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Orphanet J Rare Dis 2020 Jun 11;15(1):146. Epub 2020 Jun 11.

Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology, 4700 KAUST, Thuwal, 23955, Kingdom of Saudi Arabia.

Background: Inborn errors of metabolism (IEM) represent a subclass of rare inherited diseases caused by a wide range of defects in metabolic enzymes or their regulation. Of over a thousand characterized IEMs, only about half are understood at the molecular level, and overall the development of treatment and management strategies has proved challenging. An overview of the changing landscape of therapeutic approaches is helpful in assessing strategic patterns in the approach to therapy, but the information is scattered throughout the literature and public data resources. Read More

J Inherit Metab Dis 2020 May 11. Epub 2020 May 11.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Antisense oligonucleotide (AON) therapies involve short strands of modified nucleotides that target RNA in a sequence-specific manner, inducing targeted protein knockdown or restoration. Currently, 10 AON therapies have been approved in the United States and Europe. Nucleotides are chemically modified to protect AONs from degradation, enhance bioavailability and increase RNA affinity. Read More

Adv Ther 2020 May 8;37(5):1866-1896. Epub 2020 Apr 8.

Child Nutrition and Metabolic Diseases Unit, University Hospital La Paz, Madrid, Spain.

Introduction: Liver transplantation is recognised as a treatment option for patients with propionic acidemia (PA) and those with methylmalonic acidemia (MMA) without renal impairment. In patients with MMA and moderate-to-severe renal impairment, combined liver-kidney transplantation is indicated. However, clinical experience of these transplantation options in patients with PA and MMA remains limited and fragmented. Read More

J Bras Nefrol 2020 03 20. Epub 2020 Mar 20.

Universidade Federal do Paraná, Departamento de Clínica Médica, Serviço de Nefrologia, Curitiba, PR, Brasil.

There are more than 150 different rare genetic kidney diseases. They can be classified according to diagnostic findings as (i) disorders of growth and structure, (ii) glomerular diseases, (iii) tubular, and (iv) metabolic diseases. In recent years, there has been a shift of paradigm in this field. Read More

Front Neurol 2019 18;10:1369. Epub 2020 Feb 18.

Department of Pediatrics, Emma Children's Hospital, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, Netherlands.

Progressive intellectual and neurological deterioration (PIND) is a rare but severe childhood disorder characterized by loss of intellectual or developmental abilities, and requires quick diagnosis to ensure timely treatment to prevent possible irreversible neurological damage. Inborn errors of metabolism (IEMs) constitute a group of more than 1,000 monogenic conditions in which the impairment of a biochemical pathway is intrinsic to the pathophysiology of the disease, resulting in either accumulation of toxic metabolites and/or shortage of energy and building blocks for the cells. Many IEMs are amenable to treatment with the potential to improve outcomes. Read More

J Cardiovasc Electrophysiol 2020 Feb 15;31(2):570-578. Epub 2020 Jan 15.

Cardiology Division, Cardiovascular Genetics Program, Massachusetts General Hospital, Boston, Massachusetts.

Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) can be attributed to cardiac, respiratory, metabolic, and toxicologic etiologies. Most cases of SCD are caused by coronary artery disease and approximately 40% of cardiac arrests are unexplained. Inherited arrythmias and cardiomyopathies are important contributors to SCA and SCD. Read More

J Clin Med 2019 Dec 12;8(12). Epub 2019 Dec 12.

IMAiA-Institute for Molecular Biology and RNA Technology, Faculty of Health, Universiteitssingel 50, 6229ER Maastricht, The Netherlands.

The normal function of the heart relies on a series of complex metabolic processes orchestrating the proper generation and use of energy. In this context, mitochondria serve a crucial role as a platform for energy transduction by supplying ATP to the varying demand of cardiomyocytes, involving an intricate network of pathways regulating the metabolic flux of substrates. The failure of these processes results in structural and functional deficiencies of the cardiac muscle, including inherited cardiomyopathies. Read More

Mol Genet Metab 2020 01 21;129(1):3-12. Epub 2019 Nov 21.

Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, NC, USA; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.. Electronic address:

The glycogen storage diseases are a group of inherited metabolic disorders that are characterized by specific enzymatic defects involving the synthesis or degradation of glycogen. Each disorder presents with a set of symptoms that are due to the underlying enzyme deficiency and the particular tissues that are affected. Autophagy is a process by which cells degrade and recycle unneeded or damaged intracellular components such as lipids, glycogen, and damaged mitochondria. Read More

J Clin Pathol 2020 Jul 22;73(7):384-390. Epub 2019 Nov 22.

Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Monogenic dyslipidaemia is a diverse group of multisystem disorders. Patients may present to various specialities from early childhood to late in adult life, and it usually takes longer before the diagnosis is established. Increased awareness of these disorders among clinicians is imperative for early diagnosis. Read More

Mol Genet Metab 2020 02 31;129(2):47-58. Epub 2019 Oct 31.

Paediatric Neurology Unit and Laboratories, Meyer Children's Hospital, Florence, Italy; Department of NEUROFARBA, University of Florence, Florence, Italy. Electronic address:

Lysosomal storage diseases (LSDs) are rare to extremely rare monogenic disorders. Their incidence, however, has probably been underestimated owing to their complex clinical manifestations. Sialidosis is a prototypical LSD inherited as an autosomal recessive trait and caused by mutations in the NEU1 gene that result in a deficiency of alpha-N-acetyl neuraminidase 1 (NEU1). Read More

Stem Cells Transl Med 2020 Feb 24;9(2):148-157. Epub 2019 Oct 24.

Department of Clinical Science, Intervention and Technology, Division of Obstetrics and Gynecology, Karolinska Institutet, Stockholm, Sweden.

Imagine the profits in quality of life that can be made by treating inherited diseases early in life, maybe even before birth! Immense cost savings can also be made by treating diseases promptly. Hence, prenatal stem cell therapy holds great promise for developing new and early-stage treatment strategies for several diseases. Successful prenatal stem cell therapy would represent a major step forward in the management of patients with hematological, metabolic, or immunological disorders. Read More

Adv Exp Med Biol 2019 ;1148:279-322

Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, USA.

Hypophosphatasia (HPP) is an inherited disorder that affects bone and tooth mineralization characterized by low serum alkaline phosphatase. HPP is caused by loss-of-function mutations in the ALPL gene encoding the protein, tissue-nonspecific alkaline phosphatase (TNSALP). TNSALP is expressed by mineralizing cells of the skeleton and dentition and is associated with the mineralization process. Read More

Adv Clin Chem 2019 8;92:59-103. Epub 2019 Jun 8.

Department of Pathology, UT Southwestern Medical Center, Dallas, TX, United States. Electronic address:

Inborn errors of metabolism (IEMs) are a large class of genetic disorders that result from defects in enzymes involved in energy production and metabolism of nutrients. For every metabolic pathway, there are defects that can occur and potentially result in an IEM. While some defects can go undetected in one's lifetime, some have moderate to severe clinical consequences. Read More

Adv Exp Med Biol 2019 ;1158:247-255

Molecular Brain Sciences Department, Centre for Addiction and Mental Health, Toronto, Canada.

The maternally inherited mitochondrial DNA (mtDNA) is located inside every mitochondrion, in variable number of copies, and it contains 37 crucial genes for cellular bioenergetics. This chapter will discuss the unique features of this circular genome including heteroplasmy, haplogroups, among others, along with the corresponding clinical relevance for each. The discussion also covers the nuclear-encoded mitochondrial genes (N > 1000) and the epistatic interactions between mtDNA and the nuclear genome. Read More

BMC Neurol 2019 Aug 22;19(1):203. Epub 2019 Aug 22.

Innovation center for neurological disorders, Department of Neurology, Xuan Wu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China.

Background: Vanishing white matter disease (VWMD) is one of the most prevalent inherited leukoencephalopathies, which generally presents in childhood as a progressive disorder while less beginning in adulthood. The present report describes the clinical, neuroimaging, and genetic findings of a female patient with adult-onset VWMD. In addition, to provide a clearer delineation of the clinical and genetic characteristics of female adult-onset VWMD patients, 32 genetically confirmed female adult-onset EIF2B-mutated cases are summarized. Read More

Klin Onkol 2019 ;32(Supplementum2):14-23

Expanded gene panel testing for hereditary cancer predispositions using massive parallel sequencing can identify heterozygous pathogenic variants of genes that cause autosomal recessive inherited cancer syndromes. There are no clinical guidelines regarding assessment of the risk of developing solid tumors or for developing appropriate surveillance strategies for heterozygotes for most of these genes, nor is there delineation with respect to the management for genetic testing of relatives and partners. Based on current knowledge, our aim was to create “Czech guidelines” for these cases. Read More

Hum Gene Ther 2019 10 10;30(10):1222-1235. Epub 2019 Sep 10.

Gene Therapy Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.

In the last decade, the gene therapy (GT) field experienced a renaissance, thanks to crucial understandings and innovations in vector design, stem cell manipulation, conditioning protocols, and cell/vector delivery. These efforts were successfully coupled with unprecedented clinical results of the trials employing the newly developed technology and with the novel establishment of academic-industrial partnerships. A renewed and strengthened interest is rising in the development of gene-based approaches for inherited neurometabolic disorders with severe neurological involvement. Read More

Indian J Pediatr 2019 10 13;86(10):923-938. Epub 2019 Jun 13.

Department of Diagnostic Imaging, Hospital for Sick Children / Medical Imaging, University of Toronto, Toronto, Canada.

Advances in genetics has revolutionised the way we understand, diagnose and manage neurological disorders. Notwithstanding the fact that genetic confirmation has already become standard of care in routine clinical practice, radiological and clinical phenotyping has not diminished in value; in fact it has found an enhanced role in guiding and interpreting genetic test results. Inherited neurometabolic disorders are a prominent group of disorders which are seen commonly in clinical practice and many are potentially treatable. Read More

J Diabetes Investig 2019 Nov 12;10(6):1454-1462. Epub 2019 Jun 12.

NHC Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union, Beijing, China.

Aims/introduction: The principal aim of this study was to investigate the clinical, genetic and functional characteristics of two cases of congenital hyperinsulinism (CHI) caused by glucokinase (GCK) mutations in young patients.

Materials And Methods: Novel mutations were detected by CHI next-generation sequencing, and the kinetic parameters and thermal stability of recombinant wild-type and mutant glucokinase were determined in vitro. In addition, 18 naturally occurring GCK-CHI mutations reported previously were also summarized. Read More

Rev Endocr Metab Disord 2019 06;20(2):239-250

Endocrinology Unit, Department of Clinical Medicine and Surgery, University Federico II, Via Sergio Pasini 5, 80121, Naples, Italy.

Prader-Willi syndrome (PWS) is a genetic disorder characterized by short stature, low lean body mass, muscular hypotonia, mental retardation, behavioral abnormalities, dysmorphic features, and excessive appetite with progressive obesity. It is caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13. Read More

Osteoporos Int 2019 Sep 26;30(9):1713-1722. Epub 2019 Mar 26.

Health Sciences Centre Winnipeg, Winnipeg, Canada.

Hypophosphatasia (HPP) is a rare inherited disorder of bone and mineral metabolism caused by loss of function mutations in the ALPL gene. The presentation in children and adults can be extremely variable and natural history is poorly understood particularly in adults. Careful patient evaluation is required with consideration of pharmacologic intervention in individuals meeting criteria for therapy. Read More

Hum Mutat 2019 07 13;40(7):842-864. Epub 2019 Apr 13.

Section Cell Biology of Rare Diseases, Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Mutations in the GNPTAB and GNPTG genes cause mucolipidosis (ML) type II, type III alpha/beta, and type III gamma, which are autosomal recessively inherited lysosomal storage disorders. GNPTAB and GNPTG encode the α/β-precursor and the γ-subunit of N-acetylglucosamine (GlcNAc)-1-phosphotransferase, respectively, the key enzyme for the generation of mannose 6-phosphate targeting signals on lysosomal enzymes. Defective GlcNAc-1-phosphotransferase results in missorting of lysosomal enzymes and accumulation of non-degradable macromolecules in lysosomes, strongly impairing cellular function. Read More

Blood Cells Mol Dis 2019 05 4;76:53-58. Epub 2019 Feb 4.

Pediatric Hematology & BMT Unit, Pediatrics Department, Cairo University, Cairo, Egypt. Electronic address:

Thalassemia is a common inherited monogenic disease. It is characterized by chronic hemolysis, ineffective erythropoiesis (IE) and iron overload. Despite advances in transfusion practices and chelation therapy, still many limitations in delivering these standard therapies exist. Read More

Methods Mol Biol 2019 ;1950:333-360

Department of Pediatrics, Indiana University, Indianapolis, IN, USA.

Adeno-associated virus (AAV) vectors to treat liver-specific genetic diseases are the focus of several ongoing clinical trials. The ability to give a peripheral injection of virus that will successfully target the liver is one of many attractive features of this technology. Although initial studies of AAV liver gene transfer revealed some limitations, extensive animal modeling and further clinical development have helped solve some of these issues, resulting in several successful clinical trials that have reached curative levels of clotting factor expression in hemophilia. Read More

Nat Rev Neurol 2019 03;15(3):161-178

Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA.

Batten disease (also known as neuronal ceroid lipofuscinoses) constitutes a family of devastating lysosomal storage disorders that collectively represent the most common inherited paediatric neurodegenerative disorders worldwide. Batten disease can result from mutations in 1 of 13 genes. These mutations lead to a group of diseases with loosely overlapping symptoms and pathology. Read More

J Inherit Metab Dis 2019 01;42(1):147-158

Metabolic Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, The Netherlands.

Background: Transaldolase deficiency (TALDO-D) is a rare autosomal recessive inborn error of the pentose phosphate pathway. Since its first description in 2001, several case reports have been published, but there has been no comprehensive overview of phenotype, genotype, and phenotype-genotype correlation.

Methods: We performed a retrospective questionnaire and literature study of clinical, biochemical, and molecular data of 34 patients from 25 families with proven TALDO-D. Read More

Ann Transl Med 2018 Dec;6(24):476

Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.

The lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders that are caused for the most part by enzyme deficiencies within the lysosome resulting in accumulation of undegraded substrate. This storage process leads to a broad spectrum of clinical manifestations depending on the specific substrate and site of accumulation. Examples of LSDs include the mucopolysaccharidoses, mucolipidoses, oligosaccharidoses, Pompe disease, Gaucher disease, Fabry disease, the Niemann-Pick disorders, and neuronal ceroid lipofuscinoses. Read More

J Neurol Neurosurg Psychiatry 2019 05 22;90(5):543-554. Epub 2018 Nov 22.

Department of Neuroinflammation, UCL Institute of Neurology, London, UK.

Adult-onset leukodystrophies and genetic leukoencephalopathies comprise a diverse group of neurodegenerative disorders of white matter with a wide age of onset and phenotypic spectrum. Patients with white matter abnormalities detected on MRI often present a diagnostic challenge to both general and specialist neurologists. Patients typically present with a progressive syndrome including various combinations of cognitive impairment, movement disorders, ataxia and upper motor neuron signs. Read More

Klin Monbl Augenheilkd 2018 Nov 20;235(11):1235-1241. Epub 2018 Nov 20.

Molekulargenetisches Labor, Department für Augenheilkunde, Universität Tübingen.

Hereditary optic atrophies are a heterogeneous group of rare degenerative disease affecting the retinal ganglion cells and their axons which form the optic nerve. With an estimated prevalence of 1 : 10 000 to 1 : 20 000, hereditary optic atrophies in their entirety affect about 4000 to 8000 people in Germany. The most common forms are Leber's hereditary optic atrophy (LHON) and autosomal dominant optic atrophy (ADOA). Read More

Genet Med 2019 04 12;21(4):837-849. Epub 2018 Sep 12.

INSERM, U 1127, CNRS UMR 7225, Sorbonne Universites, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle epiniere, ICM, Paris, France.

Purpose: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences.

Methods: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. Read More

Vnitr Lek Summer 2018;64(5):488-500

This review summarizes the pathophysiology, genetic background and clinical symptoms of anemias belonging to the group of inherited bone marrow failure syndromes with unilineage failure of erythropoiesis. It sums up the current knowledge of three diseases: Diamond-Blackfan anemia, congenital dyserythropoietic anemia and Fanconi anemia whose pathophysiology was elucidated in detail during the last decade, owing to the rapid development of new molecular-genetic techniques, especially next-generation sequencing. Fanconi anemia is included in this overview because of macrocytosis and/or anemia detected in the majority of the patients before they develop bone marrow failure. Read More

Vnitr Lek Spring 2018;64(4):367-374

Maturity Onset Diabetes of the Young (MODY) comprises inherited forms of diabetes mellitus caused by the mutations in the genes involved in the development, differentiation and function of beta-cells. The majority of patients with MODY remains misdiagnosed and erroneously classified as type 1 or type 2 diabetic patients. Correct MODY diagnosis is, however, essential since it enables individualization of treatment, assessment of the prognosis and identification of diabetes among patient´s relatives. Read More

Pediatr Radiol 2018 09 11;48(10):1503-1520. Epub 2018 May 11.

Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

The mucopolysaccharidoses are a heterogeneous group of inherited lysosomal storage disorders, characterized by the accumulation of undegraded glycosaminoglycans in various organs, leading to tissue damage. Mucopolysaccharidoses include eight individual disorders (IS [Scheie syndrome], IH [Hurler syndrome], II, III, IV, VI, VII and IX). They have autosomal-recessive transmission with the exception of mucopolysaccharidosis II, which is X-linked. Read More

Cogn Neuropsychol 2018 May - Jun;35(3-4):113-119

a School of Life and Health Sciences, Aston University , Birmingham , UK.

This is an introduction to the special issue on cognitive impairments in inherited metabolic diseases (IMD). It provides an overview of the studies included, focusing on the possibility of selective impairments which could provide unique evidence on the specificity of neural circuitries mediating cognitive functions. It will suggest that these circuitries have different metabolic properties which make them especially apt to carry out certain functions, but also particularly susceptible to certain forms of metabolic disruption. Read More

J Pediatr Health Care 2018 May - Jun;32(3):285-294

Lysosomal storage disorders (LSDs) are a heterogeneous group of approximately 50 rare inherited metabolic conditions that result from enzyme deficiencies that interfere with lysosome function. Although often grouped together, there is great variability regarding age of onset, severity, treatment, and outcomes for each disorder and subtype. Currently, laboratory methods are available to test newborns for seven of these conditions. Read More

Pan Afr Med J 2017 30;28:185. Epub 2017 Oct 30.

Unité de Neuropédiatrie, Service de Pédiatrie II, Hôpital d'Enfants de Rabat, Maroc.

Introduction: X-linked adrenoleukodystrophy (X-ALD) is a severe neurodegenerative disease, due to mutations in the ABCD1 gene. It manifests as a damage to the central and peripheral nervous system, adrenal insufficiency and testicular damage in children. Diagnosis is based on the determination of long-chain saturated fatty acids. Read More

J Alzheimers Dis 2018 ;62(3):913-932

Department of Pathophysiology and Transplantation, University of Milan, Centro Dino Ferrari, Fondazione Cá Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) represent the first cause of dementia in senile and pre-senile population, respectively. A percentage of cases have a genetic cause, inherited with an autosomal dominant pattern of transmission. The majority of cases, however, derive from complex interactions between a number of genetic and environmental factors. Read More

Kidney Blood Press Res 2018 16;43(2):406-421. Epub 2018 Mar 16.

Nephrology and Renal Transplant Department, Hospital Clinic, University of Barcelona, RedInRen, Barcelona, Spain.

Fabry disease (FD) is a rare, X-linked disorder caused by mutations in the GLA gene encoding the enzyme α-galactosidase A. Complete or partial deficiency in this enzyme leads to intracellular accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in many cell types throughout the body, including the kidney. Progressive accumulation of Gb3 in podocytes, endothelial cells, epithelial cells, and tubular cells contribute to the renal symptoms of FD, which manifest as proteinuria and reduced glomerular filtration rate leading to renal insufficiency. Read More

Glycobiology 2018 06;28(6):382-391

Research Unit For Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, 12808, Czech Republic.

Blood group B glycosphingolipids (B-GSLs) are substrates of the lysosomal alpha-galactosidase A (AGAL). Similar to its major substrate-globotriaosylceramide (Gb3Cer)-B-GSLs are not degraded and accumulate in the cells of patients affected by an inherited defect of AGAL activity (Fabry disease-FD).The pancreas is a secretory organ known to have high biosynthesis of blood group GSLs. Read More

Pediatr Clin North Am 2018 04;65(2):179-208

Neurology Department, Neurometabolic Unit, Hospital Sant Joan de Deu and CIBERER-ISCIII, Passeig Sant Joan de Deu 28950 Esplugues de Llobregat, Barcelona, Spain.

The specialty of inherited metabolic disease is at the forefront of progress in medicine, with new methods in metabolomics and genomics identifying the molecular basis for a growing number of conditions and syndromes. This review presents an updated pathophysiologic classification of inborn errors of metabolism and a method of clinical screening in neonates, late-onset emergencies, neurologic deterioration, and other common clinical scenarios. When and how to investigate a metabolic disorder is presented to encourage physicians to use sophisticated biochemical investigations and not miss a treatable disorder. Read More

J Genet Genomics 2018 02 14;45(2):61-70. Epub 2018 Feb 14.

Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address:

Inborn errors of metabolism (IEMs) are a large group of inherited disorders characterized by disruption of metabolic pathways due to deficient enzymes, cofactors, or transporters. The rapid advances in the understanding of the molecular pathophysiology of many IEMs, have led to significant progress in the development of many new treatments. The institution and continued expansion of newborn screening provide the opportunity for early treatment, leading to reduced morbidity and mortality. Read More

Pharmacol Res 2018 05 15;131:199-210. Epub 2018 Feb 15.

Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy. Electronic address:

OPA1 is a GTPase that controls several functions, such as mitochondrial dynamics and energetics, mtDNA maintenance and cristae integrity. In the last years, there have been described other cellular pathways and mechanisms involving OPA1 directly or through its interaction. All this new information, by implementing our knowledge on OPA1 is instrumental to elucidating the pathogenic mechanisms of OPA1 mutations. Read More

Genes (Basel) 2018 Feb 6;9(2). Epub 2018 Feb 6.

International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy, I.C.G.E.B., Padriciano 99, 34149 Trieste, Italy.

Lysosomal storage disorders (LSDs) represent a group of more than 50 severe metabolic diseases caused by the deficiency of specific lysosomal hydrolases, activators, carriers, or lysosomal integral membrane proteins, leading to the abnormal accumulation of substrates within the lysosomes. Numerous mutations have been described in each disease-causing gene; among them, about 5-19% affect the pre-mRNA splicing process. In the last decade, several strategies to rescue/increase normal splicing of mutated transcripts have been developed and LSDs represent excellent candidates for this type of approach: (i) most of them are inherited in an autosomic recessive manner and patients affected by late-onset (LO) phenotypes often retain a fair amount of residual enzymatic activity; thus, even a small recovery of normal splicing may be beneficial in clinical settings; (ii) most LSDs still lack effective treatments or are currently treated with extremely expensive approaches; (iii) in few LSDs, a single splicing mutation accounts for up to 40-70% of pathogenic alleles. Read More

Postgrad Med J 2018 May 31;94(1111):296-304. Epub 2018 Jan 31.

Molecular Physiology Laboratory, Centre for Atherothrombotic and Metabolic Disease, Hull York Medical School, University of Hull, Hull, UK.

Duchenne muscular dystrophy (DMD) is a progressive wasting disease of skeletal and cardiac muscles, representing one of the most common recessive fatal inherited genetic diseases with 1:3500-1:5000 in yearly incidence. It is caused by mutations in the DMD gene that encodes the membrane-associated dystrophin protein. Over the years, many have been the approaches to management of DMD, but despite all efforts, no effective treatment has yet been discovered. Read More

Nat Rev Neurol 2018 02 5;14(2):94-105. Epub 2018 Jan 5.

Division of Neurology, Children's Hospital of Philadelphia, Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.

The leukodystrophies are a group of inherited white matter disorders with a heterogeneous genetic background, considerable phenotypic variability and disease onset at all ages. This Review focuses on leukodystrophies with major prevalence or primary onset in adulthood. We summarize 20 leukodystrophies with adult presentations, providing information on the underlying genetic mutations and on biochemical assays that aid diagnosis, where available. Read More

Ther Umsch 2018 ;75(10):601-606

1 Institut für Medizinische Genetik und Pathologie, Universitätsspital Basel, Basel.

Hereditary Colorectal Cancer: Clinics, Diagnostics and Management About five percent of all colorectal cancers are caused by highly penetrant, autosomal dominantly or recessively inherited tumour predispositions. Current molecular genetic diagnostics, making use of high-throughput sequencing technologies, allow a cost-efficient, prompt and comprehensive investigation. In contrast to sporadic colorectal cancer hereditary forms are often associated with an elevated lifetime risk for additional, extracolonic tumours which necessitate specific long-term interdisciplinary prevention measures and surveillance. Read More

Sci Rep 2017 12 15;7(1):17641. Epub 2017 Dec 15.

Department of Human Genetics, CHU Sart-Tilman, University of Liège, Liège, Belgium.

The range of applications performed on dried blood spots (DBS) widely broadened during the past decades to now include next-generation sequencing (NGS). Previous publications provided a general overview of NGS capacities on DBS-extracted DNA but did not focus on the identification of specific disorders. We thus aimed to demonstrate that NGS was reliable for detecting pathogenic mutations on genomic material extracted from DBS. Read More

Indian J Ophthalmol 2017 Nov;65(11):1087-1092

Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tami Nadu, India.

Leber's hereditary optic neuropathy (LHON) is a common inherited mitochondrial disorder that is characterized by the degeneration of the optic nerves, leading to vision loss. The major mutations in the mitochondrial genes ND1, ND4, and ND6 of LHON subjects are found to increase the oxidative stress experienced by the optic nerve cell, thereby leading to nerve cell damage. Accurate treatments are not available and drugs that are commercially available like Idebenone, EPI-743, and Bendavia with their antioxidant role help in reducing the oxidative stress experienced by the cell thereby preventing the progression of the disease. Read More

Mol Genet Metab 2017 12 7;122(4):145-152. Epub 2017 Oct 7.

Children's National Health System, Division of Genetics and Metabolism, United States; Rare Diseases Institute, Division of Genetics and Metabolism, United States. Electronic address:

Propionyl-CoA carboxylase (PCC) is the enzyme which catalyzes the carboxylation of propionyl-CoA to methylmalonyl-CoA and is encoded by the genes PCCA and PCCB to form a hetero-dodecamer. Dysfunction of PCC leads to the inherited metabolic disorder propionic acidemia, which can result in an affected individual presenting with metabolic acidosis, hyperammonemia, lethargy, vomiting and sometimes coma and death if not treated. Individuals with propionic acidemia also have a number of long term complications resulting from the dysfunction of the PCC enzyme. Read More