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2.
J Perinatol ; 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395954

RESUMO

OBJECTIVE: To determine the proportion of infant deaths occurring in the setting of a confirmed genetic disorder. STUDY DESIGN: A retrospective analysis of the electronic medical records of infants born from 1 January, 2011 to 1 June, 2017, who died prior to 1 year of age. RESULTS: Five hundred and seventy three deceased infants were identified. One hundred and seventeen were confirmed to have a molecular or cytogenetic diagnosis in a clinical diagnostic laboratory and an additional seven were diagnosed by research testing for a total of 124/573 (22%) diagnosed infants. A total of 67/124 (54%) had chromosomal disorders and 58/124 (47%) had single gene disorders (one infant had both). The proportion of diagnoses made by sequencing technologies, such as exome sequencing, increased over the years. CONCLUSIONS: The prevalence of confirmed genetic disorders within our cohort of infant deaths is higher than that previously reported. Increased efforts are needed to further understand the mortality burden of genetic disorders in infancy.

3.
Am J Hum Genet ; 105(2): 413-424, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31327508

RESUMO

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.

4.
Eur J Hum Genet ; 27(9): 1398-1405, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30979967

RESUMO

Clinical exome sequencing (CES) is increasingly being utilized; however, a large proportion of patients remain undiagnosed, creating a need for a systematic approach to increase the diagnostic yield. We have reanalyzed CES data for a clinically heterogeneous cohort of 102 probands with likely Mendelian conditions, including 74 negative cases and 28 cases with candidate variants, but reanalysis requested by clinicians. Reanalysis was performed by an interdisciplinary team using a validated custom-built pipeline, "Variant Explorer Pipeline" (VExP). This reanalysis approach and results were compared with existing literature. Reanalysis of candidate variants from CES in 28 cases revealed 1 interpretation that needed to be reclassified. A confirmed or potential genetic diagnosis was identified in 24 of 75 CES-negative/reclassified cases (32.0%), including variants in known disease-causing genes (n = 6) or candidate genes (n = 18). This yield was higher compared with similar studies demonstrating the utility of this approach. In summary, reanalysis of negative CES in a research setting enhances diagnostic yield by about a third. This study suggests the need for comprehensive, continued reanalysis of exome data when molecular diagnosis is elusive.

5.
Mol Genet Metab ; 126(4): 368-376, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718057

RESUMO

BACKGROUND: GALT deficiency is a rare genetic disorder of carbohydrate metabolism. Due to the decreased activity or absence of the enzyme galactose-1-phosphate uridylyltransferase (GALT), cells from affected individuals are unable to metabolize galactose normally. Lactose consumption in the newborn period could potentially lead to a lethal disease process with multi-organ involvement. In contrast to the newborn-stage disease, however, a galactose-restricted diet does not prevent long-term complications such as central nervous system (CNS) dysfunction with speech defects, learning disability and neurological disease in addition to hypergonadotropic hypogonadism or primary ovarian insufficiency (POI) in females. As the literature suggests an association between GALT enzyme activity and the long-term complications, it is of importance to have a highly sensitive assay to quantify the GALT enzyme activity. To that end, we had developed a sensitive and accurate LC-MS/MS method to measure GALT enzyme activity. Its ability to predict outcome is the subject of this report. MATERIALS AND METHODS: The GALT enzyme activity in erythrocytes from 160 individuals, in which 135 with classic, clinical variant or biochemical variant galactosemia, was quantified by LC-MS/MS. Individuals with GALT deficiency were evaluated for the long-term complications of speech defects, dysarthria, ataxia, dystonia, tremor, POI, as well as intellectual functioning (full scale IQ). The LC-MS/MS results were compared to a variety of assays: radioactive, [14C]-galactose-1-phosphate, paper chromatography with scintillation counting, enzyme-coupled assays with spectrophotometric or fluorometric readout or high-pressure liquid chromatography with UV detection of UDP-galactose. RESULTS: The LC-MS/MS method measured GALT activity as low as 0.2%, whereas other methods showed no detectable activity. Largely due to GALT activities that were over 1%, the LC-MS/MS measurements were not significantly different than values obtained in other laboratories using other methodologies. Severe long-term complications were less frequently noted in subjects with >1% activity. Patients with a p.Q188R/p.Q188R genotype have no residual enzyme activity in erythrocytes. CONCLUSION: Our LC-MS/MS assay may be necessary to accurately quantify residual GALT activities below 5%. The data suggest that patients with >1% residual activity are less likely to develop diet-independent long-term complications. However, much larger sample sizes are needed to properly assess the clinical phenotype in patients with residual enzyme activities between 0.1 and 5%.

6.
Fertil Steril ; 108(1): 168-174, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28579413

RESUMO

OBJECTIVE: To study pregnancy chance in adult women with classic galactosemia and primary ovarian insufficiency. Despite dietary treatment, >90% of women with classic galactosemia develop primary ovarian insufficiency, resulting in impaired fertility. For many years, chance of spontaneous conception has not been considered, leading to counseling for infertility. But an increasing number of reports on pregnancies in this group questions whether current counseling approaches are correct. DESIGN: Multicenter retrospective observational study. SETTING: Metabolic centers. PATIENT(S): Adult women (aged >18 y) with confirmed classic galactosemia and primary ovarian insufficiency were included. INTERVENTION(S): Participants and medical records were consulted to obtain study data in a standardized manner with the use of a questionnaire. MAIN OUTCOME MEASURE(S): Conception opportunities, time to pregnancy, pregnancy outcome, hormone replacement therapy use, fertility counseling, and the participants' vision of fertility were evaluated. Potential predictive factors for increased pregnancy chance were explored. RESULT(S): Eighty-five women with classic galactosemia and primary ovarian insufficiency participated. Twenty-one women actively attempted to conceive or did not take adequate contraceptive precautions. Of these 21 women, nine became pregnant spontaneously (42.9%). This was higher than reported in primary ovarian insufficiency due to other causes (5%-10%). After a period of 12 months, a cumulative proportion of 27.8% of couples had conceived, which increased to 48.4% after 24 months and 61.3% after 27 months. Predictive factors could not be identified. A considerable miscarriage rate of 30% was observed (6 of 20 pregnancies). Although a substantial proportion of women expressed a child-wish (n = 28/53; 52.8%), the vast majority of participants (n = 43/57; 75.4%) considered conceiving to be highly unlikely, owing to negative counseling in the past. CONCLUSION(S): The pregnancy rate in women with classic galactosemia and primary ovarian insufficiency was higher than for women with primary ovarian insufficiency of any cause. This shifting paradigm carries significant implications for fertility counseling and potential application of fertility preservation techniques.


Assuntos
Galactosemias/epidemiologia , Infertilidade Feminina/epidemiologia , Infertilidade Feminina/terapia , Complicações na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Insuficiência Ovariana Primária/epidemiologia , Adolescente , Adulto , Comorbidade , Feminino , Galactosemias/diagnóstico , Humanos , Incidência , Infertilidade Feminina/diagnóstico , Pessoa de Meia-Idade , Gravidez , Complicações na Gravidez/diagnóstico , Insuficiência Ovariana Primária/diagnóstico , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
7.
J Child Neurol ; 32(9): 840-845, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28545339

RESUMO

ACO2 encodes aconitase 2, catalyzing the second step of the tricarboxylic acid. To date, there are only 6 reported families with 5 unique ACO2 mutations. Affected individuals can develop intellectual disability, epilepsy, brain atrophy, hypotonia, ataxia, optic atrophy, and retinal degeneration. Here, we report an 18-year-old boy with a novel ACO2 variant discovered on whole-exome sequencing. He presented with childhood-onset ataxia, impaired self-help skills comparable to severe-profound intellectual disability, intractable epilepsy, cerebellar atrophy, peripheral neuropathy, optic atrophy, and pigmentary retinopathy. His variant is the sixth unique ACO2 mutation. In addition, compared to mild cases (isolated optic atrophy) and severe cases (infantile death), our patient may be moderately affected, evident by increased survival and some preserved cognition (ability to speak full sentences and follow commands), which is a novel presentation. This case expands the disease spectrum to include increased survival with partly spared cognition.


Assuntos
Aconitato Hidratase/genética , Ataxia/genética , Deficiência Intelectual/genética , Retinite Pigmentosa/genética , Adolescente , Ataxia/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Mutação da Fase de Leitura , Humanos , Deficiência Intelectual/diagnóstico por imagem , Masculino , Mutação de Sentido Incorreto , Fenótipo , Retina/patologia , Retinite Pigmentosa/patologia
8.
J Inherit Metab Dis ; 40(2): 171-176, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27858262

RESUMO

Classical galactosemia (CG) is an inborn error of galactose metabolism. Evidence-based guidelines for the treatment and follow-up of CG are currently lacking, and treatment and follow-up have been demonstrated to vary worldwide. To provide patients around the world the same state-of-the-art in care, members of The Galactosemia Network (GalNet) developed an evidence-based and internationally applicable guideline for the diagnosis, treatment, and follow-up of CG. The guideline was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. A systematic review of the literature was performed, after key questions were formulated during an initial GalNet meeting. The first author and one of the working group experts conducted data-extraction. All experts were involved in data-extraction. Quality of the body of evidence was evaluated and recommendations were formulated. Whenever possible recommendations were evidence-based, if not they were based on expert opinion. Consensus was reached by multiple conference calls, consensus rounds via e-mail and a final consensus meeting. Recommendations addressing diagnosis, dietary treatment, biochemical monitoring, and follow-up of clinical complications were formulated. For all recommendations but one, full consensus was reached. A 93 % consensus was reached on the recommendation addressing age at start of bone density screening. During the development of this guideline, gaps of knowledge were identified in most fields of interest, foremost in the fields of treatment and follow-up.


Assuntos
Galactosemias/diagnóstico , Galactosemias/tratamento farmacológico , Medicina Baseada em Evidências/métodos , Seguimentos , Galactose/metabolismo , Galactosemias/metabolismo , Humanos , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/tratamento farmacológico
9.
Am J Med Genet A ; 170(9): 2265-73, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27282546

RESUMO

Mutations in BRAT1, encoding BRCA1-associated ATM activator 1, are associated with a severe phenotype known as rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL; OMIM # 614498), characterized by intractable seizures, hypertonia, autonomic instability, and early death. We expand the phenotypic spectrum of BRAT1 related disorders by reporting on four individuals with various BRAT1 mutations resulting in clinical severity that is either mild or moderate compared to the severe phenotype seen in RMFSL. Representing mild severity are three individuals (Patients 1-3), who are girls (including two sisters, Patients 1-2) between 4 and 10 years old, with subtle dysmorphisms, intellectual disability, ataxia or dyspraxia, and cerebellar atrophy on brain MRI; additionally, Patient 3 has well-controlled epilepsy and microcephaly. Representing moderate severity is a 15-month-old boy (Patient 4) with severe global developmental delay, refractory epilepsy, microcephaly, spasticity, hyperkinetic movements, dysautonomia, and chronic lung disease. In contrast to RMFSL, his seizure onset occurred later at 4 months of age, and he is still alive. All four of the individuals have compound heterozygous BRAT1 mutations discovered via whole exome sequencing: c.638dupA (p.Val214Glyfs*189); c.803+1G>C (splice site mutation) in Patients 1-2; c.638dupA (p.Val214Glyfs*189); c.419T>C (p.Leu140Pro) in Patient 3; and c.171delG (p.Glu57Aspfs*7); c.419T>C (p.Leu140Pro) in Patient 4. Only the c.638dupA (p.Val214Glyfs*189) mutation has been previously reported in association with RMFSL. These patients illustrate that, compared with RMFSL, BRAT1 mutations can result in both moderately severe presentations evident by later-onset epilepsy and survival past infancy, as well as milder presentations that include intellectual disability, ataxia/dyspraxia, and cerebellar atrophy. © 2016 Wiley Periodicals, Inc.


Assuntos
Estudos de Associação Genética , Mutação , Proteínas Nucleares/genética , Fenótipo , Encéfalo/patologia , Cerebelo/anormalidades , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Epilepsia/diagnóstico , Epilepsia/genética , Exoma , Facies , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Imagem por Ressonância Magnética , Masculino , Linhagem , Índice de Gravidade de Doença
10.
Fam Cancer ; 13(3): 469-75, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24633857

RESUMO

Pilot study to evaluate whether the use of a standardized questionnaire to document family history of cancer improves identification of women who warrant referral to cancer genetic services (CGS) for increased risk of hereditary cancer, compared to their identification in usual care. Prospective intervention study with historic control group. Gynecology outpatient clinic, Maastricht University Medical Centre, the Netherlands. The prospective intervention group consisted of new outpatients between June 1 and August 1, 2011. The historic control group consisted of new outpatients between May 1, 2009 and April 30, 2010. A standardized questionnaire based on established referral criteria for hereditary breast/ovarian cancer and Lynch syndrome was completed for the intervention group. The referral rate in routine consultation, based on non-standardized family history recording, was determined retrospectively for the control group. The difference in referral rate between intervention and control group, tested by Chi square test. In the control group, 8 of 3,036 women (0.26 %) were referred to CGS. In the intervention group, 209 (42 %) of 500 screening questionnaires were completed. Nineteen women (9, 1 %) met the referral guidelines, of which 5 were newly referred to CGS (2, 4 %). Referral rates differed significantly (p < 0.001) between the two groups. This pilot study shows that the routine use of a screening questionnaire may improve detection and referral rate to CGS of individuals at risk for hereditary cancer. Improving genetic literacy of physicians and use of web-site questionnaires deserve attention in future studies.


Assuntos
Neoplasias dos Genitais Femininos/diagnóstico , Neoplasias dos Genitais Femininos/genética , Anamnese/métodos , Encaminhamento e Consulta , Inquéritos e Questionários , Adulto , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Projetos Piloto
11.
Orphanet J Rare Dis ; 8: 107, 2013 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-23866841

RESUMO

Almost every female classic galactosemia patient develops primary ovarian insufficiency (POI) as a diet-independent complication of the disease. This is a major concern for patients and their parents, and physicians are often asked about possible options to preserve fertility. Unfortunately, there are no recommendations on fertility preservation in this group. The unique pathophysiology of classic galactosemia with a severely reduced follicle pool at an early age requires an adjusted approach. In this article recommendations for physicians based on current knowledge concerning galactosemia and fertility preservation are made. Fertility preservation is only likely to be successful in very young prepubertal patients. In this group, cryopreservation of ovarian tissue is currently the only available technique. However, this technique is not ready for clinical application, it is considered experimental and reduces the ovarian reserve. Fertility preservation at an early age also raises ethical questions that should be taken into account. In addition, spontaneous conception despite POI is well described in classic galactosemia. The uncertainty surrounding fertility preservation and the significant chance of spontaneous pregnancy warrant counseling towards conservative application of these techniques. We propose that fertility preservation should only be offered with appropriate institutional research ethics approval to classic galactosemia girls at a young prepubertal age.


Assuntos
Preservação da Fertilidade , Galactosemias/patologia , Criopreservação/métodos , Feminino , Fertilidade/fisiologia , Humanos , Gravidez , Insuficiência Ovariana Primária/patologia
12.
J Inherit Metab Dis ; 36(1): 29-34, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22729817

RESUMO

FSH inactivity due to secondary hypoglycosylation has been suggested as a potential mechanism for primary ovarian insufficiency in classic galactosemia. To investigate the role of FSH and to gain insight in the timing of the damage, ovarian stimulation tests were performed and data on ovarian imaging collected. Fifteen patients with primary ovarian insufficiency underwent ovarian stimulation with gonadotropins. Only one patient showed a normal increase in estradiol level, all the others had a low or no estradiol response. Anti-Müllerian hormone measurement in all girls and women showed levels below the detection limit of 0.10 µg/l. Ovarian volumes were evaluated by MRI in 14 patients and compared to age matched controls, prepubertal controls and postmenopausal controls. The ovarian volumes of the galactosemic girls were smaller than those of the age matched controls (p = 0.001) and the prepubertal ovaries (p = 0.008), and did not differ significantly from postmenopausal ovarian volumes (p = 0.161). In conclusion we found no evidence that FSH inactivity plays a role in primary ovarian insufficiency in classic galactosemia. Moreover, ovarian imaging results point to an early onset of ovarian failure in this disease.


Assuntos
Hormônio Foliculoestimulante/metabolismo , Galactosemias/fisiopatologia , Insuficiência Ovariana Primária/fisiopatologia , Adolescente , Adulto , Hormônio Antimülleriano/metabolismo , Criança , Feminino , Galactosemias/metabolismo , Gonadotropinas/metabolismo , Humanos , Ovário/metabolismo , Ovário/fisiopatologia , Insuficiência Ovariana Primária/metabolismo , Adulto Jovem
13.
J Inherit Metab Dis ; 36(5): 779-86, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23053469

RESUMO

Previous studies examining reproductive parameters in men with galactosemia have inconsistently demonstrated abnormalities. We hypothesized that men with galactosemia may demonstrate evidence of reproductive dysfunction. Pubertal history, physical examination, hormone levels and semen analyses were examined in 26 males with galactosemia and compared to those in 46 controls. The prevalence of cryptorchidism was higher in men with galactosemia than in the general population [11.6% vs. 1.0% (95%CI: 0.75-1.26; p <0.001)]. Testosterone (461±125 vs. 532± 33 ng%; p=0.04), inhibin B (144±66 vs. 183±52 pg/mL; p=0.002) and sperm concentration (46±36 vs. 112±75×10(6) spermatozoa/mL; p=0.01) were lower and SHBG was higher (40.7±21.5 vs 26.7±14.6; p=0.002) in men with galactosemia compared to controls. Semen volume was below normal in seven out of 12 men with galactosemia. Men with galactosemia have a higher than expected prevalence of cryptorchidism and low semen volumes. The subtle decrease in testosterone and inhibin B levels and sperm count may indicate mild defects in Sertoli and Leydig cell function, but does not point towards severe infertility causing reproductive impairment. Follow-up studies are needed to further determine the clinical consequences of these abnormalities.


Assuntos
Criptorquidismo/fisiopatologia , Galactosemias/fisiopatologia , Reprodução/fisiologia , Adulto , Criptorquidismo/metabolismo , Galactosemias/sangue , Galactosemias/metabolismo , Humanos , Inibinas/metabolismo , Masculino , Pessoa de Meia-Idade , Sêmen/metabolismo , Sêmen/fisiologia , Contagem de Espermatozoides/métodos , Testosterona/metabolismo , Adulto Jovem
14.
J Inherit Metab Dis ; 35(2): 279-86, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21779791

RESUMO

BACKGROUND: Classic galactosemia is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase (GALT) deficiency. Newborn screening and early treatment do not completely prevent tremor, speech deficits, and diminished IQ in both sexes and premature ovarian insufficiency (POI) in women. Data on how individuals with galactosemia fare as adults will improve our ability to predict disease progression. METHODS: Thirty-three adults (mean age = 32.6 ± 11.7 years; range = 18-59) with classic galactosemia, confirmed by genotype and undetectable GALT enzyme activity, were evaluated. Analyses assessed associations among age, genotype, clinical features and laboratory measures. RESULTS: The sample included 17 men and 16 women. Subjects exhibited cataracts (21%), low bone density (24%), tremor (46%), ataxia (15%), dysarthria (24%), and apraxia of speech (9%). Subjects reported depression (39%) and anxiety (67%). Mean full scale IQ was 88 ± 20, (range = 55-122). All subjects followed a dairy-free diet and 75-80% reported low intake of calcium and vitamin D. Mean height, weight and body mass were within established norms. All female subjects had been diagnosed with POI. One woman and two men had had children. Logistic regression analyses revealed no associations between age, genotype or gender with IQ, tremor, ataxia, dysarthria, apraxia of speech or anxiety. Each 10- year increment of age was associated with a twofold increase in odds of depression. CONCLUSIONS: Taken together, these data do not support the hypothesis that galactosemia is a progressive neurodegenerative disease. However, greater attention to depression, anxiety, and social relationships may relieve the impact of this disorder in adults.


Assuntos
Galactosemias/diagnóstico , Adolescente , Adulto , Progressão da Doença , Feminino , Galactosemias/enzimologia , Galactosemias/genética , Genótipo , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Triagem Neonatal/métodos , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Fenótipo , UTP-Hexose-1-Fosfato Uridililtransferase/deficiência , UTP-Hexose-1-Fosfato Uridililtransferase/genética , Adulto Jovem
15.
J Inherit Metab Dis ; 34(2): 357-66, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20978943

RESUMO

Primary or premature ovarian insufficiency (POI) is the most common long-term complication experienced by girls and women with classic galactosemia; more than 80% and perhaps more than 90% are affected despite neonatal diagnosis and careful lifelong dietary restriction of galactose. In this review we explore the complexities of timing and detection of galactosemia-associated POI and discuss potential underlying mechanisms. Finally, we offer recommendations for follow-up care with current options for intervention.


Assuntos
Galactosemias/diagnóstico , Galactosemias/genética , Adolescente , Adulto , Animais , Criança , Epigênese Genética , Escherichia coli/metabolismo , Feminino , Hormônio Foliculoestimulante/metabolismo , Galactose/metabolismo , Humanos , Ovário/patologia , Insuficiência Ovariana Primária/genética , Puberdade , Sepse/genética
16.
J Inherit Metab Dis ; 34(2): 387-90, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20814826

RESUMO

Female classic galactosemia patients suffer from primary ovarian insufficiency (POI). The cause for this long-term complication is not fully understood. One of the proposed mechanisms is that hypoglycosylation of complex molecules, a known secondary phenomenon of galactosemia, leads to FSH dysfunction. An earlier study showed less acidic isoforms of FSH in serum samples of two classic galactosemia patients compared to controls, indicating hypoglycosylation. In this study, FSH isoform patterns of five classic galactosemia patients with POI were compared to the pattern obtained in two patients with a primary glycosylation disorder (phosphomannomutase-2-deficient congenital disorders of glycosylation, PMM2-CDG) and POI, and in five postmenopausal women as controls. We used FPLC chromatofocussing with measurement of FSH concentration per fraction, and discovered that there were no significant differences between galactosemia patients, PMM2-CDG patients and postmenopausal controls. Our results do not support that FSH dysfunction due to a less acidic isoform pattern because of hypoglycosylation is a key mechanism of POI in this disease.


Assuntos
Hormônio Foliculoestimulante/sangue , Hormônio Foliculoestimulante/química , Galactosemias/sangue , Idoso , Estudos de Casos e Controles , Cromatografia/métodos , Feminino , Galactosemias/complicações , Glicosilação , Humanos , Concentração de Íons de Hidrogênio , Pessoa de Meia-Idade , Pós-Menopausa , Insuficiência Ovariana Primária/sangue , Insuficiência Ovariana Primária/complicações , Isoformas de Proteínas
17.
Fertil Steril ; 91(4): 1293.e13-6, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19200962

RESUMO

OBJECTIVE: To report a pregnancy in a patient with classic galactosemia despite signs of no ovarian reserve to draw attention to the limited predictive value of ovarian reserve tests in these patients. DESIGN: Case report. SETTING: Secondary and tertiary care center. PATIENT(S): A patient with classic galactosemia with premature ovarian failure and two previous pregnancies. INTERVENTION(S): Exogenous FSH ovarian reserve test and anti-Müllerian hormone (AMH) measurement. MAIN OUTCOME MEASURE(S): 17beta-Estradiol response, AMH level. RESULT(S): Pregnancy despite undetectable AMH (<0.1 microg/L) and no E(2) response (exogenous FSH ovarian reserve test). CONCLUSION(S): Fluctuating premature ovarian failure makes fertility counseling of patients with classic galactosemia difficult. Commonly used ovarian function and reserve tests seem to have no significance.


Assuntos
Hormônio Antimülleriano/análise , Galactosemias/diagnóstico , Complicações na Gravidez/diagnóstico , Adulto , Hormônio Antimülleriano/sangue , Técnicas de Diagnóstico Endócrino , Feminino , Galactosemias/sangue , Galactosemias/complicações , Número de Gestações , Humanos , Gravidez , Complicações na Gravidez/sangue , Insuficiência Ovariana Primária/sangue , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/etiologia
18.
Obstet Gynecol Surv ; 63(5): 334-43, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18419833

RESUMO

UNLABELLED: 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.


Assuntos
Fertilidade , Galactosemias/diagnóstico , Galactosemias/terapia , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/terapia , Feminino , Galactosemias/complicações , Aconselhamento Genético , Humanos , Gravidez , Complicações na Gravidez/etiologia , Cuidado Pré-Natal
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