scholarly journals Insights into the Pathophysiology of Infertility in Females with Classical Galactosaemia

2019 ◽  
Vol 20 (20) ◽  
pp. 5236 ◽  
Author(s):  
Zaza Abidin ◽  
Eileen P. Treacy
Keyword(s):  
Inborn Error ◽  
Primary Ovarian Insufficiency ◽  
Future Prospects ◽  
Ovarian Dysfunction ◽  
Galactose Metabolism ◽  
Ovarian Insufficiency ◽  
New Horizons ◽  
Classical Galactosaemia ◽  
Rare Inborn Error

Classical galactosaemia (CG) (OMIM 230400) is a rare inborn error of galactose metabolism caused by the deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT, EC 2.7.7.12). Primary ovarian insufficiency (POI) is the most common long-term complication experienced by females with CG, presenting with hypergonadotrophic hypoestrogenic infertility affecting at least 80% of females despite new-born screening and lifelong galactose dietary restriction. In this review, we describe the hypothesized pathophysiology of POI from CG, implications of timing of the ovarian dysfunction, and the new horizons and future prospects for treatments and fertility preservation.

scholarly journals Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Mendy M Welsink-Karssies ◽  
Sacha Ferdinandusse ◽  
Gert J Geurtsen ◽  
Carla E M Hollak ◽  
Hidde H Huidekoper ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Newborn Screening ◽  
Clinical Outcomes ◽  
Movement Disorders ◽  
Brain Mri ◽  
Primary Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Classical Galactosemia ◽  
Intellectual Outcome

Abstract Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G N-glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and N-glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 ± 14) and was <85 in 62%. Movement disorders were found in 17 (47%) of the 36 tested patients. In females aged 12 years and older, primary ovarian insufficiency was diagnosed in 12 (71%) of the 17 patients. Significant differences in N-glycan peaks were found between controls and patients. However, no significant differences in either N-glycans or galactose-1-phosphate levels were found between patients with a poor (intellectual outcome < 85) and normal intellectual outcome (intellectual outcome ≥ 85), and with or without movement disorders or primary ovarian insufficiency. The variant patients detected by newborn screening, with previously unknown geno- and phenotypes and currently no long-term complications, demonstrated significantly lower galactose-1-phospate levels than classical patients (P < 0.0005). Qualitative analysis of the MRI’s demonstrated brain abnormalities in 18 of the 21 patients, more severely in patients with a lower intellectual outcome and/or with movement disorders. This study demonstrates a large variability in clinical outcome, which varies from a below average intelligence, movement disorders and in females primary ovarian insufficiency to a normal clinical outcome. In our cohort of classical galactosemia patients, galactose-1-phosphate levels and N-glycan variations were not associated with clinical outcomes, but galactose-1-phosphate levels did differentiate between classical and variant patients detected by newborn screening. The correlation between brain abnormalities and clinical outcome should be further investigated by quantitative analysis of the MR images. The variability in clinical outcome necessitates individual and standardized evaluation of all classical galactosemia patients.

scholarly journals Rationale and design of a cohort study on primary ovarian insufficiency in female survivors of Hodgkin’s lymphoma: influence on long-term adverse effects (SOPHIA)

BMJ Open ◽  
2018 ◽  
Vol 8 (9) ◽  
pp. e018120
Author(s):  
Inge M Krul ◽  
Annemieke W J Opstal-van Winden ◽  
Josée M Zijlstra ◽  
Yolande Appelman ◽  
Sanne B Schagen ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Hodgkin’S Lymphoma ◽  
Primary Ovarian Insufficiency ◽  
Hodgkin's Lymphoma ◽  
Reverse Causality ◽  
Mineral Density ◽  
Cvd Risk ◽  
Ovarian Insufficiency

IntroductionHodgkin’s lymphoma (HL) has become the prototype of a curable disease. However, many young survivors suffer from late adverse effects of treatment. Both chemotherapy (CT) and radiotherapy (RT) may induce primary ovarian insufficiency (POI), which has been associated with reduced bone mineral density (BMD), neurocognitive dysfunction and possibly cardiovascular disease (CVD). While the general assumption is that POI increases CVD risk, other hypotheses postulate reverse causality, suggesting that cardiovascular risk factors determine menopausal age or that biological ageing underlies both POI and CVD risk. None of these hypotheses are supported by convincing evidence. Furthermore, most studies on POI-associated conditions have been conducted in women with early natural or surgery-induced menopause with short follow-up times. In this study, we will examine the long-term effects of CT-induced and/or RT-induced POI on BMD, cardiovascular status, neurocognitive function and quality of life in female HL survivors.Methods and analysisThis study will be performed within an existing Dutch cohort of HL survivors. Eligible women were treated for HL at ages 15–39 years in three large hospitals since 1965 and survived for ≥8 years after their diagnosis. Women visiting a survivorship care outpatient clinic will be invited for a neurocognitive, cardiovascular and BMD assessment, and asked to complete several questionnaires and to provide a blood sample. Using multivariable regression analyses, we will compare the outcomes of HL survivors who developed POI with those who did not. Cardiovascular status will also be compared with women with natural POI.Ethics and disseminationThis study has been approved by the Institutional Review Board of the Netherlands Cancer Institute and has been registered at ‘Toetsingonline’ from the Dutch Central Committee on Research involving Human Subjects (file no. NL44714.031.13). Results will be disseminated through peer-reviewed publications and will be incorporated in follow-up guidelines for HL survivors.

scholarly journals Uterine Cells Improved Ovarian Function in a Murine Model of Ovarian Insufficiency

2019 ◽  
Vol 26 (12) ◽  
pp. 1633-1639 ◽  
Author(s):  
Andres Reig ◽  
Ramanaiah Mamillapalli ◽  
Alexis Coolidge ◽  
Joshua Johnson ◽  
Hugh S. Taylor
Keyword(s):  
Stem Cells ◽  
Young Women ◽  
Murine Model ◽  
Ovarian Function ◽  
Fluorescent Protein ◽  
Primary Ovarian Insufficiency ◽  
Age Group ◽  
Ovarian Dysfunction ◽  
Ovarian Insufficiency ◽  
Green Fluorescent

Primary ovarian insufficiency (POI) is defined as ovarian dysfunction in women younger than 40 years. It affects 1% of the women in this age-group and can occur iatrogenically after chemotherapy. Stem cells have been used in attempt to restore ovarian function in POI. In particular, endometrial mesenchymal stem cells (eMSCs) are easily obtainable in humans and have shown great potential for regenerative medicine. Here, we studied the potential for uterine cell (UC) suspensions containing eMSCs to improve ovarian function in a murine model of chemotherapy-induced POI. Green fluorescent protein (GFP)-labeled UC or phosphate-buffered solution (PBS) was delivered intravenously after chemotherapy. There was a significant increase in oocytes production and serum anti-Müllerian hormone concentrations after 6 weeks, as well as a 19% higher body mass in UC-treated mice. Similarly, we observed an increased number of pups in mice treated with UC than in mice treated with PBS. None of the oocytes or pups incorporated GFP, suggesting that there was no contribution of these stem cells to the oocyte pool. We conclude that treatment with UC indirectly improved ovarian function in mice with chemotherapy-induced POI. Furthermore, our study suggests that endometrial stem cell therapy may be beneficial to young women who undergo ovotoxic chemotherapy.

Galactosaemia occurring in association with primary ovarian insufficiency, Addison’s disease and chronic myeloid leukaemia

2021 ◽  
Vol 14 (8) ◽  
pp. e244788
Author(s):  
Brandon Khoury ◽  
Mohamed KM Shakir ◽  
Thanh Duc Hoang
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Failure To Thrive ◽  
Primary Ovarian Insufficiency ◽  
Nutritional Deficiencies ◽  
Ovarian Insufficiency ◽  
Gonadal Dysfunction ◽  
Increased Risk ◽  
Severe Type

Classic galactosaemia is the most severe type, inherited in an autosomal recessive fashion and normally detected on newborn screening. It is caused by an inability to digest galactose due to a deficiency of galactose-1-phosphate uridyltransferase (GALT), resulting in an intolerance of feeds in the neonatal period, failure to thrive, hypoglycaemia, jaundice, cataracts, hepatomegaly, vomiting, diarrhoea, developmental delay and an increased risk of Escherichia coli sepsis. The long-term sequelae of this disorder include cognitive impairment, neurological symptoms, such as ataxia, nutritional deficiencies, such as calcium and vitamin D, and gonadal dysfunction. We report here a case of a 34-year-old woman with classic galactosaemia diagnosed in adulthood, developing primary ovarian insufficiency and osteoporosis as well as primary adrenal insufficiency and chronic myeloid leukaemia, which are two associations not seen in current literature. Further studies are needed to determine if an association exists between these diseases.

scholarly journals Pathophysiology and Management of Classic Galactosemic Primary Ovarian Insufficiency

2021 ◽  
Author(s):  
Synneva Hagen-Lillevik ◽  
John S. Rushing ◽  
Leslie Appiah ◽  
Nicola Longo ◽  
Ashley Andrews ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Young Women ◽  
Early Onset ◽  
Inborn Error ◽  
Primary Ovarian Insufficiency ◽  
Adolescent Patient ◽  
Clinical Practices ◽  
Ovarian Insufficiency ◽  
Classic Galactosemia ◽  
Galactose Metabolites

Classic Galactosemia is an inborn error of carbohydrate metabolism associated with early-onset primary ovarian insufficiency (POI) in young women. Our understanding of the consequences of galactosemia upon fertility and fecundity of affected women is expanding, but there are important remaining gaps in our knowledge and tools for management, and a need for continued dialogue so that the special features of the condition can be better managed. Here, we review galactosemic POI and its reproductive endocrinological clinical sequelae and summarize current best clinical practices for its management. Special consideration is given to the very early-onset nature of the condition in the pediatric/adolescent patient. Afterward, we summarize our current understanding of the reproductive pathophysiology of galactosemia, including the potential action of toxic galactose metabolites upon the ovary. Our work establishing that ovarian cellular stress reminiscent of endoplasmic reticulum (ER) stress is present in a mouse model of galactosemia, as well as work by other groups, are summarized.

scholarly journals Mitochondrial Dysfunction in Primary Ovarian Insufficiency

Endocrinology ◽  
2019 ◽  
Vol 160 (10) ◽  
pp. 2353-2366 ◽  
Author(s):  
Dov Tiosano ◽  
Jason A Mears ◽  
David A Buchner
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Sleep Disturbances ◽  
Single Gene ◽  
Hot Flashes ◽  
Primary Ovarian Insufficiency ◽  
Molecular Defect ◽  
Ovarian Insufficiency ◽  
Replication Gene

Abstract Primary ovarian insufficiency (POI) is defined by the loss or dysfunction of ovarian follicles associated with amenorrhea before the age of 40. Symptoms include hot flashes, sleep disturbances, and depression, as well as reduced fertility and increased long-term risk of cardiovascular disease. POI occurs in ∼1% to 2% of women, although the etiology of most cases remains unexplained. Approximately 10% to 20% of POI cases are due to mutations in a single gene or a chromosomal abnormality, which has provided considerable molecular insight into the biological underpinnings of POI. Many of the genes for which mutations have been associated with POI, either isolated or syndromic cases, function within mitochondria, including MRPS22, POLG, TWNK, LARS2, HARS2, AARS2, CLPP, and LRPPRC. Collectively, these genes play roles in mitochondrial DNA replication, gene expression, and protein synthesis and degradation. Although mutations in these genes clearly implicate mitochondrial dysfunction in rare cases of POI, data are scant as to whether these genes in particular, and mitochondrial dysfunction in general, contribute to most POI cases that lack a known etiology. Further studies are needed to better elucidate the contribution of mitochondria to POI and determine whether there is a common molecular defect in mitochondrial function that distinguishes mitochondria-related genes that when mutated cause POI vs those that do not. Nonetheless, the clear implication of mitochondrial dysfunction in POI suggests that manipulation of mitochondrial function represents an important therapeutic target for the treatment or prevention of POI.

Ovarian Dysfunction in Fetally Irradiated Beagles

1977 ◽  
Vol 35 ◽  
pp. 658-659
Author(s):  
T. M. Seed ◽  
M. H. Sanderson ◽  
D. L. Gutzeit ◽  
T. E. Fritz ◽  
D. V. Tolle ◽  
...  
Keyword(s):  
Gamma Rays ◽  
Low Dose ◽  
Long Term Effects ◽  
Ovarian Dysfunction ◽  
Dose Rates ◽  
Highly Sensitive ◽  
Microscopic Evaluation ◽  
Ovarian Pathology ◽  
Normal Offspring

The developing mammalian fetus is thought to be highly sensitive to ionizing radiation. However, dose, dose-rate relationships are not well established, especially the long term effects of protracted, low-dose exposure. A previous report (1) has indicated that bred beagle bitches exposed to daily doses of 5 to 35 R 60Co gamma rays throughout gestation can produce viable, seemingly normal offspring. Puppies irradiated in utero are distinguishable from controls only by their smaller size, dental abnormalities, and, in adulthood, by their inability to bear young.We report here our preliminary microscopic evaluation of ovarian pathology in young pups continuously irradiated throughout gestation at daily (22 h/day) dose rates of either 0.4, 1.0, 2.5, or 5.0 R/day of gamma rays from an attenuated 60Co source. Pups from non-irradiated bitches served as controls. Experimental animals were evaluated clinically and hematologically (control + 5.0 R/day pups) at regular intervals.

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