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Am J Med Genet A 2022 01 30;188(1):237-242. Epub 2021 Aug 30.

Department of Neurology, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China.

Hartnup disease cases were rare, and the genotype-phenotype correlation was not fully understood. Here we reported two unrelated young men diagnosed as Hartnup disease, who carried novel compound heterozygote mutations in the SLC6A19 gene and presented with new phenotypes. Other than intermittent encephalopathy and photosensitive rashes, they displayed symptoms and signs of spastic paraplegia and severe peripheral nerve damages. Read More

Front Neurosci 2021 28;15:673600. Epub 2021 May 28.

Department of Paediatrics, University Hospital Center Zagreb and University of Zagreb School of Medicine, Zagreb, Croatia.

Increasing evidence suggests that the autism spectrum disorder (ASD) may be associated with inborn errors of metabolism, such as disorders of amino acid metabolism and transport [phenylketonuria, homocystinuria, S-adenosylhomocysteine hydrolase deficiency, branched-chain α-keto acid dehydrogenase kinase deficiency, urea cycle disorders (UCD), Hartnup disease], organic acidurias (propionic aciduria, L-2 hydroxyglutaric aciduria), cholesterol biosynthesis defects (Smith-Lemli-Opitz syndrome), mitochondrial disorders (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes-MELAS syndrome), neurotransmitter disorders (succinic semialdehyde dehydrogenase deficiency), disorders of purine metabolism [adenylosuccinate lyase (ADSL) deficiency, Lesch-Nyhan syndrome], cerebral creatine deficiency syndromes (CCDSs), disorders of folate transport and metabolism (cerebral folate deficiency, methylenetetrahydrofolate reductase deficiency), lysosomal storage disorders [Sanfilippo syndrome, neuronal ceroid lipofuscinoses (NCL), Niemann-Pick disease type C], cerebrotendinous xanthomatosis (CTX), disorders of copper metabolism (Wilson disease), disorders of haem biosynthesis [acute intermittent porphyria (AIP)] and brain iron accumulation diseases. In this review, we briefly describe etiology, clinical presentation, and therapeutic principles, if they exist, for these conditions. Additionally, we suggest the primary and elective laboratory work-up for their successful early diagnosis. Read More

Photodermatol Photoimmunol Photomed 2021 Mar 2;37(2):99-104. Epub 2021 Feb 2.

Dermatology Department, College of Medicine, University of Malawi, Blantyre, Malawi.

Pellagra is a clinical syndrome caused by a deficiency of niacin (nicotinic acid) and/or its precursor tryptophan. The cardinal manifestations are 4 D's: dermatitis, diarrhoea, dementia and in worst case death. Increased use of isoniazid prophylaxis along with antiretroviral therapy in countries where latent tuberculosis is common has been associated with increased presentations with pellagra. Read More

Sci Rep 2020 12 14;10(1):21836. Epub 2020 Dec 14.

Department of Clinical and Experimental Oncology, Paulista School of Medicine, Federal University of São Paulo, São Paulo, Brazil.

The aim of this study was to identify novel plasma metabolic signatures with possible relevance during multiple myeloma (MM) development and progression. A biochemical quantitative phenotyping platform based on targeted electrospray ionization tandem mass spectrometry technology was used to aid in the identification of any eventual perturbed biochemical pathway in peripheral blood plasma from 36 MM patients and 73 healthy controls. Our results showed that MM cases present an increase in short and medium/long-chain species of acylcarnitines resembling Multiple AcylCoA Dehydrogenase Deficiency (MADD), particularly, associated with MM advanced International Staging System (ISS). Read More

J Glob Health 2020 Dec;10(2):021102

Centre for Global Health, Usher Institute, University of Edinburgh, UK.

Background: Influenza vaccination prevents people from influenza-related diseases and thereby mitigates the burden on national health systems when COVID-19 circulates and public health measures controlling respiratory viral infections are relaxed. However, it is challenging to maintain influenza vaccine services as the COVID-19 pandemic has the potential to disrupt vaccination programmes in many countries during the 2020/21 winter. We summarise available recommendations and strategies on influenza vaccination, specifically the changes in the context of the COVID-19 pandemic. Read More

Clin Sci (Lond) 2020 11;134(21):2823-2833

Institute of Physiology, University of Zurich, Zurich, Switzerland.

ACE2 is a type I membrane protein with extracellular carboxypeptidase activity displaying a broad tissue distribution with highest expression levels at the brush border membrane (BBM) of small intestine enterocytes and a lower expression in stomach and colon. In small intestinal mucosa, ACE2 mRNA expression appears to increase with age and to display higher levels in patients taking ACE-inhibitors (ACE-I). There, ACE2 protein heterodimerizes with the neutral amino acid transporter Broad neutral Amino acid Transporter 1 (B0AT1) (SLC6A19) or the imino acid transporter Sodium-dependent Imino Transporter 1 (SIT1) (SLC6A20), associations that are required for the surface expression of these transport proteins. Read More

Cell Mol Neurobiol 2022 Jan 25;42(1):217-224. Epub 2020 Aug 25.

Neuroscience Center, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, 70112‑2272, USA.

The gateway for invasion by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into human host cells is via the angiotensin-converting enzyme 2 (ACE2) transmembrane receptor expressed in multiple immune and nonimmune cell types. SARS-CoV-2, that causes coronavirus disease 2019 (COVID-19; CoV-19) has the unusual capacity to attack many different types of human host cells simultaneously via novel clathrin- and caveolae-independent endocytic pathways, becoming injurious to diverse cells, tissues and organ systems and exploiting any immune weakness in the host. The elicitation of this multipronged attack explains in part the severity and extensive variety of signs and symptoms observed in CoV-19 patients. Read More

Eat Weight Disord 2021 Jun 20;26(5):1647-1651. Epub 2020 Jul 20.

Department of Molecular and Translational Medicine, University of Brescia, Brescia, 25123, Italy.

Since the outbreak of COVID-19, clinicians have tried every effort to fight the disease, and multiple drugs have been proposed. However, no proven effective therapies currently exist, and different clinical phenotypes complicate the situation. In clinical practice, many severe or critically ill COVID-19 patients developed gastrointestinal (GI) disturbances, including vomiting, diarrhoea, or abdominal pain, even in the absence of cough and dyspnea. Read More

Am J Med Genet A 2019 12 13;179(12):2459-2468. Epub 2019 Sep 13.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Hartnup disease is an autosomal recessive condition characterized by neutral aminoaciduria and behavioral problems. It is caused by a loss of B AT1, a neutral amino acid transporter in the kidney and intestine. CLTRN encodes the protein collectrin that functions in the transportation and activation of B AT1 in the renal apical brush bordered epithelium. Read More

JAMA Psychiatry 2019 10;76(10):1026-1034

Schizophrenia Research Foundation, Chennai, India.

Importance: Genome-wide association studies (GWASs) in European populations have identified more than 100 schizophrenia-associated loci. A schizophrenia GWAS in a unique Indian population offers novel findings.

Objective: To discover and functionally evaluate genetic loci for schizophrenia in a GWAS of a unique Indian population. Read More

SLAS Discov 2019 02 27;24(2):111-120. Epub 2018 Dec 27.

1 In Vitro Biology, Integrated Drug Discovery, Sanofi-Genzyme, Waltham, MA, USA.

SLC6A19 (BAT1) is a neutral amino acid transporter, the loss of function of which results in Hartnup disease. SLC6A19 is also believed to have an important role in amino acid homeostasis, diabetes, and weight control. A small-molecule inhibitor of human SLC6A19 (hSLC6A19) was identified using two functional cell-based assays: a fluorescence imaging plate reader (FLIPR) membrane potential (FMP) assay and a stable isotope-labeled neutral amino acid uptake assay. Read More

Open Life Sci 2018 Jan 20;13:22-27. Epub 2018 Mar 20.

Department of Neurology, Second Affiliated Hospital of Harbin Medical University, Harbin, China.

Aim: The aim of the study is to investigate a variation in the gene in a female patient with Hartnup disorder manifested only by seizure.

Methods: DNA samples collected from the patient and her parents were analyzed and twelve exons of the gene were amplified and sequenced.

Results: We found c. Read More

BMC Pediatr 2014 Dec 20;14:311. Epub 2014 Dec 20.

Makassed Hospital, Alquds University, Medical College, Jerusalem, Palestine.

Background: Celiac disease (CD) is a complex autoimmune disorder that can lead to an inflammatory small intestinal villous atrophy and malabsorption. Hartnup disease is an autosomal recessive disorder caused by increased urinary excretion of neutral amino acids. Co-occurrence of Hartnup disease and CD is extremely rare with only a single case reported. Read More

Hum Mol Genet 2014 Dec 31;23(25):6935-43. Epub 2014 Jul 31.

deCODE Genetics, 101 Reykjavik, Iceland Faculty of Medicine

Chronic kidney disease (CKD) is a complex disorder with a strong genetic component. A number of common sequence variants have been found to associate with serum creatinine (SCr), estimated glomerular filtration rate (eGFR) and/or CKD. We imputed 24 million single-nucleotide polymorphisms and insertions/deletions identified by whole-genome sequencing of 2230 Icelanders into 81 656 chip-typed individuals and 112 630 relatives of genotyped individuals over the age of 18 with SCr measurements. Read More

Microbes Infect 2013 Nov 17;15(13):866-73. Epub 2013 Aug 17.

IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.

The renin-angiotensin system (RAS) is a complex network that regulates blood pressure, electrolyte and fluid homeostasis, as well as the function of several organs. Angiotensin-converting enzyme 2 (ACE2) was identified as an enzyme that negatively regulates the RAS by converting Ang II, the main bioactive molecule of the RAS, to Ang 1-7. Thus, ACE2 counteracts the role of angiotensin-converting enzyme (ACE) which generates Ang II from Ang I. Read More

Handb Clin Neurol 2013 ;112:1213-7

Division of Pediatric Neurology, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.

The approach to the child with ataxia requires a detailed history and careful general and neurological examination as well as selected blood work and brain imaging and increasingly available genetic testing for inherited ataxias that usually have an episodic or progressive presentation. The differential of acute and recurring ataxia covered in this chapter includes intoxication (e.g. Read More

Rev Neurol 2012 Apr;54(7):394-8

Hospital Sant Joan de Deu, 08950 Esplugues de Llobregat, Espana.

Introduction: Studying the amino acids in cerebrospinal fluid (CSF) is essential in the diagnosis of some neurological diseases and is an important aid in the diagnosis of others. No research has been published in the literature to prove the physiological relationship between the values of amino acids in CSF and plasma in the paediatric population.

Aim: To define a set of ratios for amino acids in plasma and CSF in the paediatric population that can be used in daily clinical practice. Read More

Channels (Austin) 2011 Sep-Oct;5(5):410-23. Epub 2011 Sep 1.

INRA/AgroParisTech, Paris, France.

Neutral amino acid transporters of the SLC6 family are expressed at the apical membrane of kidney and/or small intestine, where they (re-)absorb amino acids into the body. In this review we present the results concerning the dependence of their apical expression with their association to partner proteins. We will in particular focus on the situation of B0AT1 and B0AT3, that associate with members of the renin-angiotensin system (RAS), namely Tmem27 and angiotensin-converting enzyme 2 (ACE2), in a tissue specific manner. Read More

J Biol Chem 2011 Jul 2;286(30):26638-51. Epub 2011 Jun 2.

Research School of Biology, Australian National University, Canberra, Australian Capital Territory 0200, Australia.

Amino acid uptake in the intestine and kidney is mediated by a variety of amino acid transporters. To understand the role of epithelial neutral amino acid uptake in whole body homeostasis, we analyzed mice lacking the apical broad-spectrum neutral (0) amino acid transporter B(0)AT1 (Slc6a19). A general neutral aminoaciduria was observed similar to human Hartnup disorder which is caused by mutations in SLC6A19. Read More

Am J Physiol Gastrointest Liver Physiol 2011 Jul 24;301(1):G128-37. Epub 2011 Feb 24.

ZIEL Research Center of Nutrition and Food Sciences, Abteilung Biochemie, Technische Universität München, Freising, Germany.

The intestinal peptide transporter PEPT1 mediates the uptake of di- and tripeptides derived from dietary protein breakdown into epithelial cells. Whereas the transporter appears to be essential to compensate for the reduced amino acid delivery in patients with mutations in amino acid transporter genes, such as in cystinuria or Hartnup disease, its physiological role in overall amino acid absorption is still not known. To assess the quantitative importance of PEPT1 in overall amino acid absorption and metabolism, PEPT1-deficient mice were studied by using brush border membrane vesicles, everted gut sacs, and Ussing chambers, as well as by transcriptome and proteome analysis of intestinal tissue samples. Read More

J Health Popul Nutr 2010 Aug;28(4):413-5

Department of Pediatric Endocrinology and Metabolism, Ataturk University, Erzurum, Turkey.

This report describes an 11-month old girl with Hartnup disease presenting with kwashiorkor and acrodermatitis enteropathica-like skin lesions but free of other clinical findings. This case with kwashiorkor had acrodermatitis enteropathica-like desquamative skin eruption. Since zinc level was in the normal range, investigation for a metabolic disorder was considered, and Hartnup disease was diagnosed. Read More

Pediatr Neurol 2010 May;42(5):369-71

Department of Pediatrics, Genetic and Metabolic Clinic, Children's Hospital, Pusan National University, Gyeongnam, South Korea.

Hartnup disorder is caused by an inborn error of neutral amino acid transport in the kidneys and intestines. It is characterized by pellagra-like rash, ataxia, and psychotic behavior. Elevated urinary neutral amino acids are the first indicator of the disorder. Read More

Nihon Eiseigaku Zasshi 2010 Jan;65(1):37-47

Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Genetic dissection of diseases is one of the epoch-making achievements in modern medicine. Positional cloning is a key method to isolate disease-related genes. For positional cloning, there are two conventional methods: family-based studies and case-control studies. Read More

Circ J 2010 Mar 4;74(3):405-10. Epub 2010 Feb 4.

Department of Biological Informatics and Experimental Therapeutics, the Global COE program, Akita University Graduate School of Medicine, Japan.

Angiotensin-converting enzyme 2 (ACE2), a first homolog of ACE, regulates the renin-angiotensin system by counterbalancing ACE activity. Accumulating evidence in recent years has demonstrated a physiological and pathological role of ACE2 in the cardiovascular, renal and respiratory systems. For instance, in the acute respiratory distress syndrome (ARDS), ACE, AngII, and AT1R promote the disease pathogenesis, whereas ACE2 and the AT2R protect from ARDS. Read More

IUBMB Life 2009 Jun;61(6):591-9

School of Biology, College of Medicine, Biology and Environment, Australian National University, Canberra, Australian Capital Territory, Australia.

Hartnup disorder (OMIM 234500) is an autosomal recessive disorder, which was first described in 1956 as an aminoaciduria of neutral amino acids accompanied by a variety of symptoms, such as a photo-sensitive skin-rash and cerebellar ataxia. The disorder is caused by mutations in the neutral amino acid transporter B(0)AT1 (SLC6A19). To date 21 mutations have been identified in more than twenty families. Read More

Int J Dermatol 2009 Apr;48(4):388-92

Department of Dermatology, Peking University First and Third Hospital, Beijing and He Ping Hospital, Chang Zhi Medical College, Changzhi, China.

Background: Hartnup disease is a rare autosomal-recessive abnormality of renal and gastrointestinal neutral amino acid transport associated with neurologic, psychiatric, and dermatologic symptoms. Mutations in the SLC6A19 gene have been proposed to be responsible for the underlying changes in this disorder.

Aim: To investigate a pedigree with Hartnup disorder and to search for the mutation in the SLC6A19 gene in this pedigree. Read More

Gastroenterology 2009 Mar 29;136(3):872-82. Epub 2008 Oct 29.

Institute of Physiology and Zürich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.

Background & Aims: Hartnup amino acid transporter B(0)AT1 (SLC6A19) is the major luminal sodium-dependent neutral amino acid transporter of small intestine and kidney proximal tubule. The expression of B(0)AT1 in kidney was recently shown to depend on its association with collectrin (Tmem27), a protein homologous to the membrane-anchoring domain of angiotensin-converting enzyme (ACE) 2.

Methods: Because collectrin is almost absent from small intestine, we tested the hypothesis that it is ACE2 that interacts with B(0)AT1 in enterocytes. Read More

Clin Exp Dermatol 2009 Mar 6;34(2):178-82. Epub 2008 Nov 6.

Department of Dermatology, Tawam Hospital in affiliation with Johns Hopkins Medicine, Al Ain, UAE.

Exfoliative erythema of malnutrition is a collective term for skin lesions caused by a combination of multiple deficiencies in vitamins, microelements, essential fatty acids and amino acids. We report a 3-year-old Iraqi girl with malnutrition due to coexisting coeliac and Hartnup's disease. On admission to hospital, she presented with kwashiorkor, anaemia, hepatitis and hypoalbuminia. Read More

BMC Psychiatry 2008 Jul 18;8:58. Epub 2008 Jul 18.

Division of Human Molecular Genetics, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.

Background: Based on the glutamatergic dysfunction hypothesis for schizophrenia pathogenesis, we have been performing systematic association studies of schizophrenia with the genes involved in glutametergic transmission. We report here association studies of schizophrenia with SLC1A4, SLC1A5 encoding neutral amino acid transporters ASCT1, ASCT2, and SLC6A5, SLC6A9 encoding glycine transporters GLYT2, GLYT1, respectively.

Methods: We initially tested the association of 21 single nucleotide polymorphisms (SNPs) distributed in the four gene regions with schizophrenia using 100 Japanese cases-control pairs and examined allele, genotype and haplotype association with schizophrenia. Read More