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Галактоземия

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 http://www.twolines.ru/publish/index.php?ELEMENT_ID=2438&backurl=%2Fpublish%2F

Что такое неонатальный скрининг? Как проводится обследование?
Неонатальный скрининг – массовое обследование новорожденных детей, один из эффективных способов выявления наиболее распространенных врожденных и наследственных заболеваний. Неонатальный скрининг начинается в родильном доме: у каждого новорожденного берется капля крови на специальный тест-бланк, который направляется в медико-генетическую консультацию для проведения исследования. В случае обнаружения в крови маркера заболевания родители с новорожденным ребенком приглашаются в медико-генетическую консультацию для проведения повторного исследования крови для подтверждения диагноза и назначения лечения. В дальнейшем ведется динамическое наблюдение за ребенком. Неонатальный скрининг позволяет обеспечить раннее выявление наследственных заболеваний и их своевременное лечение, остановить развитие тяжелых проявлений заболеваний (умственной отсталости, слепоты, карликовости и других), ведущих к инвалидизации.
На выявление каких врожденных и наследственных заболеваний направлено массовое обследование новорожденных детей?
В соответствии с международными рекомендациями в России на протяжении 15 лет проводится неонатальный скрининг на фенилкетонурию и врожденный гипотиреоз. 
В рамках реализации приоритетного национального проекта «Здоровье» (приказ Минздравсоцразвития России от 22.03.2006 г. №185 «О массовом обследовании новорожденных детей на наследственные заболевания») с 2006 года в неонатальный скрининг начато внедрение диагностики таких заболеваний, как адреногенитальный синдром, галактоземия и муковисцидоз.С 2007 года в перечень выявляемых заболеваний включен аудиологический скрининг детей первого года жизни, который позволит своевременно провести диагностику нарушений слуха у ребенка и последующую реабилитацию тугоухости.
В какие сроки предполагается внедрение обследования новорожденных на адреногенитальный синдром, галактоземию и муковисцидоз? Расширение программы неонатального скрининга на наследственные заболевания началось с июня 2006 года. За семь месяцев 2006 года на адреногенитальный синдром были обследованы 651 872 новорожденных, на муковисцидоз – 668 113 детей, на галактоземию 312 696. В 2007 году планируется обследование не менее 1,3 млн родившихся детей. Финансирование данного направления приоритетного национального проекта «Здоровье» в 2006 году составило 400 млн руб., расходы на 2007 год также запланированы в размере 400 млн руб.
Как часто диагностируются скринируемые заболевания и что делать в случае их обнаружения?
В 2006 году из числа обследованных детей был выявлен 71 случай адреногенитального синдрома, 56 случаев муковисцидоза, 5 случаев галактоземии. Детям начата специфическая терапия.
Почему именно эти пять заболеваний – фенилкетонурия, врожденный гипотиреоз, адреногенитальный синдром, галактоземия и муковисцидоз – были выбраны для проведения неонатального скрининга?
При выборе заболеваний для неонатального скрининга, в соответствии с рекомендациями Всемирной организации здравоохранения, учитывались такие факторы, как тяжесть проявления заболеваний, частота распространения данных заболеваний, а также простота и достоверность применяемых методов диагностики, наличие доступных и эффективных средств лечения. 

В каких регионах проводится массовое обследование новорожденных на адреногенитальный синдром, галактоземию и муковисцидоз дополнительно к фенилкетонурии и врожденному гипотиреозу? С 2006 года расширенный неонатальный скрининг был начат в 53 субъектах Российской Федерации. С 2007 года неонатальный скрининг на пять наследственных заболеваний (адреногенитальный синдром, галактоземия, муковисцидоз, фенилкетонурия и врожденный гипотиреоз) планируется проводить во всех субъектах Российской Федерации. Для обеспечения неонатального скрининга в 2006 году в 16 медико-генетических консультациях было заменено устаревшее оборудование, в 8 - установлены дополнительные лаборатории, в 5 – созданы новые лабораторные подразделения. Одновременно, для оптимизации исследования образцов крови новорожденных, в 36 медико-генетических консультаций были поставлены комплекты специальных автоматических устройств к лабораториям. Для 53 регионов были закуплены наборы тест-систем на адреногенитальный синдром, галактоземию и муковисцидоз в количестве 4 650 штук.
Проводится ли обучение специалистов для проведения расширенного неонатального скрининга?Да, в целях повышения квалификации и обучения специалистов с января по июнь 2006 года Российская медицинская академия последипломного образования Росздрава провела циклы занятий для специалистов медико-генетической службы, было обучено 135 врачей. Одновременно 249 врачей-педиатров, неонатологов и эндокринологов прошли обучение по вопросам неонатального скрининга, диагностики и лечения наследственных заболеваний на циклах тематического усовершенствования Московской медицинской академии им. И.М. Сеченова Росздрава.
По данным официального сайта Совета при Президенте России
по реализации приоритетных национальных проектов и демографической политике


J Pediatr. 2009 May;154(5):721-6. Epub 2009 Feb 1. Links

Outcomes of siblings with classical galactosemia.
Hughes J, Ryan S, Lambert D, Geoghegan O, Clark A, Rogers Y, Hendroff U, Monavari A, Twomey E, Treacy EP.
National Centre for Inherited Metabolic Disorders, Children's University Hospital, Dublin, Ireland.
OBJECTIVES: To determine the long-term outcome of dietary intervention in siblings from 14 Irish families with classical galactosemia (McKusick 230400), an autosomal recessive disorder of carbohydrate metabolism and galactose-1-phosphate uridyltransferase (GALT) deficiency. STUDY DESIGN: Outcomes in siblings on dietary galactose restriction were studied to evaluate whether birth order (ie, time of commencement of diet) and compliance with lactose-restricted diet (galactose intake > or < 20 mg /day), assessed by dietary recall and biochemical monitoring of galactose-1-phosphate [Gal-1-P] and galactitol values, affected outcomes. The outcome variables assessed were IQ, speech, and language assessment scores, neurologic examination results, and magnetic resonance imaging (MRI) of the brain. RESULTS: There was a high incidence of complications in the overall group, particularly speech and language delay (77%) and low IQ (71%). There was no significant difference in outcome between earlier-treated and later-treated siblings or any correlation with mean Gal-1-P or galactitol values. In most cases, cerebral white matter disease was evident on MRI scanning, with evidence of progressive cerebellar degeneration seen in 2 highly compliant families. CONCLUSION: The subjects with a higher galactose intake did not exhibit an increased incidence of complications; conversely, those who were very compliant with dietary restrictions did not have more favorable outcomes.
PMID: 19181333 [PubMed - in process]
IQ 70:30 

J Inherit Metab Dis. 2008 Aug;31(4):524-32. Epub 2008 Jul 12. Links

Correlates of language impairment in children with galactosaemia.
Potter NL, Lazarus JA, Johnson JM, Steiner RD, Shriberg LD.
Department of Speech and Hearing Sciences, Washington State University-Spokane, Spokane, Washington, USA. nlpotter@wsu.edu
PURPOSE: This study describes risk factors associated with language impairment in children with classic galactosaemia. METHOD: Thirty-three 4-16-year-old participants with classic galactosaemia and a history of speech sound disorders completed a battery of cognitive and language measures and their parents completed a family history questionnaire. RESULTS: Nine of the sixteen (56%) participants with typical cognitive development and 15 of the 17 (88%) with borderline-low cognitive development had language impairments. Participants with typical cognitive development more often had an expressive language disorder, whereas those with borderline-low cognitive development more often had a mixed receptive-expressive language disorder. Participants with Q188R/Q188R genotypes had increased risk for both cognitive and language impairments. The IQs of younger siblings who did not consume milk postnatally were 10-56 points higher than the IQs of their older siblings with galactosaemia who had consumed milk postnatally. However, 4 of 5 younger siblings who were lactose-restricted from birth had language impairments. Typically-reported risk factors for language disorder, including parental history of speech/learning problems and low parental education level, were not significantly associated with cognitive or language impairments in the present sample of children with galactosaemia. CONCLUSIONS: Children with galactosaemia and speech disorders have a 4-6 times greater risk for language impairment than children with early speech disorders of unknown origin. Early dietary lactose may increase the risk for cognitive and language impairments; however, the lack of significant associations of language impairment with days of milk consumption, and other familial and educational risk factors, is consistent with prenatal causation.
PMID: 18649009 [PubMed - indexed for MEDLINE]

Biosci Hypotheses. 2008;1(5):263-271. Links

ARHI: A new target of galactose toxicity in Classic Galactosemia.
Lai K, Tang M, Yin X, Klapper H, Wierenga K, Elsas L.
The Dr. John T. Macdonald Foundation Center for Medical Genetics, The Leonard M. Miller School of Medicine, University of Miami, Miami, FL33101, USA.
In humans, deficiency of galactose-1-phosphate uridyltransferase (GALT) activity can lead to a potentially lethal disease called Classic Galactosemia. Although a galactose-restricted diet can prevent the acute lethality associated with the disorder, chronic complications persist in many well-treated patients. Approximately 85% of young women with Classic Galactosemia experience hypergonadotropic hypogonadism and premature ovarian failure (POF). Others suffer from mental retardation, growth restriction, speech dyspraxia, and ataxia. Despite decades of intense biochemical characterization, little is known about the molecular etiology, as well as the chronology of the pathological events leading to the poor outcomes. Several hypotheses have been proposed, most of which involved the accumulation of the intermediates and/or the deficit of the products, of the blocked GALT pathway. However, none of these hypotheses satisfactorily explained the absence of patient phenotypes in the GALT-knockout mice. Here we proposed that the gene encoded the human tumor suppressor gene aplysia rashomolog I (ARHI) is a target of toxicity in Classic Galactosemia, and because ARHI gene is lost in rodents in through evolution, it thus accounts for the lack of clinical phenotypes in the GALT-knockout mice.
PMID: 19122833 [PubMed] 

Ann N Y Acad Sci. 2008;1135:112-7. Links

Galactosemia and amenorrhea in the adolescent.
Berry GT.
Division of Genetics, Children's Hospital Boston, Boston, Masschusetts 02115, USA. gerard.berry@childrens.harvard.edu
Hereditary galactosemia is a biochemical genetic disease due to a deficiency of galactose-1-phosphate uridyltransferase (GALT) enzyme activity (OMIM 606999). Acute manifestations occur in the neonatal period and are, with rare exceptions, related to lactose ingestion. They include poor feeding and growth, emesis, jaundice, liver disease, bleeding diathesis, anemia, renal tubulopathy, cataracts, encephalopathy and death from E. coli sepsis. Chronic manifestations, which also develop in prospectively treated patients, involve (a) the brain, resulting in delayed language acquisition, speech defects, and learning problems, and (b) the ovary, in the majority of females, producing hypergonadotropic hypogonadism. The serum FSH level is elevated in infancy/early childhood in many, but not all patients with a severe phenotype. There are few reports of patients with classic galactosemia having undergone pregnancy, labor, and delivery. The pathologic findings in the ovary, including a persistence of primordial follicles and streak gonads, have been variable. The etiology of primary ovarian insufficiency (POI) in galactosemia is unknown. Clinical surveillance includes screening for abnormalities in ovarian function at an early age. Treatment consists of estrogen/progesterone supplementation at the appropriate age. Reduced BMD has been reported. Future research is needed (1) to delineate the mechanisms behind reduced ovarian function in these young women; (2) to determine the timing of the lesion: prenatal, postnatal, and both pre- and postnatal; (3) to determine whether elevated galactose-1-phosphate is both necessary and sufficient to induce primary ovarian insufficiency; and (4) to understand the mechanism(s) behind the reduced BMD seen in children and adolescents with galactosemia.
PMID: 18574215 [PubMed - indexed for MEDLINE 

Obstet Gynecol Surv. 2008 May;63(5):334-43. Links

Fertility and impact of pregnancies on the mother and child in classic galactosemia.
Gubbels CS, Land JA, Rubio-Gozalbo ME.
Department of Pediatrics, University Hospital Maastricht, The Netherlands.
Despite the high prevalence of premature ovarian failure (POF) and subsequent infertility in galactosemic women, spontaneous pregnancies occur and may not be as rare as is generally assumed. This is important for counseling these women on fertility. The purpose of this review is to assess the occurrence and predicting factors of pregnancy, and to evaluate the impact of pregnancy on the mother's and child's health. The female Dutch galactosemia population (age > 18 years) was studied, and a literature search on articles reporting pregnancy in galactosemic women, published between January 1971 and December 2007, was performed. Twenty-two galactosemic women were studied. Nine women have tried to conceive, of which 4 were successful. Three mothers were diagnosed with POF before the first pregnancy and/or in between pregnancies. In literature, 50 pregnancy reports were found. In 10 pregnancy reports from the literature, the mother's genotype is known. Four women were homozygous for the Q188R mutation, which equals the incidence of 40-45% of classic galactosemia caused by this mutation. This study challenges the current opinion that the chance of becoming pregnant is small in classic galactosemia. Despite POF in most galactosemic women, pregnancies do occur. The genotype and GALT-activity do not seem to predict the chance of becoming pregnant, whereas the occurrence of spontaneous menarche might. No evidence for the need of additional check-ups during the pregnancy and puerperium was found. Elevations in galactose-metabolites do occur, but without evidence of clinical impact for the mother or the child, although possible long-term effects have not been thoroughly investigated. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to summarize the purported causes and sequelae of galactosemia, explain the possible sequelae of galactosemia, distinguish alterations of the ovary and the hypothalamic-pituitary axis, identify the frequency of pregnancy and the possible outcome of the offspring, and outline dietary management of patients with galactosemia.
PMID: 18419833 [PubMed - indexed for MEDLINE]
Tags: Галактоземия
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