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1
McKusick, Victor A. Mendelian inheritance in man: Catalogs of autosomal dominant, autosomal recessive, and X-linked phenotypes. 9th ed. Baltimore: Johns Hopkins University Press, 1990.
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2
Mendelian inheritance in man: Catalogs of autosomal dominant, autosomal recessive, and x-linked phenotypes. 7th ed. Baltimore: Johns Hopkins University Press, 1986.
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3
A, Francomano Clair, and Antonarakis Stylianos E, eds. Mendelian inheritance in man: Catalogs of autosomal dominant, autosomal recessive, and X-linked phenotypes. Baltimore: Johns Hopkins University Press, 1992.
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4
Mendelian inheritance in man: Catalogs of autosomal dominant, autosomal recessive, and X-linked phenotypes. 8th ed. Baltimore: Johns Hopkins University Press, 1988.
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5
Shakkottai, Vikram G. Ataxias. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0014.
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Autosomal recessive cerebellar ataxias are a group of inherited neurological disorders with progressive balance and gait difficulties. In these disorders, cerebellar ataxia is often accompanied by eye movement abnormalities and peripheral nervous system involvement. A unifying mechanism for disease pathogenesis that is common to all the recessive ataxias likely does not exist. Nevertheless, some pathophysiological pathways are common to several autosomal recessive cerebellar ataxias. Specific gene defects in each disorder are summarized in the chapter. The most common recessively inherited ataxias are Friedreich ataxia and Ataxia telangiectasia. A recessive ataxia must be considered for any individual with progressive cerebellar ataxia with onset less than 30 years. The treatment is primarily supportive, but some recessive ataxias have specific treatment.
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Lachmann, Robin H., and Timothy M. Cox. Disorders of Fructose Metabolism. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0003.
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Hereditary fructose intolerance is an autosomal recessive disease which is manifest at weaning but formal diagnosis is often delayed until late childhood or adult life. Fructose, sucrose and sorbitol present in offending foods and drinks induce hypoglycaemia, hypophosphatemia, acidosis, hyperuricemia and hypermagnesemia. If unrecognized, the disease causes failure to thrive, a reno-tubular syndrome with nephrocalcinosis, jaundice, and ultimately liver injury. Parenteral administration of fructose or its congeners can be fatal. Molecular analysis of the aldolase B gene has revolutionized diagnosis. Treatment by a strict dietary exclusion (supplemented by water-soluble vitamins) is successful and, if instituted in a timely manner, is compatible with a normal life span. Early diagnosis and dietary modification are critical for well-being and normal development in affected children.
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Tuschl, Karin, Peter T. Clayton, and Philippa B. Mills. Disorders of Manganese Metabolism. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0045.
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Manganese is an essential trace metal for numerous metalloenzymes. Manganese homeostasis requires tight regulation in vivo and disruption of this balance can lead to manganese overload and subsequent accumulation of manganese in brain, liver, and blood. Mutations in SLC30A10, a cell surface-localized manganese efflux transporter, cause an autosomal recessive hypermanganesemia syndrome with two distinct phenotypes: childhood onset dystonia and adult onset Parkinsonism, associated with chronic liver disease, polycythemia and features of iron depletion. MRI brain appearances are characteristic of Mn deposition with hyperintense basal ganglia on T1-weighted images. Chelation therapy with disodium calcium edetate and iron supplementation effectively lower blood manganese levels, halt liver disease progression and improve neurological symptoms.The inherited form of hypermanganesemia can be distinguished from acquired causes of manganese overload including environmental overexposure and acquired hepatocerebral degeneration in cases of end stage liver disease.
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Foggensteiner, Lukas, and Philip Beales. Bardet–Biedl syndrome and other ciliopathies. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0314.
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Ciliopathies encompass a genotypically complex and phenotypically variable and overlapping series of disorders that makes the general term ‘ciliopathies’ very useful. The genes behind these conditions encode parts of the machinery of the primary cilium. This is also true of the major cystic kidney disorders autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease, but the ‘long tails’ of other ciliopathies are characterized by variable nephropathy (often without cyst formation), retinopathy, and effects on brain and skeletal development. Not all have substantial renal phenotypes. Bardet–Biedl syndrome (BBS) is an autosomal dominant condition characterized by obesity, retinopathy, nephropathy, and learning difficulty, but renal abnormalities are varied and end-stage renal failure occurs in only a minority. Many BBS genes have been described. Alström syndrome is a rare recessive disorder again associated with obesity and retinopathy, but also deafness and dilated cardiomyopathy. Renal failure is a common but later feature. Joubert syndrome is an autosomal dominant condition but can arise from mutations in at least 10 genes. It has a wide phenotypic variation with a common link being hypodysplasia of the cerebellar vermis and other abnormalities giving rise to the ‘molar tooth sign’ on cerebral magnetic resonance imaging scanning, associated with hypotonia in infancy, central ataxia, ocular apraxia, developmental delay, and varying degrees of cognitive impairment. Jeune syndrome is a recessive condition characterized by osteochondrodysplasia which can give rise to hypodevelopment of the chest wall known as suffocating thoracic dystrophy, in addition to other manifestations.
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Maegawa, Gustavo H. B. Lysosomal Storage Disorders. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0068.
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The lysosomal storage disorders (LSDs) are a group of inborn organelle disorders, clinically heterogeneous, and biochemically characterized by accumulation of nondegraded macromolecules primarily in the lysosomal and other cellular compartments. Given the common and essential cellular function of the lysosomal system in different organs and systems, patients afflicted with these disorders present a broad range of clinical problems, including neurological problems, visceromegaly, and skeletal deformities. Onset of symptoms may range from fetal period to adulthood. The neurological problems include developmental delay, seizures, acroparesthesia, motor weakness, muscle wasting, behavioral/psychiatric disturbances, cerebrovascular ischemic events, and extrapyramidal signs. Patients may present with symptoms later that include psychiatric manifestations, are slowly progressive, and may precede other neurologic or systemic features. Most of LSDs are autosomal recessive; however, a few are X-linked with symptpmatic female carriers (e.g., Fabry disease). In most of them, the diagnosis is established by biochemical and/or molecular assays. In terms of management, disease-modifying therapies include enzyme replacement, hematopoietic stem cell transplantation, and substrate reduction therapy. Patients and their families require genetic counseling regarding reproductive risks, disease prognosis, and therapeutic options. Investigations of disease molecular mechanisms provide insights into potential targets for the development of therapeutic strategies. Supportive care has been the key and essential for most LSDs, resulting in substantial improvement in quality of life of patients and families.
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Sayer, John A. Nephronophthisis and medullary cystic kidney disease. Edited by Neil Turner. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199592548.003.0316_update_001.
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The inherited cystic kidney conditions nephronophthisis (NPHP) and medullary cystic kidney disease (MCKD) have previously been referred to as a NPHP–MCKD complex. This descriptive term was based on histological studies where the renal pathological features were common to both disorders. Both conditions may also present with insidious renal impairment and a urine concentrating defect, but they are genetically distinct. NPHP is an autosomal recessive disorder leading to established renal failure usually within the first three decades of life, and it is a ciliopathy. In contrast, MCKD is an autosomal dominantly inherited disorder leading to renal failure in later life, typically between 30 and 60 years of age. A molecular genetic diagnosis is helpful for both disorders, allowing a more precise diagnosis, screening of at risk relatives and avoiding the need for renal biopsy. Treatment of both conditions remains supportive.
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Pigg, Maritta. Molecular Genetic Studies of 3 Autosomal Recessive Disorders: Sjogren-Larsson Syndrome, Glutathione Synthetase Deficiency and Congenital Ichthyosis (Comprehensive ... Summaries of Uppsala Dissertations, 928). Uppsala Universitet, 2000.
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12
Firth, Helen V., Jane A. Hurst, and Judith G. Hall. Appendix. Oxford University Press, 2011. http://dx.doi.org/10.1093/med/9780192628961.003.0204.
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Bayes’ theorem 646Behavioural pattern profile (Shalev and Hall 2004) 648Carrier frequency and carrier testing for autosomal recessive disorders 650Centile charts for boys height and weight 652Centile charts for girls height and weight 656Centile charts for occipital-frontal circumference (OFC) 660CK (Creatine kinase) levels in carriers of Duchenne muscular dystrophy (DMD) ...
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Fox, Susan H. Seizures and Shakes. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780190607555.003.0017.
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Wilson’s disease is an autosomal recessive, treatable heredodegenerative disorder characterized by excessive deposition of copper in the liver, brain, and other tissues including the kidneys, pancreas, and joints. Early recognition of the disorder, which can present with a variety of movement disorders and neuropsychiatric phenomena, is critical to avoid irreversible end organ damage through the initiation of copper chelating agents. Diagnosis relies first on demonstrating evidence of brain iron deposition on magnetic resonance imaging of brain and elevated urinary copper excretion in the appropriate clinical context. Genetic testing for mutations in the ATP7B gene will identify a mutation in up to 90% of cases.
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Steensma, David P. Benign Hematology. Oxford University Press, 2012. http://dx.doi.org/10.1093/med/9780199755691.003.0294.
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The major forms of benign hematologic conditions are anemia, neutropenia, transfusion reactions, Gaucher disease, and porphyria. Anemia is a sign of disease rather than a disease itself. Anemia results from 1 or more of 3 pathologic mechanisms: inadequate production of red blood cells (RBCs) by the bone marrow, blood loss, or premature destruction of RBCs. The major causes of neutropenia include hematologic neoplasm, metastatic neoplasm involving the marrow, irradiation, vitamin B12 deficiency and folate deficiency, drugs, infections, congenital or acquired primary disorders of hematopoiesis, autoimmune neutropenia, hypersplenism, hemodilution, and benign idiopathic neutropenia. The porphyrias are enzyme disorders that are autosomal dominant with low disease penetrance, except for congenital erythropoietic porphyria, which is autosomal recessive, and porphyria cutanea tarda, which may be acquired and is associated with hepatitis C and hemochromatosis.
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Smith, Ashley. Mucopolysaccharidoses. Edited by Kirk Lalwani, Ira Todd Cohen, Ellen Y. Choi, and Vidya T. Raman. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190685157.003.0049.
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Mucopolysaccharidoses (MPS) are a group of genetic diseases that affect connective tissues via lack of key lysosomal enzymes. This deficiency leads to storage of partially degraded glycosaminoglycans that build up in multiple organ systems. There are many types of MPS disorders and each has varying features, expected lifespan, enzyme affected, and resulting clinical effect. All MPS are autosomal recessive except Hunter syndrome, which is X-linked. Because each type has a different enzyme deficiency, each has different comorbidities and unique treatment modalities. These patients require multiple anesthetics for diagnostic and surgical interventions. This chapter discusses treatment ad complication issues regarding MPS.
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Dukhovny, Stephanie. Prenatal Genetics for Women with Neurology Disease. Edited by Emma Ciafaloni, Cheryl Bushnell, and Loralei L. Thornburg. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190667351.003.0006.
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The genetic evaluation of heritability of genetic disease, as well as screening of the fetus for neurologic diseases, have evolved a great deal since the 1970s. Screening and diagnostic evaluation now includes the ability to detect fetuses with anatomic abnormalities of the central nervous system and rare autosomal recessive disorders with neurologic features. Preimplantation genetic diagnosis now allows families with confirmed genetic abnormalities to utilize in vitro fertilization technologies to avoid affected pregnancies. For families that have not received a prenatal diagnosis, newborn screening allows for detection of diseases with potential neurologic implications in the child’s early newborn period.
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Bosch, Annet M., and Elaine Murphy. Galactosemia. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0002.
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There are three known inherited disorders of galactose metabolism: classic galactosemia (galactose-1-phosphate uridyltransferase deficiency), galactokinase deficiency, and uridine diphosphate galactose 4-epimerase deficiency. Classic galactosemia presents in the newborn period with liver and renal impairment and failure to thrive. Acute symptoms resolve when lactose is excluded from the diet, but long-term complications are frequent and include neurocognitive and social difficulties, speech and language problems, motor problems, and premature ovarian insufficiency. Patients with galactokinase deficiency develop cataracts, while the clinical spectrum of uridine diphosphate galactose 4-epimerase deficiency is broad, from a benign condition to a severe disorder similar to classic galactosemia. All are autosomal recessive conditions. Diagnosis is by measurement of enzyme activity in erythrocytes, confirmed by mutation analysis of the specific genes, GALT, GALK, or GALE.
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Hendriksz, Christian J., and Francois Karstens. Mucopolysaccharidosis in Adults. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0054.
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There are 8 different types of diseases of the mucopolysaccharides, each caused by a deficiency in one of 10 different enzymes involved in the degradation of glycosaminoglycans (GAGs). Partially degraded GAGs accumulate within the lysosomes of many different cell types and lead to clinical symptoms and excretion of large amounts of GAGs in the urine. Heritability is autosomal recessive except for MPS type II, which is X-linked. The disorders are chronic and progressive and, although the specific types all have their individual features, they share an abundance of clinical similarities. All involve the musculoskeletal, the cardiovascular, the pulmonary and the central nervous system.
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Uffman, Joshua C. Neuronal Ceroid Lipofuscinoses (Batten Disease). Edited by Kirk Lalwani, Ira Todd Cohen, Ellen Y. Choi, and Vidya T. Raman. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190685157.003.0042.
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Neuronal ceroid lipofuscinoses (NCL) are a group of autosomal recessive genetic disorders which represent the most common form of childhood neurodegenerative disease. Classically the disease was described according to the age of diagnosis resulting in four common phenotypes: (i) infantile or Santavuori-Haltia, (ii) late infantile or Jansky-Bielschowsky, (iii) juvenile or Spielmeyer-Vogt, and (iv) adult or Kufs. With advances in genetic mutational analysis techniques and improved understanding of NCL disease as a whole, disease classification now focuses on which of the known genetic defects is responsible for the disease. Regardless of genetic defect or age of onset, patients typically present with language delay, seizures, blindness, and ataxia. The term “Batten disease” is used to refer to the group as a whole in addition to specifically referring to the juvenile form. Anesthetic implications focus on disease symptoms at presentation, with special attention to maintaining normorthermia and the possibility of bradycardia.
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Groothoff, Jaap W. Primary Hyperoxaluria. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0065.
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Primary hyperoxalurias (PH) are rare autosomal recessive metabolic disorders characterized by an increased endogenous oxalate production which leads to the development of urolithiasis, nephrocalcinosis, and ultimately to renal failure.PH patients with severe renal failure develop life-threatening systemic oxalosis, which affects many organs such as bone, skin, retina, myocardium, vessel walls, and the central nervous system. So far, combined or sequential liver-kidney transplantation is the only therapeutic option for patients with advanced disease. Contrary to the former impression of a relatively mild course of disease in patients diagnosed as adults, recent data have shown that patients diagnosed in adulthood mostly present with established ESRD and systemic oxalosis. The fact that some of these patients respond to pyridoxine therapy underlines the importance of early diagnosis and measures to prevent renal failure and systemic oxalosis. All children with stone disease or nephrocalcinosis and all adults with recurrent stone disease should therefore be screened for PH.
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Heidet, Laurence, Bertrand Knebelmann, and Marie Claire Gubler. Alport syndrome. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0323.
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The diagnosis of Alport syndrome is suspected from the clinical features and confirmed by identifying the almost pathognomonic ultrastructural changes to the basement membrane in a family member with early disease (so that glomeruli are not too sclerosed), or in modern times by identifying a causative mutation in one or more of the three implicated COL4 genes. Genetic testing is becoming simpler and cheaper, but is still out of the reach of many. Eighty-five per cent of cases are caused by COL4A5 mutations and 10–15% by autosomal recessive disease. A significant proportion of morbidity in X-linked disease occurs in female ‘carriers’ heterozygous for the disease. Changes by light microscopy are non-specific, and can be misleading unless accompanied by electron microscopy. Immunohistology can be helpful but may not be definitive as some causative mutations are not associated with absence of protein product. As COL4A5 is expressed in skin, skin studies are theoretically useful, but they are technically challenging and only a definite negative result is helpful. It is important to distinguish other disorders causing renal disease with deafness, and other causes of glomerular haematuria. Two rare syndromes are caused by extended deletions beyond the COL4A5 gene: X-linked Alport syndrome with diffuse oesophageal leiomyomatosis in which smooth muscle leoimyomas is transmitted in a dominant fashion, and X-linked Alport syndrome with mental retardation.
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Grom, Alexei A., and Athimalaipet V. Ramanan. Macrophage activation syndrome. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0168.
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Macrophage activation syndrome (MAS) is a life-threatening condition caused by excessive activation and proliferation of T lymphocytes and haemophagocytic macrophages. Although MAS has been reported in association with almost any rheumatic disease, it is by far most common in systemic juvenile idiopathic arthritis. Flares of the underlying disease or infection are most common triggers of MAS. The pathognomonic feature of MAS is typically found in bone marrow: numerous, well-differentiated macrophagic histiocytes phagocytosing normal haematopoietic elements. The expansion of these histiocytes leads to a massive systemic inflammatory reaction associated with three cardinal clinical features: severe cytopenias, liver dysfunction, and coagulopathy consistent with disseminated intravascular coagulation. Clinically, MAS is strikingly similar to the autosomal recessive disorders collectively known as familial haemophagocytic lymphohistiocytosis (FHLH). FHLH has been associated with various genetic defects affecting the cytolytic pathway. Cytolytic function is profoundly depressed in MAS patients as well, and this abnormality is caused by both genetic and acquired factors. Studies in animals suggest that uncontrolled expansion of activated CD8+ T lymphocytes secreting cytokines that activate macrophages is central to the pathophysiology of haemophagocytic syndromes. Consistent with this view, the combination of steroids and ciclosporin, an immunosuppressant that preferentially inhibits T lymphocytes, is an effective treatment for the majority of MAS patients. Patients in whom MAS remains active despite this treatment present a serious challenge and require more aggressive immunosuppression. However, in MAS triggered by infection, the optimal level of immunosuppression is difficult to determine. As a result, reported mortality rates reach 20%.
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Keshav, Satish, and Palak Trivedi. Genetic liver disease. Edited by Patrick Davey and David Sprigings. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199568741.003.0214.
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This chapter discusses three of the major inherited forms of liver disease (all autosomal recessive): hereditary haemochromatosis, Wilson’s disease, and alpha-1-antitrypsin deficiency. Hereditary haemochromatosis is characterized by excessive absorption of dietary iron, with a pathological increase in total body iron that accumulates in tissues and organs, disrupting their function. Wilson’s disease (hepatolenticular degeneration) is an autosomal recessive genetic disorder in which copper accumulates in tissues. Alpha-1-antitrypsin deficiency is characterized by reduced circulating levels of alpha-1-antitrypsin, a liver-derived protease inhibitor, and accumulation within the hepatocytes of the abnormal, poorly degraded protein; the consequent excessive activity of proteases such as elastase in pulmonary alveoli, unopposed by protease inhibitors, leads to emphysema, and the accumulation of alpha-1-antitrypsin in hepatocytes causes liver dysfunction.
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Bright-Thomas, Rowland J., and Andrew M. Jones. Cystic fibrosis. Edited by Patrick Davey and David Sprigings. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199568741.003.0132.
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Cystic fibrosis is the most common lethal autosomal recessive disorder in Caucasians. There is no known survival advantage of the heterozygote carrier state. Chronic progressive pulmonary infection and bronchiectasis are the major causes of morbidity and mortality. The disease affects all ductal systems where the basic defect is manifest, including the pancreas, gastrointestinal tract, sinuses, hepatobiliary system, and male reproductive system, and has significant effects on nutrition and growth.
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Frawley, Geoff. Mucopolysaccharidoses. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199764495.003.0064.
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The mucopolysaccharidoses (MPS) are a group of seven chronic progressive diseases caused by deficiencies of 11 different lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs). Hurler syndrome (MPS IH) is an autosomal recessive storage disorder caused by a deficiency of α-L-iduronidase. Hunter syndrome (MPS II) is an X-linked recessive disorder of metabolism involving the enzyme iduronate-2-sulfatase. Many of the MPS clinical manifestations have potential anesthetic implications. Significant airway issues are particularly common due to thickening of the soft tissues, enlarged tongue, short immobile neck, and limited mobility of the cervical spine and temporomandibular joints. Spinal deformities, hepatosplenomegaly, airway granulomatous tissue, and recurrent lung infections may inhibit pulmonary function. Odontoid dysplasia and radiographic subluxation of C1 on C2 is common and may cause anterior dislocation of the atlas and spinal cord compression.
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Wolf, Barry, and Sara Elrefai. Biotinidase Deficiency and Biotin Holocarboxylase Synthetase Deficiency. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0026.
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Biotin holocarboxylase synthetase and biotinidase deficiencies are biotin-dependent, autosomal recessively inherited disorders. Untreated individuals with both disorders usually develop neurological and cutaneous symptoms during childhood. There is limited information about older children or adults with holocarboxylase synthetase deficiency. Older individuals with biotinidase deficiency may exhibit spastic paresis, scotomata, and progressive optic neuropathy. Both disorders are readily treated with oral biotin supplementation. Asymptomatic individuals with biotinidase deficiency are at risk of developing symptoms at any age. Newborn screening for both disorders has been adopted in many countries. Newborn screening has facilitated identification of presymptomatic individuals, thereby allowing for early treatment and prevention of symptoms.
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Burghes, Arthur H. M., and Vicki L. McGovern. Spinal Muscular Atrophy. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0034.
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Spinal muscular atrophies affect the lower motor neuron. The most common SMA maps to 5q is an autosomal recessive disorder. SMA is caused by loss or mutation of the SMN1 gene and retention of the SMN2 gene, and these genes lie in a complex area of the genome. Mild missense alleles of SMN1 work to complement SMN2 to give function and therapeutics that restore SMN levels are in clinical testing. Modifiers that lie outside the SMN gene locus and influence severity clearly exist, but what they are remains unknown as do the critical genes affected by SMN deficiency.
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Introne, Wendy J. Alkaptonuria. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0015.
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Alkaptonuria is an autosomal recessive disorder with an incidence of 1:250,000 to 1:500,000. Aside from urine that darkens, the disease is relatively asymptomatic in childhood. As a result, the diagnosis is often overlooked early in life and not considered in many patients until they begin to manifest symptoms as adults. Features include pigment deposition (ochronosis) on the eyes, ears, and hands; early-onset, progressive arthritis, particularly of the spine and large joints; valvular heart disease; and renal and prostate stones. Management continues to be symptomatic, but specific treatment with nitisinone appears promising with additional clinical trials being planned.
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Murphy, Elaine. Tyrosinemia Type II. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0014.
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Tyrosinemia type II is a rare oculocutaneous disorder that in some individuals is also associated with developmental delay or other neurological problems. Bilateral keratitis and painful hyperkeratotic lesions of the palms and soles are the typical presenting lesions. Diagnosis is suggested by the clinical picture, elevated plasma tyrosine levels, and specific urinary metabolites. It is an autosomal recessive condition caused by mutations in the tyrosine aminotransferase (TAT) gene. Treatment is aimed at reducing plasma tyrosine levels and consists of a low-protein diet with age-appropriate amino acid (phenylalanine-free and tyrosine-free), vitamin, and mineral supplements. Significant maternal hypertyrosinemia is associated with a poor fetal outcome.
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Heidet, Laurence, Bertrand Knebelmann, and Marie Claire Gubler. Alport syndrome. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0321.
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Alport syndrome is an inherited renal disorder characterized by early haematuria, progressing to proteinuria, sensorineural hearing loss, and progressive renal failure typically in the third or fourth decade but with wide variation. It is responsible for about 1% of end-stage renal failure. Over 80% of cases are X-linked and young men are most affected, but heterozygous carriers of the abnormal gene are also at significantly increased risk of end-stage renal failure in their lifetime. Those affected by the autosomal recessive variant are phenotypically very similar. It is caused by mutations in tissue-specific isoforms of basement membrane (type IV) collagen encoded by COL4A5 (X chromosome), COL4A3, and COL4A4 (chromosome 2).
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Vernon, Hilary. Phenylketonuria. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0064.
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Phenylketonuria is an autosomal recessive biochemical disorder most often resulting from a deficiency of phenylalanine hydroxylase, the enzyme which catalyzes the conversion of phenylalanine to tyrosine. The remainder of the cases are caused by abnormalities in the phenylalanine hydroxylase cofactor, tetrahydrobiopterin. Phenylketonuria can be divided into three subgroups based on the elevation of plasma phenylalanine in the untreated state: “classical,” “variant,” and “benign.” Untreated individuals with classical phenylketonuria develop neurocognitive abnormalities including seizures, microcephaly, and severe intellectual disability. Other clinical effects include a musty body odor, eczema, and reduced skin pigmentation. Treatment, which includes dietary restriction of phenylalanine, supplementation with synthetic protein, and, in some cases, administration of a synthetic form of tetrahydrobiopterin, is successful in preventing the long-term consequences of phenylketonuria.
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Dionisi-Vici, Carlo, Diego Martinelli, Enrico Bertini, and Claude Bachmann. HHH Syndrome. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0020.
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Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder of the urea cycle characterized by impaired transport of ornithine across the inner mitochondrial membrane. As seen in other urea cycle defects, in the acute phase the disease is characterized by intermittent episodes of hyperammonemia accompanied by vomiting, lethargy, and coma, with or without signs of acute liver failure. The disease course is characterized by a pyramidal tract dysfunction associated with myoclonic seizures and cerebellar symptoms. Most patients reaching adulthood manifest variable degrees of cognitive impairment and abnormal behavior. Long-term treatment consists of a low-protein diet supplemented with citrulline, arginine, or ornithine. Protein restriction may be combined with sodium benzoate. If plasma creatine levels are low, creatine supplementation should be instituted. Acute treatment is similar to other urea cycle defects.
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Dinopoulos, Argirios. Atypical Nonketotic Hyperglycinemia. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0030.
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Nonketotic hyperglycinemia (NKH) or glycine encephalopathy (GE) is an autosomal recessive inborn error of glycine degradation due to a defect in the glycine cleavage system (GCS). Accumulation of glycine, particularly in the central nervous system, leads to a variety of neurological symptoms, which may be progressive in infants. Clinical symptoms in atypical NKH are heterogeneous and, according to the age of presentation, cases can be divided in three forms: neonatal, infantile, and late onset. Late-onset atypical cases display an intermittent or a chronic course and may become apparent in adulthood. Psychiatric symptoms are common, and diagnosis may be difficult due to the rarity of the disorder. The CSF/plasma glycine ratio is diagnostic but in atypical cases is usually lower than the diagnostic cut-point for classical NKH. Treatment consists of dietary measures, but no consistent outcomes have been reported.
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Servais, Aude, and Bertrand Knebelmann. Cystinuria. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0024.
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Cystinuria (OMIM #220100) is an autosomal recessive disorder of a dibasic amino acid transport in the apical membrane of epithelial cells of the renal proximal tubule and small intestine. It leads to increased urinary cystine excretion and recurrent urolithiasis. The cystine transporter is an heterodimeric transporter which is composed of a heavy subunit, rBAT, linked to a light subunit, b0,+AT. Two genes, SLC3A1 (solute carrier family 3 member 1) and SLC7A9, coding for rBAT and b0,+AT, account for the genetic basis of cystinuria. Cystinuria may lead to obstruction, infections, and ultimately to renal insufficiency. The diagnosis of cystinuria mainly relies on stone analysis, urinary cystine measurement, or urinary cystine crystal identification. Medical treatment is based upon a stepwise strategy using hydration and alkalinization as basic measures, with the addition of thiol derivatives in refractory cases. Urological interventions are often indicated for the management of cystine stones >5 mm in diameter.
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Servais, Aude. Nephropathic Cystinosis in Adults. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0060.
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Cystinosis is an autosomal recessive lysosomal storage disorder caused by a defect in the carrier-mediated system that normally transports cystine out of lysosomes. As a consequence, tissues accumulate variable amounts of the disulphide amino acid cystine. Three overlapping clinical phenotypes are recognized, varying in severity and age of onset. The most severe, the infantile nephropathic form (MIM 219800), appears in the first year of life. The late-onset form (MIM 219900) is also nephropathic, while ocular, non-nephropathic cystinosis manifests largely with corneal crystal deposition (MIM 219750). Infantile cystinosis is the most common form. Affected children develop renal proximal tubulopathy at 6 to 12 months of age. In the absence of treatment, renal failure occurs, with progression to end-stage renal disease (ESRD). Cystine crystal deposition in the cornea leads to photophobia and continuous widespread cystine accumulation eventually leads to rickets, retinal, endocrinological (hypothyroidism and impaired glucose tolerance), hepatic, gastrointestinal, muscular, and neurological abnormalities.
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Murphy, Elaine, Yann Nadjar, and Christine Vianey-Saban. Fatty Acid Oxidation, Electron Transfer and Riboflavin Metabolism Defects. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0008.
Full textAbstract:
The fatty acid oxidation disorders are a group of autosomally recessively inherited disorders of energy metabolism that may present with life-threatening hypoketotic hypoglycemia, encephalopathy and hepatic dysfunction, muscle symptoms, and/or cardiomyopathy. Milder phenotypes may present in adulthood, causing exercise intolerance, episodic rhabdomyolysis, and neuropathy. Specific investigations include acylcarnitine profiling, urine organic acid analysis, fibroblast or leucocyte studies of fatty acid oxidation flux/enzyme activity, and genetic testing. Management varies depending on the condition but includes avoidance of precipitants such as fasting, fever, and intense exercise, a high-carbohydrate, low-fat diet, and supplementation with carnitine or riboflavin. Inborn errors of riboflavin transport mainly present with Brown-Vialetto-Van Laere syndrome. Some patients respond dramatically to riboflavin supplementation; therefore it has to be tried in all suspected patients.
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van der Ploeg, Ans T., and Pascal Laforêt. Pompe Disease. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0055.
Full textAbstract:
Pompe disease, also named acid maltase deficiency and glycogen storage disease type II (GSDII), is a rare autosomal recessive disorder caused by the deficiency of the glycogen-degrading lysosomal enzyme acid α-glucosidase. The clinical spectrum of this disease is broad, varying from a lethal infantile-onset generalized myopathy including cardiomyopathy, to late-onset slowly progressive muscle weakness mimicking limb-girdle muscular dystrophy. Respiratory insufficiency is a frequent complication and the main cause of death. The prognosis of Pompe disease has changed considerably with the use of enzyme replacement therapy using recombinant acid α-glucosidase (alglucosidase alfa), which has been widely available since 2006. Improvements in survival and major motor achievements can be observed in patients with infantile forms, and recent studies demonstrate improvement of walking distance and stabilization of pulmonary function in late-onset forms. A longer-term study of the safety and efficacy of ERT, based on data gathering across the complete spectrum of Pompe disease via national or international patient registries, is needed in order to formulate more precise guidelines for treatment.
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Syrris, Petros, and Alexandros Protonotarios. Arrhythmogenic right ventricular cardiomyopathy: genetics. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0359.
Full textAbstract:
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder of the heart muscle which is typically inherited in an autosomal dominant manner. It is believed to be familial in over 50% of cases. A recessive mode of inheritance has also been reported in syndromic cases with cardiocutaneous features. The classic form of the disorder is considered to be ‘a disease of the desmosome’ as pathogenic variants have been identified in five genes encoding key desmosomal proteins: plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2. Mutations in these genes account for 30–50% of ARVC cases. A further eight non-desmosomal genes have also been implicated in the pathogenesis of the disorder but only account for rare cases. Studies of patients with ARVC-associated gene mutations have revealed marked genetic heterogeneity and very limited genotype–phenotype correlation. Disease expression often varies significantly amongst individuals carrying the same mutation. It has been proposed that the presence of more than one sequence variant is required to determine overt clinical disease and patients with multiple variants have a more severe phenotype compared to single variant carriers. Identification of a potentially pathogenic variant comprises a major criterion in the diagnosis of ARVC but informative integration of genetic testing into clinical practice remains challenging. Gene testing should be used to identify asymptomatic family members at risk and only aids diagnosis in cases of high suspicion for ARVC, along with other evident features of the disease already present. However, genetic findings should be used with caution in clinical practice and their interpretation must be performed in expert centres.
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Levtchenko, Elena N., and Mirian C. Janssen. Cystinosis. Edited by Neil Turner. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199592548.003.0339_update_001.
Full textAbstract:
Cystinosis is a rare autosomal recessive disease caused by mutations in the lysosomal cystine transporter cystinosin encoded by the CTNS gene (17p.13.2). Cystinosis is characterized by lysosomal cystine accumulation throughout the body with renal Fanconi syndrome being the most common presenting symptom of a multisystem disorder. It must be distinguished from cystinuria in which formation of cystine stones is the core problem. When left untreated, kidney dysfunction gradually progresses towards end-stage renal failure during the first 10 years of life. The advent of renal replacement therapy allowed cystinosis patients to survive into adulthood, but revealed numerous extrarenal manifestations of the disease, affecting eyes, endocrine organs, gastrointestinal tract, muscles, and central and peripheral nervous systems. The disease mechanism of cystinosis is not fully understood. The administration of the cystine-depleting agent cysteamine slows down renal and extrarenal organ damage, pointing to the pivotal role of cystine accumulation in the disease pathogenesis. Treatment with cysteamine should be initiated as early as possible and continued lifelong, and also after kidney transplantation for protecting extrarenal organs. Cysteamine eye drops are an indispensable part of the treatment of corneal cystine accumulation. Life expectancy of cystinosis patients has substantially improved and is now above 50 years.
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Sarphare, Geeta, Ryan Lee, and Elaine Tierney. Smith-Lemli-Opitz Syndrome and Role of Cholesterol in Autism. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199744312.003.0012.
Full textAbstract:
Cholesterol is manufactured throughout the body, but predominantly in the liver, and is essential for many metabolic processes. Cholesterol plays a critical role in forming membranes and myelin sheaths and is a precursor molecule for the synthesis of steroid hormones, neuroactive steroids, oxysterols, and vitamin D. It is also essential in the production of bile acids, which in turn helps the body absorb cholesterol and fat-soluble vitamins. Cholesterol is essential in embryonic and fetal development and is also critical in regulating lipid raft processes such as signaling and trafficking (Korade & Kenworthy, 2008). Cholesterol biosynthesis begins with the formation of squalene and ends with the reduction of 7-dehydrocholesterol (7DHC) into cholesterol by the enzyme 7DHC reductase, and then its spontaneous isomer, 8-dehydrocholesterol (8DHC). Smith-Lemli-Opitz syndrome (SLOS, Mendelian Inheritance in Man #270400) is an autosomal recessive disorder due to an inborn error of cholesterol biosynthesis (Elias et al., 1993; Irons, Elias, Salen, Tint, & Batta, 1993; Tint et al., 1994). Smith-Lemli-Opitz syndrome has an estimated incidence among individuals of European ancestry in Canada and the United States of 1 in 15,000 to 1 in 60,000 births (Bzdúch, Behulova, & Skodova, 2000; Lowry & Yong, 1980; Opitz, 1999; Ryan, Bartlett, Clayton, Eaton, Mills, Donnai, & Burn, 1998) and a carrier frequency of 1 in 30 to 1 in 50 (Nowaczyk & Waye, 2001).