Asesoramiento genético: Mucopolysacharidosis (MPS)

· Mucopolysacharidosis (MPS) Contenido 1 Contratación 2 Medical history 3 Update Pedigree 4 Visión general 5 Incidencia 6 Tratamiento 7 ERT 8 Types of MPS 9 General symptoms 10 Three subgroups of MPSI according to severity 11 Inheritance and risks 12 Diagnóstico 13 Genetic Testing 14 MPS II (Hunter syndrome -differential diagnosis) 15 Visión general 16 Risks and inheritance 17 Description of symptoms 18 Other Differentials 19 Drug-induced lysosomal storage disease 20 Psychosocial considerations 21 Support and Information Organizations 22 Referencias 23 Notes Contracting Can you explain to me your main purpose in visiting genetics? What are your main concerns about the diagnosis? Outline session First I will update the medical and family history Doctor will then probably want to perform physical exam Then we will address any concerns or questions Medical history Follow interim history form and focus on potential health problems/ symptoms described later in outline Update Pedigree Any other brothers or sisters Full biological? Any other family members with: Genetic conditions Multiple miscarriages Birth defects Chronic illnesses MR learning difficulties Any chance that you and his father related by blood Country where relatives are from originally Overview Group of inherited metabolic disorders Caused by a deficiency of the specific lysosomal enzymes needed to break down mucopolysaccharides Mucopolysaccharides are long chains of sugar molecules used to build connective tissues and organs in the body When mutations occur in the genes for the enzymes that break down mucopolysaccharides, excess amounts of them are stored in the body This causes progressive damage to organs and tissues Eight clinical types and numerous subtypes have been identified Although each type differs clinically, generally, people with mucopolysaccharidoses experience a period of normal development followed by a decline in physical and/or mental function Some of the excess mucopolysaccharides are excreted through the urine and diagnosis often can be made through clinical examination and urine tests Incidence Estimated 1 en 25,000 births in U.S. have some form of MPS: Treatment No simple cure for the mucopolysaccharidoses Treatment is symptomatic and supportive In several individuals, bone marrow transplants have been attempted with varying degrees of success Enzyme replacement trials (ERT) are under investigation for MPS I and MPS II Kakkis et al. (2001) treated 10 patients with MPS I (aged 5 Para 22 años) with recombinant human alpha-L-iduronidase at a dose of 125,000 U per kg of body weight given intravenously once weekly for 52 semanas. Hepatosplenomegaly decreased significantly in all patients, and the size of the liver was normal for body weight and age in 8 patients by 26 semanas. The rate of growth in height and weight increased by a mean of 85 y 131%, respectivamente, en 52 weeks in the 6 prepubertal patients. The mean maximum range of motion of shoulder flexion and elbow extension increased significantly. The number of episodes of apnea and hypopnea during sleep decreased by 61%. New York Heart Association functional class improved by 1 o 2 classes in all patients. Urinary glycosaminoglycan excretion decreased after 3 Para 4 weeks of treatment; the mean reduction at 52 weeks was 63% of baseline values. Five patients had transient urticaria during infusions. Serum antibodies to alpha-L-iduronidase were detected in 4 patients ERT treatment consists of a modified form of the alpha-L-iduronidase enzyme given intravenously takes approximately two hours for a person to receive the treatment, and the treatment is usually given every two weeks Enzyme replacement therapy can stop and often reverse the symptoms of the disorder Disadvantages of the enzyme replacement therapy are its high cost and the fact that it is a lifelong process Potential adverse reactions including "allergic type reaction" Initial evidence of potential treatment for Hurler syndrome (Keeling KM et al, 2001) Gentamicin-mediated suppression of Hurler syndrome stop mutations restored a low level of alpha-L-iduronidase activity and reduced lysosomal glycosaminoglycan accumulation results suggest that the suppression of premature stop mutations may provide an effective treatment for Hurler syndrome patients with premature stop mutations in the IDUA gene Types of MPS MPS type I Hurler, Scheie, and Hurler/Sheie syndromes also known respectively as MPS-IH, MPS-IS, and MPS-IH/S Hurler syndrome takes its name from Gertrud Hurler, the doctor who described a boy and girl with the condition in 1919 En 1962, Dr. Scheie, a consultant ophthalmologist, wrote about some of his patients who were more mildly affected Patients who seem not to fit clearly in either the severe or the mild end of the disorder are said to have *Hurler/Scheie syndrome All are caused by missing enzyme - alpha-L-iduronidase Alpha-L-iduronidase breaks down (mucopolysaccharides) heparan sulfate and dermatan Found at locus 4p16.3 No reliable way of telling from biochemical tests how severe the disorder will be residual alpha-L-iduronidase activity in Hurler fibroblasts is heat-stable whereas that in Scheie fibroblasts is heat-labile Progression and severity of disease are highly variable within the spectrum of MPS) General symptoms multiple organ and tissue involvement Joint stiffness Skeletal deformities Enlarged liver Obstructive airway disease; respiratory infection and cardiac complications are the most common direct causes of death Ophthalmologic manifestations and hearing disorders Three subgroups of MPSI according to severity Sheie syndrome corneal opacities aortic valve disease normal stature mild or absent intellectual impairment nearly normal life span seldom recognized during infancy or early childhood No neurologic involvement Joint stiffness, carpet tunnel syndrome Mild hepatosplenomegaly Hurler/Sheie Onset of symptoms between 3 y 8 years of age death in 2nd or 3rd decade normal or near normal intelligence more severe physical symptoms than those with Scheie syndrome short stature dysostosis multiplex hepatosplenomegaly corneal clouding umbilical or inguinal hernia psychotic symptoms may appear later in life Hurler syndrome Most severe form Occurs in infancy Macrocephaly (*may appear early in infancy while complete clinical picture develops during second year of life) Respiratory infections* Limited hip abduction* Apnea or difficulty breathing Coarse (gargyloid) facies accelerated growth from infancy followed by progressive decline in the rate of development progressive physical disability progressive mental retardation dysostosis multiplex corneal clouding death usually before the age of 10 years usually result of pneumonia and heart failure Inheritance and risks AR inheritance, panethnic Parents of affected child have ¼ chance of each pregnancy being affected Unaffected sibs of patient have 2/3 chance of being carrier Combined frequency: aproximadamente 1 en 50,000 Hurler: 1 en 100,000 Hurler-Scheie: 1 en 115,000 Scheie: 1 en 500,000 Diagnosis can be diagnosed with a blood looking at levels of alpha-L-iduronidase low level of this enzyme in a person's white blood cells is characteristic of the disease confirmed by this absence of alpha-L-iduronidase in the white blood cells, the excretion of dermatan sulfate and heparan sulfate in the urine, and by physical appearance Molecular (ADN) analysis can also be used to verify the diagnosis Genetic Testing Prenatal diagnosis possible once a diagnosis has been made in the family and a genetic alteration identified (CVS and amount of alpha-L-iduronidase can be measured in the amniotic cells or chorionic villi Molecular (ADN) analysis can be used to verify the diagnosis prenatally, by looking for the same genetic alteration that is present in the family member Carrier testing Enzyme analysis using white blood cells is not effective or reliable in identifying carriers of these disorders However, a study in 2002 (Mandelli J et al) showed that leukocyte IDUA from MPS I heterozygotes differed from the normal enzyme in terms of optimum pH, Km, and Vmax of the reaction and thermostability at 50 degrees C. They claimed these parameters provide a simple and reliable tool for the detection of carriers for MPS I. molecular (ADN) analysis is used to identify carriers first test someone in the family who has already been diagnosed with the disorder, so that the laboratory can identify the genetic alteration present in that individual and look for that same alteration in at-risk family members MPS II (Hunter syndrome -differential diagnosis) Overview named after Charles Hunter, the professor of medicine in Manitoba, Canadá, who first described two brothers with the disorder in 1917 Hunter syndrome is less common than MPS I and has no corneal clouding and pursues a slower course than MPS I Some think there are two distinct types of the condition, the mild and the severe Others believe there is just one disorder with a wide range in the severity of the problems it causes Risks and inheritance X-linked recessive Rarely girls have been diagnosed Mother of affected boy is carrier 50% risk to future boys maternal aunts and sisters at risk of being carrier carrier testing available Description of symptoms Severe form: Joint stiffness Mental deterioration Dwarfing Progressive deafness Death by age 15 Mild form: Short stature Limitation of motion Enlarged forehead, tongue and lips Life span may be normal Other Differentials MPS III,or Sanfilippo syndrome experience progressive dementia and mental deterioration in childhood Death usually occurs in the late teens MPS IV,or Morquio syndrome Symptoms usually appear in infancy and may include severe dwarfing and corneal clouding Intelligence is normal Cardiac or respiratory disease may cause death in the third or fourth decade of life MPS VI,or Maroteauz-Lamy syndrome resembles Hurler syndrome Onset is in infancy intelligence is normal Individuals may live into the second or third decade MPS VII, Sly disease experience corneal clouding, skeletal irregularities, and enlargement of the liver and spleen Intellectual impairments vary for this type of MPS Drug-induced lysosomal storage disease example of phenocopy thought that drugs of widely differing pharmacologic activity can interact with polar lipids within the lysosomes to yield lipid-drug complexes resistant to enzymatic digestion Psychosocial considerations Assess how this disease is viewed by patient and family members Probably difficult to watch progression of disease may feel helpless May seek out every possible therapy (including alternative med. tx) Difficulty accepting that life-span may be shortened May have been overprotected by parents May struggle with feelings of dependence on others Discuss support group Support and Information Organizations National MPS Society, Inc. 102 Aspen Drive Downingtown, PAPÁ 19335 [email protected] Tel: 610-942-0100 Fax: 610-942-7188 Organización Nacional de Trastornos Raros (NORTE) P.O. Box 1968 (55 Kenosia Avenue) Danbury, Connecticut 06813-1968 [email protected] Tel: 203-744-0100 Voice Mail 800-999-NORD (6673) Fax: 203-798-2291 National Tay-Sachs and Allied Diseases Association 2001 Beacon Street Suite 204 Boston, MAMÁ 02135 [email protected] Tel: 617-277-4463 800-90-NTSAD (906-8723) Fax: 617-277-0134 HTTP:// --National Institute of Neurological :Disorders and Stroke References Mandelli J, Wajner A, Pires RF, Giugliani R, Coelho JC. Detection of mucopolysaccharidosis type I heterozygotes based on the biochemical characteristics of leukocyte alpha-L-iduronidase. Arch Med Res 2002 Jan-Feb;33(1):20-4 Keeling KM, Brooks DA, Hopwood JJ, Li P, Thompson JN, Bedwell DM. Gentamicin-mediated suppression of Hurler syndrome stop mutations restores a low level of alpha-L-iduronidase activity and reduces lysosomal glycosaminoglycan accumulation. Hum Mol Genet 2001 Feb 1;10(3):291-9 HTTP:// --National Institute of Neurological Disorders and Stroke Notes The information in this outline was last updated in 2002. Este material ha sido importado de Wikilibros. "Asesoramiento genético"[ HTTP://] bajo la Licencia de Documentación Libre GNU. Se concede permiso para copiar, distribuir y/o modificar este documento bajo los términos de la Licencia de Documentación Libre GNU, Versión 1.2 o cualquier versión posterior publicada por la Free Software Foundation; sin secciones invariantes, sin textos de portada, y sin textos de contraportada. Se incluye una copia de la licencia en la sección titulada "Licencia de documentación libre GNU."

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