. To the best of our knowledge, we are reporting the first Colombian patient with FCS due to an <i>APOC2</i> mutation. We propose that this mutation caused recurrent hypertriglyceridemic pancreatitis.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"13 ","pages":"63-69"},"PeriodicalIF":3.1,"publicationDate":"2020-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S243148","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37826529","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":"PHEX Gene Mutation in a Patient with X-Linked Hypophosphatemic Rickets in a Developing Country.","authors":"Jessica María Forero-Delgadillo,&nbsp;Daniela Cleves,&nbsp;Vanessa Ochoa,&nbsp;Hernando Londoño-Correa,&nbsp;Jaime Manuel Restrepo,&nbsp;José Antonio Nastasi-Catanese,&nbsp;Harry Pachajoa","doi":"10.2147/TACG.S232448","DOIUrl":"https://doi.org/10.2147/TACG.S232448","url":null,"abstract":"<p><strong>Introduction: </strong>X-linked hypophosphatemic rickets is part of a larger group of hereditary diseases characterized by renal phosphate loss, which causes growth disorders, rickets, and osteomalacia. These conditions are characterized by disorders in phosphate equilibrium, which is essential for bone formation.</p><p><strong>Case report: </strong>A female patient presented with bone deformities of the inferior extremities, prominent joints, and loss of teeth. She received initial management with oral calcium and orthotics in inferior extremities, with poor clinical outcome. PHEX gene sequencing revealed a pathogenic variant c.1601C>T (p.Pro534Leu).</p><p><strong>Discussion: </strong>XLHR is caused by mutations in the PHEX gene; to date, more than 460 mutations have been associated with the disease. Clinically, it is characterized by bowing of the lower extremities, decreased growth, musculoskeletal complaints, dental abscesses, and other clinical signs and symptoms of rickets.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"13 ","pages":"57-62"},"PeriodicalIF":3.1,"publicationDate":"2020-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S232448","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37682045","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":"Molybdenum Cofactor Deficiency: Mega Cisterna Magna in Two Consecutive Pregnancies and Review of the Literature.","authors":"M C Alonzo Martínez,&nbsp;E Cazorla,&nbsp;E Cánovas,&nbsp;K Anniuk,&nbsp;A E Cores,&nbsp;A M Serrano","doi":"10.2147/TACG.S239917","DOIUrl":"https://doi.org/10.2147/TACG.S239917","url":null,"abstract":"<p><p>The molybdenum cofactor deficiency is an autosomal recessive disease, characterized by rapidly progressive and severe neurological damage that mimics a hypoxic-ischemic encephalopathy due to the accumulation of toxic metabolites that cause rapid neurodegeneration after the delivery. It is eventually lethal, in a similar way to the rare isolated sulfite oxidase deficiency. This serious pathology usually causes death in the immediate neonatal period in the more severe variants. We report a case of two consecutive pregnancies with enlarged cisterna magna as the only prenatal pathological finding since 26 weeks of gestation (WG) and the subsequent death of the newborns in the first week after birth. After the second pregnancy, we reached the diagnosis of molybdenum cofactor deficiency due to MOCS1 gene mutation. According to the cases reported in the literature, this is the case with the earliest neuroimage prenatal findings.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"13 ","pages":"49-55"},"PeriodicalIF":3.1,"publicationDate":"2020-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S239917","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37677650","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":"Alkaptonuria: Current Perspectives.","authors":"Andrea Zatkova,&nbsp;Lakshminarayan Ranganath,&nbsp;Ludevit Kadasi","doi":"10.2147/TACG.S186773","DOIUrl":"https://doi.org/10.2147/TACG.S186773","url":null,"abstract":"<p><p>The last 15 years have been the most fruitful in the history of research on the metabolic disorder alkaptonuria (AKU). AKU is caused by a deficiency of homogentisate dioxygenase (HGD), the enzyme involved in metabolism of tyrosine, and is characterized by the presence of dark ochronotic pigment in the connective tissue that is formed, due to high levels of circulating homogentisic acid. Almost 120 years ago, Sir Archibald Garrod used AKU to illustrate the concept of Mendelian inheritance in man. In January 2019, the phase III clinical study SONIA 2 was completed, which tested the effectiveness and safety of nitisinone in the treatment of AKU. Results were positive, and they will serve as the basis for the application for registration of nitisinone for treatment of AKU at the European Medicines Agency. Therefore, AKU might become a rare disease for which a cure will be found by 2020. We understand the natural history of the disease and the process of ochronosis much more, but at the same time there are still unanswered questions. One of them is the issue of the factors influencing the varying severity of the disease, since our recent genotype-phenotype study did not show that differences in residual homogentisic acid activity caused by the different mutations was responsible. Although nitisinone has proved to arrest the process of ochronosis, it has some unwanted effects and does not cure the disease completely. As such, enzyme replacement or gene therapy might become a new focus of AKU research, for which a novel suitable mouse model of AKU is available already. We believe that the story of AKU is also a story of effective collaboration between scientists and patients that might serve as an example for other rare diseases.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"13 ","pages":"37-47"},"PeriodicalIF":3.1,"publicationDate":"2020-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S186773","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37726214","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}