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Nutrients 2022 Jun 17;14(12). Epub 2022 Jun 17.

Department of Pharmacology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.

The trace element zinc (Zn) binds to over ten percent of proteins in eukaryotic cells. Zn flexible chemistry allows it to regulate the activity of hundreds of enzymes and influence scores of metabolic processes in cells throughout the body. Deficiency of Zn in humans has a profound effect on development and in adults later in life, particularly in the brain, where Zn deficiency is linked to several neurological disorders. Read More

Drug Des Devel Ther 2022 16;16:1827-1845. Epub 2022 Jun 16.

Department of Internal Medicine, Section on Gastroenterology and Hepatology, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Small interfering ribonucleic acids [siRNAs] are short ribonucleic acid (RNA) fragments cleaved from double-stranded RNA molecules that target and bind to specific sequences on messenger RNA (mRNA), leading to their destruction. Therefore, the siRNA down-regulates the formation of selected mRNAs and their protein products. Givosiran is one such siRNA that uses this mechanism to treat acute hepatic porphyrias. Read More

Orphanet J Rare Dis 2022 06 18;17(1):236. Epub 2022 Jun 18.

Pfizer Inc, New York, NY, USA.

Background: Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disease caused by the accumulation of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in the heart, peripheral nerves, and other tissues and organs.

Methods: Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal observational study of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This descriptive analysis examines baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2021). Read More

Nutrients 2022 May 30;14(11). Epub 2022 May 30.

Department of Cardiovascular Diseases, John Ochsner Heart & Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA 70121, USA.

The etiology of obesity is complex and idiosyncratic-with inherited, behavioral, and environmental factors determining the age and rate at which excessive adiposity develops. Moreover, the etiologic status of an obese phenotype (how and when it developed initially) strongly influences both the short-term response to intervention and long-term health trajectories. Nevertheless, current management strategies tend to be 'one-size-fits-all' protocols that fail to anticipate the heterogeneity of response generated by the etiologic status of each individual's phenotype. Read More

Continuum (Minneap Minn) 2022 06;28(3):750-780

Purpose Of Review: This article gives a broad overview of vascular cognitive impairment and dementia, including epidemiology, pathophysiology, clinical approach, and management. Emphasis is placed on understanding the common underlying types of cerebrovascular disease (including atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy) and awareness of rare inherited cerebrovascular disorders.

Recent Findings: The pathophysiology of vascular cognitive impairment and dementia is heterogeneous, and the most recent diagnostic criteria for vascular cognitive impairment and dementia break down the diagnosis of major vascular dementia into four phenotypic categories, including subcortical ischemic vascular dementia, poststroke dementia, multi-infarct dementia, and mixed dementia. Read More

Int J Mol Sci 2022 May 20;23(10). Epub 2022 May 20.

Pediatric Neurology Department, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland.

Neuronal ceroid lipofuscinoses (NCLs) are a group of rare, inherited, neurodegenerative lysosomal storage disorders that affect children and adults. They are traditionally grouped together, based on shared clinical symptoms and pathological ground. To date, 13 autosomal recessive gene variants, as well as one autosomal dominant gene variant, of NCL have been described. Read More

Klin Onkol 2022 ;35(2):119-127

Background: Ionizing radiation DNA damage is the main mechanism of radiotherapy (RT) action and the outcome of treatment and healthy tissue toxicity is influenced by a number of external and internal factors, including mutations in DNA damage recognition and repair. Disorders of DNA repair may result in increased sensitivity to cancer treatment.

Purpose: The mechanism of DNA repair and an overview of genetic syndromes with mutations in genes involved in DNA repair clarify the accelerated carcinogenesis and increased radiosensitivity in RT cancers. Read More

CNS Neurol Disord Drug Targets 2022 Apr 18. Epub 2022 Apr 18.

Faculté de médecine, Université Laval, Québec, Canada.

The autosomal recessive cerebellar ataxias (ARCAs) compose a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by prominent cerebellar ataxia, dysmetria, dysarthria, and nystagmus that are inherited in an autosomal recessive fashion. The diagnosis of ARCAs is challenging because of their low prevalence, poor medical recognition, and heterogeneous clinical presentation with many overlapping features between entities. There currently exist no disease-modifying therapies for most ARCAs, and treatment is mainly symptomatic, aimed at prolonging independence and maintaining quality of life. Read More

Crit Care 2022 03 31;26(1):88. Epub 2022 Mar 31.

Pediatric Intensive Care Unit, Department of Pediatric Surgery, • Erasmus MC - Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Management and monitoring of pain and sedation to reduce discomfort as well as side effects, such as over- and under-sedation, withdrawal syndrome and delirium, is an integral part of pediatric intensive care practice. However, the current state of management and monitoring of analgosedation across European pediatric intensive care units (PICUs) remains unknown. The aim of this survey was to describe current practices across European PICUs regarding the management and monitoring of pain and sedation. Read More

Hum Mutat 2022 Jul 14;43(7):832-858. Epub 2022 Apr 14.

Department of Ophthalmology, Otorhinolaryngology, and Head and Neck Surgery, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Read More

Genes (Basel) 2022 03 12;13(3). Epub 2022 Mar 12.

Departments of Pediatrics and Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, 1012 WX Amsterdam, The Netherlands.

Understanding the genetic architecture of metabolic epilepsies is of paramount importance, both to current clinical practice and for the identification of further research directions. The main goals of our study were to identify the scope of metabolic epilepsies and to investigate their clinical presentation, diagnostic approaches and treatments. The International Classification of Inherited Metabolic Disorders and IEMbase were used as a basis for the identification and classification of metabolic epilepsies. Read More

Am J Emerg Med 2022 05 9;55:138-142. Epub 2022 Mar 9.

Department of Medical Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.

Introduction: An increasing number of pediatric patients with inherited metabolic disorders are reaching adulthood. In addition, many patients are diagnosed for the first time in adult life due to improved awareness of these disorders and the availability of advanced diagnostic technology. Knowledge of these inherited metabolic disorders in adults is crucial for the emergency physician to promptly recognize their acute illness and appropriately manage them in the emergency department. Read More

Cell Mol Life Sci 2022 Mar 1;79(3):166. Epub 2022 Mar 1.

Department of Molecular Genetics, Erasmus MC Cancer Institute, Oncode Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.

The XPG/ERCC5 endonuclease was originally identified as the causative gene for Xeroderma Pigmentosum complementation group G. Ever since its discovery, in depth biochemical, structural and cell biological studies have provided detailed mechanistic insight into its function in excising DNA damage in nucleotide excision repair, together with the ERCC1-XPF endonuclease. In recent years, it has become evident that XPG has additional important roles in genome maintenance that are independent of its function in NER, as XPG has been implicated in protecting replication forks by promoting homologous recombination as well as in resolving R-loops. Read More

J Clin Med 2022 Feb 18;11(4). Epub 2022 Feb 18.

Institute for Biomedical Research and Innovation, National Research Council, Via Paolo Gaifami 18, 95026 Catania, Italy.

Hyperphenylalaninemia (HPA), the most common amino acid metabolism disorder, is caused by defects in enzymes involved in phenylalanine metabolism, with the consequent accumulation of phenylalanine and its secondary metabolites in body fluids and tissues. Clinical manifestations of HPA include mental retardation, and its early diagnosis with timely treatment can improve the prognosis of affected patients. Due to the genetic complexity and heterogeneity of HPA, high-throughput molecular technologies, such as next-generation sequencing (NGS), are becoming indispensable tools to fully characterize the etiology, helping clinicians to promptly identify the exact patients' genotype and determine the appropriate treatment. Read More

Cells 2022 02 5;11(3). Epub 2022 Feb 5.

IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy.

Inherited blood disorders comprise a large spectrum of diseases due to germline mutations in genes with key function in the hematopoietic system; they include immunodeficiencies, anemia or metabolic diseases. For most of them the only curative treatment is bone marrow transplantation, a procedure associated to severe complications; other therapies include red blood cell and platelet transfusions, which are dependent on donor availability. An alternative option is gene therapy, in which the wild-type form of the mutated gene is delivered into autologous hematopoietic stem cells using viral vectors. Read More

Hemoglobin 2021 Sep 13;45(5):287-295. Epub 2022 Feb 13.

Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Gizan, Saudi Arabia.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited metabolic abnormality of red blood cells (RBCs), affecting 400 million individuals worldwide. Patients with G6PD deficiency anemia might exhibit severe clinical manifestations, including acute hemolytic anemia (AHA), neonatal hyperbilirubinemia (jaundice), favism, and chronic non-spherocytic hemolytic anemia (CNSHA). The aim of the current review is to report the prevalence and genetic variants of G6PD deficiency anemia in Saudi Arabia. Read More

Neurol Sci 2022 Mar 22;43(3):1617-1626. Epub 2022 Jan 22.

2nd Department of Neurology, Aristotle University of Thessaloniki, AHEPA Hospital, Stilp. Kyriakidi 1, 546 36, Thessaloniki, Greece.

Acute encephalopathy is a widely used term, implying a rapidly progressive multifocal or diffuse brain dysfunction, caused by acute structural disturbance or a myriad of metabolic, toxic, epileptic, or infection-related factors. Apart from the more common acquired causes, a broad range of rare inherited disorders may produce spells of encephalopathy in adulthood, posing diagnostic challenges to clinicians. Among the latter, neurometabolic disorders and epileptic syndromes constitute typical examples. Read More

BMC Cancer 2022 Jan 3;22(1). Epub 2022 Jan 3.

Department of Psychology, Babeş-Bolyai University, Cluj-Napoca, Romania.

Background: Approximately 5% of colorectal cancer (CRC) cases are part of a well-defined inherited genetic syndrome and up to approximately 30% of these cases have a clinically defined familial basis. Psychosocial interventions in familial colorectal cancer address aspects mainly focused on affective, cognitive and behavioural outcomes. The present review aims to systematically map out the available psychosocial interventions for individuals with a family history of CRC and describe the current state of the research. Read More

Mol Genet Metab 2021 Nov 8. Epub 2021 Nov 8.

Department of Pediatrics, Amalia Children's Hospital, Radboud Centre for Mitochondrial Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Departments of Human Genetics and Pediatrics, Emma Children's Hospital, Amsterdam University Medical Centres, Amsterdam, the Netherlands; Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada. Electronic address:

Cerebral palsy (CP) is a debilitating condition characterized by abnormal movement or posture, beginning early in development. Early family and twin studies and more recent genomic investigations clearly demonstrate that genetic factors of major effect contribute to the etiology of CP. Most copy number variants and small alterations of nucleotide sequence that cause CP arise as a result of de novo mutations, so studies that estimate heritability on basis of recurrence frequency within families substantially underestimate genetic contributions to the etiology. Read More

Neurotherapeutics 2021 10 30;18(4):2286-2302. Epub 2021 Nov 30.

Amyloidosis Research and Treatment Centre, IRCCS Fondazione Policlinico San Matteo, Viale Golgi, 19, 27100, Pavia, Italy.

The past few years have witnessed an unprecedented acceleration in the clinical development of novel therapeutic options for hereditary transthyretin amyloidosis. Recently approved agents and drugs currently under investigation not only represent a major breakthrough in this field but also provide validation of the therapeutic potential of innovative approaches, like RNA interference and CRISPR-Cas9-mediated gene editing, in rare inherited disorders. In this review, we describe the evolving therapeutic landscape for hereditary transthyretin amyloidosis and discuss how this highly disabling and fatal condition is turning into a treatable disease. Read More

Neuromuscul Disord 2021 12 29;31(12):1251-1258. Epub 2021 Sep 29.

Neurogenetics Unit, 1st Department of Neurology, Eginitio University Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Comprehensive data on variant transthyretin amyloidosis polyneuropathy (ATTRv-PN) in Greece are lacking. We presently provide an overview of ATTRv-PN in Greece, focusing on unexplored non-endemic regions of the country. In total, we identified 57 cases of ATTRv-PN diagnosed over the past 25 years, including 30 from the island of Crete, an apparent endemic region. Read More

Front Pediatr 2021 18;9:727301. Epub 2021 Oct 18.

Center for Molecular Medicine, Children's Hospital of Fudan University, Shanghai, China.

Neonatal metabolic acidosis (NMA) is a common problem, particularly in critically ill patients in neonatal intensive care units (NICUs). Complex etiologies and atypical clinical signs make diagnosis difficult; thus, it is crucial to investigate the underlying causes of NMA rapidly and provide disorder-specific therapies. Our study aims to provide an overview of the genetic causes of NMA in patients from NICUs. Read More

J Neurol Sci 2022 Feb 1;433:120020. Epub 2021 Oct 1.

Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy. Electronic address:

Ataxia is not a common feature in Parkinson's disease. Nevertheless, some rare forms of parkinsonism have ataxia as one of the main features in their clinical picture, especially those with juvenile or early-onset. On the other side, in cerebellar degenerative diseases, parkinsonism might accompany the typical symptoms and even become predominant in some cases. Read More

Cells 2021 10 7;10(10). Epub 2021 Oct 7.

Department of Pathology and Immunology, School of Medicine, University of Geneva, Rue Michel Servet 1, 1206 Geneva, Switzerland.

Metabolic disorders are very common in the population worldwide and are among the diseases with the highest health utilization and costs per person. Despite the ongoing efforts to develop new treatments, currently, for many of these disorders, there are no approved therapies, resulting in a huge economic hit and tension for society. In this review, we recapitulate the recent advancements in stem cell (gene) therapy as potential tools for the long-term treatment of both inherited (lysosomal storage diseases) and acquired (diabetes mellitus, obesity) metabolic disorders, focusing on the main promising results observed in human patients and discussing the critical hurdles preventing the definitive jump of this approach from the bench to the clinic. Read More

Molecules 2021 Oct 15;26(20). Epub 2021 Oct 15.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68106, USA.

Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal, inherited neurodegenerative lysosomal storage disorders. Numerous genes (CLN1-CLN8, CLN10-CLN14) were identified in which mutations can lead to NCL; however, the underlying pathophysiology remains elusive. Despite this, the NCLs share some of the same features and symptoms but vary in respect to severity and onset of symptoms by age. Read More

Brain Behav 2021 11 17;11(11):e2389. Epub 2021 Oct 17.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neurology, Berlin, Germany.

Acute hepatic porphyrias (AHP) can cause severe neurological symptoms involving the central, autonomic, and peripheral nervous system. Due to their relative rarity and their chameleon-like presentation, delayed diagnosis and misdiagnosis are common. AHPs are genetically inherited disorders that result from heme biosynthesis enzyme deficiencies and comprise four forms: acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and ALA-dehydratase porphyria (ALADP). Read More

J Neuromuscul Dis 2022 ;9(1):193-210

Institut de Myologie, Paris, France.

Background: Clinical and molecular data on the occurrence and frequency of inherited neuromuscular disorders (NMD) in the Lebanese population is scarce.

Objective: This study aims to provide a retrospective overview of hereditary NMDs based on our clinical consultations in Lebanon.

Methods: Clinical and molecular data of patients referred to a multi-disciplinary consultation for neuromuscular disorders over a 20-year period (1999-2019) was reviewed. Read More

Diabetologia 2021 12 16;64(12):2687-2700. Epub 2021 Sep 16.

Institute of Medical Biochemistry and Molecular Biology, University Medicine Rostock, Rostock, Germany.

Aims/hypothesis: The mammalian enzyme glucokinase (GK), expressed predominantly in liver and pancreas, plays an essential role in carbohydrate metabolism. Monogenic GK disorders emphasise the role of GK in determining the blood glucose set point.

Methods: A family with congenital hyperinsulinism (CHI) was examined for GCK gene variants by Sanger sequencing. Read More

Int J Mol Sci 2021 Sep 4;22(17). Epub 2021 Sep 4.

Department of Cell-to-Cell Communication, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.

Nrf2 is a basic region leucine-zipper transcription factor that plays a pivotal role in the coordinated gene expression of antioxidant and detoxifying enzymes, promoting cell survival in adverse environmental or defective metabolic conditions. After synthesis, Nrf2 is arrested in the cytoplasm by the Kelch-like ECH-associated protein 1 suppressor (Keap1) leading Nrf2 to ubiquitin-dependent degradation. One Nrf2 activation mechanism relies on disconnection from the Keap1 homodimer through the oxidation of cysteine at specific sites of Keap1. Read More

Nucleic Acids Res 2021 09;49(17):9686-9695

Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.

Diagnosing mitochondrial disorders remains challenging. This is partly because the clinical phenotypes of patients overlap with those of other sporadic and inherited disorders. Although the widespread availability of genetic testing has increased the rate of diagnosis, the combination of phenotypic and genetic heterogeneity still makes it difficult to reach a timely molecular diagnosis with confidence. Read More