Ebook: Metabolic Diseases
The 2nd Edition of Metabolic Diseases provides readers with a completely updated description of the Foundations of Clinical Management, Genetics, and Pathology. A distinguished group of 31 expert authors has contributed 25 chapters as a tribute to Enid Gilbert-Barness and the late Lewis Barness--- both pioneers in this topic. Enid’s unique perspectives on the pathology of genetic disorders and Lew’s unsurpassed knowledge of metabolism integrated with nutrition have inspired the contributors to write interdisciplinary descriptions of generally rare, and always challenging, hereditary metabolic disorders. Discussions of these interesting genetic disorders are organized in the perspective of molecular abnormalities leading to morphologic disturbances with distinct pathology and clinical manifestations.
The book emphasizes recent advances such as development of improved diagnostic methods and discovery of new, more effective therapies for many of the diseases. It includes optimal strategies for diagnosis and information on access to specialized laboratories for specific testing. The target audience is a wide variety of clinicians, including pediatricians, neonatologists, obstetricians, maternal-fetal specialists, internists, pathologists, geneticists, and laboratorians engaged in prenatal and/or neonatal screening. In addition, all scientists and health science professionals interested in metabolic diseases will find the comprehensive, integrated chapters informative on the latest discoveries. It is our hope that the 2nd Edition will open new avenues and vistas for our readers and that they will share with us the interest, excitement and passion of the research into all these challenging disorders.
Twelve years have elapsed since the first edition of Metabolic Diseases: Foundations of Clinical Management, Genetics and Pathology was published. In the 21st century, traditional morphologic descriptions of pathologic processes have at least in part, been replaced by in-depth understanding of molecular genetics and by the use of newer techniques for Metabolic Diseases that affect the development and function of the embryo, fetus and infant. This second edition of Metabolic Diseases has been expanded to include the advances in molecular and genetic sciences. We have invited the knowledge and expertise of 31 authors: Karl Anderson, Heather Bartlett, Michael Bennett, Nancy Braverman, Randy Chandler, Margaret Chen, Maria Daniela D'Agostino, Philip Farrell, Carlos Ferreira, Can Ficicioglu, Theodore Friedman, Larissa Furtado, William Gahl, Eric Gou, Cary Harding, Richard Kelley, Uta Lichter-Konicki, Jennifer Mayer, William Nyhan, John Opitz, Dinesh Rakheja, J. Carter Ralphe, Allen Root, Pierre Russo, Bruce Schnapf, Lee Shulman, Jürgen Spranger, Mariana Usatli, Charles Venditti, Charles Weinstein, and Kondi Wong with the aim to present a comprehensive and detailed account which brings together and covers a wide spectrum of metabolic diseases. It is our hope that these volumes will open new avenues and vistas for our readers and that they will share with us the interest, excitement and passion of all these challenging disorders.
The approach to the diagnosis and access to specialized laboratories for specific testing has been included. Numerous tables, diagrams, and line drawings have been enhanced. Three appendices have been rewritten and updated, but the information from the others such as the one providing treatment recommendations has been incorporated into the relevant chapters. A current genome map has not been included because the available versions are being constantly improved, with updated gene sequences and locations of intronic elements, revised lists of benign SNPs, additional reference genomes, databases of variant frequencies that are ethnicity-specific, and associations of specific genes with specific human diseases such as the cancer cell genome map initiative. More information on genome maps and references is provided in chapter 1, but readers should follow specific literature closely as this field has become more specialized.
Finally, words fall short in expressing to all the contributors our gratitude on this book and their willingness to revise and update their chapters. Over the past 40 years, Dr. Gilbert-Barness has had the extraordinary good fortune of collaborating with Dr. John Opitz, Distinguished Master of Medical Genetics, a scholar, a gentleman, and a treasured friend. This rewarding experience has been beyond all measure the highlight and most important influence in her professional career. The editors are all grateful Yale Altman for his helpful suggestions and jokes, Maureen Twaig for her support and managing this publication, and especially Kathleen Lonkey; without her efforts, enthusiasm, and expertise, this book would not have been possible. The coordinating editor, Dr. Philip Farrell, in his efforts to ensure a completely updated book has greatly appreciated the encouragement and efforts of the contributing authors and is especially grateful to Dr. William Gahl for advice on the appendices and other components of this edition. Dr. Farrell also expresses his deep gratitude to his wife of 50 years, Alice, and their family for patience and support during the intensive 2 year period needed to complete this project on behalf of our good friends, Enid and Lew.
Enid Gilbert-Barness, Lewis A. Barness, and Philip M. Farrell
Inborn errors of metabolism are generally categorized as rare diseases. Their presentations are often so subtle and insidious as to cause daunting diagnostic challenges for even the most astute clinicians. Thus, irreversible morbidity and preventable mortality have been unavoidable until recent decades because of delayed diagnoses. This unfortunate circumstance has led to newborn screening programs worldwide for 40 or more hereditary metabolic disorders beginning with the dramatic improvements for patients with phenylketonuria in the 1960's. Increasingly sophisticated testing procedures such as tandem mass spectrometry and other multiplex technologies applied to dried blood spot specimens are now having greater impact without raising costs significantly. The advent of next generation sequencing methods is likely to stimulate further progress and lead to whole genome or exome sequencing as prenatal and neonatal screening expands further. With early diagnosis through screening and expedited therapies better outcomes are routinely possible, and even preventive therapies amounting to “cures” can be anticipated through research.
This chapter provides a review of selected metabolic disorders resulting from genetic mutations and the diagnostic methods used to identify them prenatally or in the early neonatal period. Prenatal and neonatal diagnostic technologies have evolved gradually over four decades, but they are expanding and changing dramatically in the 21st century, as is their application in population-based screening and/or targeted assessment of at-risk couples. For instance, preimplantation genetic diagnosis has been a major advance. Emphasis herein has been placed on prototype Sachs that have stimulated seminal efforts to improve medical practices in these fields. Future developments in prenatal screening and diagnosis, along newborn screening expansion, seem likely to continue rapid translation to the bedside because of extraordinary biotechnological advances.
This chapter discusses disorders of 8 different amino acids (phenylalanine, tetrahydrobiopterin, tyrosine, methionine, glycine, tryptophan, lysine, and serine). Creatine deficiency syndromes, Sulfite oxidase and Molybdenum cofactor deficiency, defects of GABA metabolism and γ-Glutamyl Cycle have been included in this chapter as well. Although it is not an amino acid disorder, oculocerebrorenal syndrome (OCRL) (Lowe syndrome) remains in this chapter because it was included here in the first edition of the book. I summarize the biochemical abnormalities and pathology for each condition, and then discuss the clinical findings, diagnosis and treatment. For some of these disorders detected through newborn screening, early the morbidity and mortality in patients. For others, there are not yet any effective treatment options.
The three essential branched-chain amino acids (BCAAs), leucine, isoleucine and valine, share the first enzymatic steps in their metabolic pathways, including a reversible transamination followed by an irreversible oxidative decarboxylation to coenzyme-A derivatives. The respective oxidative pathways subsequently diverge and at the final steps yield acetyl- and/or propionyl-CoA that enter the Krebs cycle. Many disorders in these pathways are diagnosed through expanded newborn screening by tandem mass spectrometry. Maple syrup urine disease (MSUD) is the only disorder of the group that is associated with elevated body fluid levels of the BCAAs. Due to the irreversible oxidative decarboxylation step distal enzymatic blocks in the pathways don't result in the accumulation of amino acids, but rather to CoA-activated small carboxylic acids identified by gas chromatography mass spectrometry analysis of urine and are therefore classified as organic acidurias. Disorders in these pathways can present with a neonatal onset severe-, or chronic intermittent- or progressive forms. Metabolic instability and increased morbidity and mortality are shared between inborn errors in the BCAA pathways, while treatment options remain limited, comprised mainly of dietary management and in some cases solid organ transplantation.
The elimination of waste nitrogen as urea is a final and central step of amino acid catabolism. It is accomplished by one of the most essential pathways of terrestrial animals, the urea cycle. This chapter describes the basic function of the 5 catalytic enzymes, the two transporters, and the cofactor synthesizing enzyme that comprise the urea cycle as well as the consequences of their deficiencies and ways to treat them. The chapter then elaborates on related disorders of metabolism that may either cause hyperammonemia or elevation of an amino acid that is key to urea cycle function.
Inherited fatty acid oxidation disorders (FAOD) are among the most common inborn errors of metabolism. The spectrum of clinical phenotypes associated with FAOD is wide, correlates to the severity of the specific enzyme deficiency, and includes cardiomyopathy, fasting or illness-induced hypoketotic hypoglycemia, or recurrent rhabdomyolysis, generally triggered by exercise or febrile illness. Diagnosis is accomplished through specialized biochemical analysis followed by either measurement of specific enzyme activity or more commonly molecular analysis of disease-associated genes. Newborn screening detects the majority of but not all infants with FAOD and frequently allows treatment initiation prior to symptom onset. Avoidance of extreme fasting prevents hypoglycemia and is life saving for at risk infants. Restriction of dietary fat intake and replacement with medium chain triglyceride (MCT) oil to provide a usable energy substrate may also be included in the treatment of individuals with defects in long chain fatty acid oxidation. Long term outcomes for many FAOD are generally satisfactory once a diagnosis has occurred and steps to avoid episodes of metabolic decompensation have been taken. However, chronic complications of peripheral neuropathy or pigmentary retinopathy associated with vision loss may occur in specific disorders of long chain FAOD despite dietary therapy.
Genetic disorders of mitochondria cause disease when they reduce subcellular energy production through a variety of impairments in the electron transport chain, thus decreasing oxidative phosphorylation. Such abnormalities typically lead to neuropathies and/or myopathies including cardiomyopathies. Hepatic and renal pathology may also occur. The age of onset and severity are variable, but signs and symptoms are often present during infancy. The metabolic hallmarks include lactic acidosis, an increased ratio of blood lactate to pyruvate, and ketonemia. Muscle biopsies show characteristic ragged red fibers, which are obvious with trichrome staining. Some disorders which are inherited through the mother, source of all mitochondrial DNA, lead to early blindness due to progressive optic neuropathy, i.e., Leber's Hereditary Optic Neuropathy. Exciting recent research with gene replacement therapy and stem cell technology has provided new insights and hope for patients with genetic blindness. Other disorders affecting mitochondrial DNA mutations may also eventually be treated with molecular (gene replacement) or advanced cellular (stem cell) therapeutic strategies. In addition, early diagnosis through newborn screening is now routinely achieved for some disorders such as biotinidase deficiency, allowing curative therapy through nutritional supplements.
The glycogen storage diseases (GSDs) are a group of inherited metabolic disorders that result from a defect in any one of several enzymes required for either glycogen synthesis or glycogen degradation. The GSDs can be divided into those with hepatic involvement, which present as hypoglycemia, and those which are associated with neuromuscular disease and weakness. The severity of the GSDs range from those that are fatal in infancy if untreated to mild disorders with a normal lifespan. The diagnosis, treatment, and prognosis for the common types of GSDs are reviewed.
This chapter provides a review of the fascinating genetic disorders known as mucopolysaccharidoses that are caused by the intralysosomal accumulation of glycosaminoglycans in various tissues. Due to absent activity of a variety of lysosomal enzymes, a characteristic clinical phenotype usually develops in early childhood and then evolves with coarse facial features, thick skin, corneal clouding as the direct expression of excessive storage, mental retardation, growth deficiency and skeletal dysplasia as manifestations of defective cellular function. Bone abnormalities referred to as dysostosis multiplex are also characteristic and often dramatic. The classical disorders are Hurler and Hunter disease which are attributable to deficiencies of α-L-Iduronidase and Iduronate-2-sulfatase, respectively. The genes causing mucopolysaccharidoses have been cloned and numerous mutations identified. Thus, the diagnoses of mucopolysaccharidoses can be readily accomplished by recognition of the clinical phenotype combined with biochemical and molecular studies. Treatments are challenging, although enzyme replacement strategies and stem cell transplantation show some promise.
Oligosaccharidoses are rare genetic disorders caused by mutations of genes that code for lysosomal enzymes that catalyse the degradation of oligosaccharides. In addition, this chapter describes a variety of hereditary metabolic disorders such as defects in glycoprotein degradation that present with signs and symptoms similar to the oligosaccharidoses. Oligosaccharides are short-chain polymers of simple sugars that are attached to polypeptides to form glycoproteins, which are important connective tissue constituents binding cells. Thus, they are integral parts of cell membranes and functional glycoproteins including antibodies. Oligosaccharidoses were identified after mucopolysaccharidoses had been delineated, and they share similar physical and pathologic features. The best described disorders are GM1Gangliosidosis, α-and β-Mannosidosis, Fucosidosis, and Sialidosis. The physical appearance of these patients may closely resemble those of mucopolysaccharidoses, especially their coarse facial features. Radiographs may show mild dysostosis multiplex. Abnormal vacuoles are seen in peripheral lymphocytes. Diagnoses are confirmed with biochemical and molecular studies described in this chapter. Determination of partially degraded urinary oligosaccharides by mass spectrometry is a major diagnostic tool in patients with a suspected oligosaccharidosis The prognosis for most patients with oligosaccharidoses is currently dismal because very little is available for treatment other than supportive care.
As a major component of the cell membrane of most eukaryotic cells, cholesterol assumes crucial roles in myelination of the central and peripheral nervous systems, in the synthesis of bile acids, steroids, and vitamin D, in sterol signaling, and in embryonic development. Inborn errors of cholesterol biosynthesis comprise a heterogeneous group of disorders characterized by developmental delays, increased tissue levels of specific sterol intermediates, and complex malformations involving many organ systems. Here we present the basics of cholesterol biosynthesis and review the clinical phenotype, biochemistry, molecular pathogenesis, and management of the 8 known errors of sterol metabolism in humans: Antley-Bixtler syndrome, Greenberg dysplasia, X-linked dominant congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome), X-linked dominant chondrodysplasia punctata (Conradi-Hünermann syndrome; CDPX2), lathosterolosis, Smith-Lemli-Opitz syndrome, desmosterolosis, and methyl sterol oxidase (SC4MOL) deficiency.
Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency of an activator protein, as occurs in the AB variant of GM2 gangliosidosis. Still other times, the accumulated lysosomal material results from failed egress of a small molecule as a consequence of a deficient transporter, as in cystinosis or Salla disease. In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases. Examples include imiglucerase, taliglucerase and velaglucerase for Gaucher disease, laronidase for Hurler disease, idursulfase for Hunter disease, elosulfase for Morquio disease, galsulfase for Maroteaux-Lamy disease, alglucosidase alfa for Pompe disease, and agalsidase alfa and beta for Fabry disease. In addition, substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease. The advent of treatment options for some of these disorders has led to newborn screening pilot studies, and ultimately to the addition of Pompe disease and Hurler disease to the Recommended Uniform Screening Panel (RUSP) in 2015 and 2016, respectively.
The disorders of purine metabolism encompass a spectrum of clinical abnormalities. Striking features are the hyperuricemia, neurologic abnormalities and unusual behavior of Lesch-Nyhan disease. Renal stone disease and deafness characterize PRPP deficiency and xanthine oxidase deficiency, as well as in orotic aciduria. In purine nucleotide phosphorylase deficiency and adenosine deaminase deficiency, there is defective immune function. Patients with deficiency of adenylosuccinase have seizures and delayed development. Myoadenylate deaminase deficiency causes myopathy. Hypouricemia is found in xanthine oxidase deficiency, molybdenum cofactor deficiency and purine nucleoside phosphorylase deficiency. Deficiency of deoxyguanine kinase deficiency leads to mitochondrial DNA depletion and hepatic failure. Deficiency of pyrimidine 5'-nucleotidase leads to hemolytic anemia. Toxic responses to customary doses of 5-Fluorouracil are found in disorders of pyrimidine metabolism, particularly dihydroprimidine dehydrogenase deficiency.
It is estimated that over a third of human proteins are bound to a metal (i.e., metalloproteins). Certain metals act as cofactors, while others are integral components of the cofactors (e.g., cobalt in cobalamin). The deficiency of a metal can then lead to decreased enzymatic activities of the respective metalloenzymes, as happens in copper deficiency due to Menkes disease, or zinc deficiency in acrodermatitis enteropathica. On the other hand, metal accumulation can result in other disorders. Metal toxicity is believed to occur through the formation of excess radical oxygen species via the Fenton reaction; examples include iron accumulation in hemochromatosis and copper accumulation in Wilson disease. The metal overload in this group of disorders can occur via either deficiency of a metal transporter-as in hypermanganesemia with dystonia, polycythemia and cirrhosis due to SLC30A10 mutations- or impaired enzyme activity because the metal fails to be incorporated into the apoenzyme. For example, in aceruloplasminemia, mutations in apo-cerulosplasmin impair the ferroxidase activity of ceruloplasmin and, as a consequence, lead to accumulation of ferrous iron. In this chapter, we review the different genetic conditions associated with altered metal metabolism.
The neuronal ceroid-lipofuscinoses (NCLs) are a group of recessively inherited diseases characterized by progressive neuronal loss, accumulation of intracellular lipofuscin-like autofluorescent storage material with distinctive ultrastructural appearance, and clinical signs and symptoms of progressive neurodegeneration. Initially classified by the age of onset of clinical signs and symptoms as well as the ultrastructural morphology of the storage material, the growing family of NCLs can now also be biologically classified by their underlying genetic defects. For a few NCLs, we now understand the functions of the proteins encoded by the NCL genes, which has enabled refining of the diagnostic algorithms and ignited hopes for finding effective treatments in the future. Ongoing research into understanding the functions of the remainder of the NCL proteins as well as continuing advancements in technology (such as massively-parallel gene sequencing) has and will continue to inform the clinical approach, diagnostic algorithms, and treatment strategies.
Cystic fibrosis (CF) is an inherited autosomal recessive disorder that is associated with chronic multi-organ disease. Recurrent sinopulmonary infections, nutritional abnormalities, and malabsorption serve as a hallmark of most of the morbidity and mortality. Major advances into the understanding of the pathophysiology has led directly to improvement in survival and quality of life. Today, CF is most commonly diagnosed through newborn screening. Newer therapies that serve as CF transmembrane conductance regulator (CFTR) modulators are able to target the basic defect of CF. CFTR mutations are categorized into 5 classes based on the effect of the gene mutation on the CFTR protein function. Best practice is promoted by consensus clinical guidelines from the CF Foundation (CFF). In addition, this centralized Foundation allows for directed and standardized care of the patient that is delivered by multidisciplinary teams of health care providers in an established network of pediatric and adult CF centers accredited and funded by the CFF. Those with CF will continue to benefit from the creation and advancement of novel therapeutic strategies, the continued efforts of clinical research networks, and the support of quality improvement initiatives for treating populations of patients with CF.
The porphyrias are metabolic diseases caused by altered activities of enzymes in the heme biosynthetic pathway. Signs and symptoms of porphyria result from overproduction and accumulation of pathway intermediates. Recognizing the different types of porphyrias can be challenging due to similarities in presentation but etiology, pathogenesis, methods for diagnosis and treatment for each are distinct. In this overview of the porphyrias, we describe the eight enzymes in the heme biosynthetic pathway associated with each type of porphyria. We classify these diseases by their erythropoietic or hepatic origin and their cutaneous or neurovisceral manifestations. The etiology and pathophysiology specific to the type of porphyria is linked to the specific enzyme in the heme biosynthetic pathway. Emphasis is placed on specific clinical features, relevant diagnostic evaluation and appropriate therapy for each porphyria pertinent to treating physicians and clinicians.
Inherited disorders of intrahepatic cholestasis include entities such as Alagille syndrome, due to mutations in the JAG1 or NOTCH2 genes, progressive familial cholestatic disorders related to mutations in the genes that code for hepatocyte canalicular transporters, bile acid synthetic disorders, and rarer entities such as North American Indian childhood cirrhosis, familial hypercholanemia and Gracile syndrome. Principal distinguishing characteristics of the major inherited disorders of intrahepatic cholestasis are shown in Table 1. Disorders of bilirubin metabolism include Crigler-Najjar, Gilbert, Dubin-Johnson and Rotor syndromes.
The myriad of identified genes involved in the regulation of the differentiation and functional integrity of the anterior pituitary lobe, neurohypophysis, thyroid and adrenal glands, ovaries, testes, and pancreatic beta cells are listed and the variations in the composition of those genes that alter gland or cell formation, growth, maturation and activity are discussed. Genetic control of the synthesis, secretion, and action of the six major hormonal products of the adenohypophysis (growth hormone, thyrotropin, prolactin, adrenocorticotropin, luteinizing hormone, follicle stimulating hormone) are detailed. Gene variants that result in either decreased or increased secretion of the anterior pituitary lobe hormones and/or tumorigenesis are described. The role of insulin-like growth factor-I in the signaling pathway of growth hormone modulated effects and the consequences of genetic errors in this circuit are discussed. Detailed discussions of the gene mutations resulting in impaired development of the anterior pituitary lobe, decreased or excessive synthesis of its products, and abnormalities of the peripheral activity of these hormones are presented. The clinical and biochemical abnormalities due to genetic variants that lead to impaired formation or function of the posterior pituitary lobe (e.g., diabetes insipidus), thyroid gland (e.g., congenital hypothyroidism), adrenal cortex (e.g., congenital adrenal hyperplasia, familial isolated glucocorticoid deficiency, adrenoleukodystrophy), adrenal medulla (e.g., pheochromocytoma), ovary, testis, and pancreatic beta cells (e.g., congenital hyperinsulinemic hypoglycemia, neonatal diabetes mellitus, maturity onset diabetes of the young) are also recorded. Discussed too are the gene mutations associated with the autoimmune polyendocrinopathies and multiple endocrine neoplastic syndromes. Clinical disorders (e.g., Noonan, Costello, cardio-facial-cutaneous syndromes) that result from genetically mediated malfunction of the intracellular mitogen activated protein kinase signal transduction pathway are explored. Monogenic forms of obesity are also presented.
Cardiomyopathies are a heterogeneous group of diseases with structural and functional myocardial abnormalities. Primary cardiomyopathies are those that predominantly affect the myocardium. Common examples are defects in contractile proteins such as myosin binding protein C and myosin heavy chain. Secondary cardiomyopathies are myocardial disorders that develop in addition to multiorgan involvement. These include glycogen storage diseases and mitochondrial disorders. Recent advances in molecular genetics, proteomics, physiology and cellular biology, as well as imaging and clinical care have led to improvements in knowledge about the etiology, mechanism and treatment. The most impressive discoveries concern the genetic basis for many cardiomyopathies, which has led to remarkable diagnostic advances, and novel targeted treatments including enzyme replacement therapy. Our knowledge of the role of mitochondria in disease has rapidly increased. Cardiovascular complications remain dominant clinical concern in most patients with metabolic cardiomyopathies but advances in care are leading to improved survival.
This chapter comprehensively describes not only the molecular origin of disorders of red blood cells, coagulation factors, fibrinolytic proteins, and platelets but also the clinical manifestations, diagnostic procedures, therapeutic approaches, and management of affected patients. Genetic mutations of the red cell membrane and enzymes resulting in severe hemolytic anemia are discussed, including hereditary spherocytosis, elliptocytosis, stomatocytosis, G6PD deficiency and pyruvate kinase deficiency. The genotypes and phenotypes of hemoglobinopathies are reviewed including sickle cell anemia, alpha thalassemia and beta thalassemia. The genetic forms of megaloblastic anemia (e.g., deficiency of intrinsic factor, transcobalamin) are presented. Molecular abnormalities of the coagulation cascade, anticoagulation pathway, and fibrinolysis are elucidated, particularly the hemophilias, von Willebrand disease, antithrombin III deficiency, factor V Leiden, protein C/S deficiency, and plasminogen deficiency. This chapter concludes with a discussion of inherited platelet problems such as Glanzmann thrombasthenia, gray platelet syndrome, and Bernard Soulier syndrome, and how clinicians diagnose and manage patients with these rare disorders.
The embryology, anatomy, and physiology of the multi-functional proximal renal tubule, thick descending tubule, thin, and thick ascending limbs of the loop of Henle, distal convoluted tubule, connecting tubule, and collecting duct are described. The clinical manifestations and biochemical abnormalities of the four forms of renal tubular acidosis (RTA: Type 1 – Distal tubule, Type 2 – Proximal tubule, Type 3 – Mixed, Type 4 – Hypoaldosteronism) are presented. Forms of pseudohypoaldosteronism are then reviewed. The pathophysiology and genetic variations underlying the Bartter, Gittleman, Liddle, and Fanconi syndromes are presented.
In “Genetic Disorders of Calcium, Phosphorus, and Bone Homeostasis” the mechanisms that regulate calcium and phosphorus metabolism and bone formation, resorption, strength, and resilience are discussed. The physiologic function and roles of vitamin D metabolites, parathyroid hormone, calcitonin, and other factors (e.g., phosphatonins, receptor activator of nuclear factor kappa B ligand, osteoprotegerin, et cetera) are presented. The functional effects of osteoblasts, osteocytes, and osteoclasts upon bone matrix and hydroxyapatite and their roles in bone development and maintenance of bone strength are described. The roles of alkaline phosphatase, collagen, non-collagenous proteins (e.g., osteocalcin, osteonectin, small integrin-binding ligand, N-linked glycoproteins such as matrix extracellular glycoprotein and dentin matrix protein that bind avidly to hydroxyapatite, the calcium phosphate crystal) in the maintenance of bone integrity and strength are examined. Genetic disorders resulting in hypocalcemia, hypercalcemia, or abnormalities of bone mineralization are then described. Variants of genes that regulate development of the parathyroid glands, synthesis or biologic effectiveness of parathyroid hormone, metabolism of vitamin D, and the calcium sensing receptor may result in hypocalcemia. Mutations in AIRE (Autoimmune regulator) lead to autosomal dominant hypoparathyoidism through dysregulation of the immune system resulting in autoimmune destruction of the parathyroid glands. Among other causes, deleterious variations in genes that regulate the expression of the calcium sensing receptor, differentiation of the parathyroid glands, production of the seven transmembrane, G-protein associated parathyroid hormone receptor, metabolism of vitamin D and continuous gene deletions (e.g., Williams-Beuren syndrome, chromosome 7q11.23) may result in hypercalcemia. Mutations in genes that regulate collagen synthesis and removal, intestinal and renal calcium, phosphorus, and hydrogen transport, and skeletal hydroxyapatite deposition and resorption may result in decreased or excessive bone mineralization – both often manifested clinically by increased bone fragility.
The peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to deficiencies of peroxisomal enzymes, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the coordinated action of multiple PEX proteins, or peroxins, encoded by PEX genes. There are two main groups of PBD: Zellweger spectrum disorder, due to defects in any one of 13 PEX genes, and Rhizomelic Chondrodysplasia Punctata spectrum, mainly due to defects in PEX7. For most patients, there is a correlation between clinical severity and effect of the mutation on PEX protein function. Diagnosis relies on biochemical measurements of peroxisome metabolites and enzymatic functions, PEX gene sequencing and, in some cases, analysis of peroxisome morphology and more detailed studies of peroxisome biology. Recent advancements in diagnosis have expanded the phenotypes observed, indicating that the full spectrum of these disorders remains to be identified. Although there are no targeted therapies, improved knowledge of peroxin functions, continued characterization of disease models, and systematic clinical studies are expected to impact treatment in the near future.