Current and Future Treatments for Classic Galactosemia.
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ABSTRACT:
SUBMITTER: Delnoy B
PROVIDER: S-EPMC7911353 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Classic galactosemia is an inborn error of the metabolism with devastating consequences. Newborn screening has been successful in markedly reducing the acute neonatal symptoms from this disorder. The dramatic response to dietary treatment is one of the major success stories of newborn screening. However, as children with galactosemia achieve adulthood, they face long-term complications. A majority of women with classic galactosemia develop primary ovarian insufficiency and resulting morbidity. The underlying pathophysiology of this complication is not clear. This review focuses on the reproductive issues seen in girls and women with classic galactosemia. Literature on the effects of classic galactosemia on the female reproductive system was reviewed by an extensive Pubmed search (publications from January 1975 to January 2017) using the keywords: galactosemia, ovarian function/dysfunction, primary ovarian insufficiency/failure, FSH, oxidative stress, fertility preservation. In addition, articles cited in the search articles and literature known to the authors was also included in the review. Our understanding of the role of galactose metabolism in the ovary is limited and the pathogenic mechanisms involved in causing primary ovarian insufficiency are unclear. The relative rarity of galactosemia makes it difficult to accumulate data to determine factors defining timing of ovarian dysfunction or treatment/fertility preservation options for this group of women. In this review, we present reproductive challenges faced by women with classic galactosemia, highlight the gaps in our understanding of mechanisms leading to primary ovarian insufficiency in this population, discuss new advances in fertility preservation options, and recommend collaboration between reproductive medicine and metabolic specialists to improve fertility in these women.
| S-EPMC5758462 | biostudies-literature
Project description:Classic galactosemia (CG) is an autosomal recessive disorder of galactose metabolism that affects approximately 1/50,000 live births in the USA. Following exposure to milk, which contains large quantities of galactose, affected infants may become seriously ill. Early identification by newborn screening with immediate dietary galactose restriction minimizes or prevents the potentially lethal acute symptoms of CG. However, more than half of individuals with CG still experience long-term complications including cognitive disability, behavioral problems, and speech impairment. Anecdotal reports have also suggested frequent gastrointestinal (GI) problems, but this outcome has not been systematically addressed. In this study we explored the prevalence of GI symptoms among 183 children and adults with CG (cases) and 190 controls. Cases reported 4.5 times more frequent constipation (95% CI 1.8-11.5) and 4.2 times more frequent nausea (95% CI 1.2-15.5) than controls. Cases with genotypes predicting residual GALT activity reported less frequent constipation than cases without predicted GALT activity but this difference was not statistically significant. Because the rigor of dietary galactose restriction varies among individuals with galactosemia, we further tested whether GI symptoms associated with diet in infancy. Though constipation was almost four times as common among cases reporting a more restrictive diet in infancy, this difference was not statistically significant. These data confirm that certain GI symptoms are more common in classic galactosemia compared to controls and suggest that future studies should investigate associations with residual GALT activity and dietary galactose restriction in early life.
| S-EPMC5413454 | biostudies-literature
Project description: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.
| S-EPMC3063565 | biostudies-literature
Project description:Classic galactosemia is a rare inborn error of galactose metabolism with a birth prevalence of about 1/30,000-60,000. Long-term complications occurring despite dietary treatment consist of premature ovarian insufficiency (POI) and neurodevelopmental impairments. We performed with the French Reference Centers for Rare Diseases a multisite collaborative questionnaire survey for classic galactosemic patients. Its primary objective was to assess their puberty, pregnancy, gonadotropic axis, and pelvic morphology by ultrasound. The secondary objective was to determine predictive factors for pregnancy without oocyte donation. Completed questionnaires from 103 patients, 56 females (median age, 19 years (3-52 years)) and 47 males (median age, 19 years (3-45 years)), were analyzed. Among the 43 females older than 13 years old, mean age for breast development first stage was 13.8 years; spontaneous menarche occurred in 21/31 females at a mean age of 14.6 years. In these 21 women, 62% had spaniomenorrhea and 7/17 older than 30 years had amenorrhea. All age-groups confounded, FSH was above reference range for 65.7% of the patients, anti-Müllerian hormone and inhibin B were undetectable, and the ovaries were small with few or no follicles detected. Among the 5 females who sought to conceive, 4 had pregnancies. Among the 47 males, 1 had cryptorchidism, all have normal testicular function and none had a desire to conceive children. Thus, spontaneous puberty and POI are both common in this population. Spontaneous menarche seems to be the best predictive factor for successful spontaneous pregnancy.
| S-EPMC7983486 | biostudies-literature
Project description:Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge. Several proposed disease mechanisms are discussed, as well as the time of damage and potential treatment options. Furthermore, we combine data from longitudinal, cross-sectional and retrospective studies with the observations of specialist teams treating this disease to depict the brain disease course over time. Based on current data and insights, the majority of patients do not exhibit cognitive decline. A subset of patients, often with early onset cerebral and cerebellar volume loss, can nevertheless experience neurological worsening. While a large number of patients with CG suffer from anxiety and depression, the increased complaints about memory loss, anxiety and depression at an older age are likely multifactorial in origin.
| S-EPMC10902464 | biostudies-literature
Project description:Purpose To test the hypothesis that children with classic galactosemia and speech disorders are at risk for co-occurring strength and coordination disorders. Method This is a case-control study of 32 children (66% male) with galactosemia and neurologic speech disorders and 130 controls (50% male) ages 4-16 years. Speech was assessed using the Percentage of Consonants Correct (PCC) metric from responses to the Goldman-Fristoe Test of Articulation-2 and from a 5-min recorded speech sample, hand and tongue strength using the Iowa Oral Performance Instrument, and coordination using the Movement Assessment Battery for Children. The number of days on milk during the neonatal period was obtained by parent report. Analyses of covariance, distributions, and correlations were used to evaluate relationships among speech, strength, coordination, age, gender, and days on milk. Results Children with galactosemia had weaker hand and tongue strength and most (66%) had significant coordination disorders, primarily affecting balance and manual dexterity. Among children with galactosemia, children with more speech errors and classified as childhood apraxia of speech (n = 7) and ataxic dysarthria (n = 1), had poorer balance and manual dexterity, but not weaker hand or tongue strength, compared to the children with fewer speech errors. The number of days on milk during the neonatal period was associated with more speech errors in males but not in females. Conclusion Children with galactosemia have a high prevalence of co-occurring speech, coordination, and strength disorders, which may be evidence of a common underlying etiology, likely associated with diffuse cerebellar damage, rather than distinct disorders.
| S-EPMC3755563 | biostudies-literature
Project description:Classic galactosemia (CG) is a rare inborn error of metabolism that results from profound deficiency of galactose-1-P uridylyltransferase (GALT). Despite early detection and rapid and lifelong dietary restriction of galactose, which is the current standard of care, most patients grow to experience a broad range of complications that can include motor difficulties. The goal of this study was to characterize hand fine motor control deficit among children and adults with classic galactosemia (CG). Specifically, we used Neuroglyphics software to collect digital Archimedes spiral drawings on a touch screen from 57 volunteers with CG (cases) and 80 controls. Hand fine motor control was scored as root mean square (RMS) of spirals drawn relative to an idealized template. Presence of tremor was defined as a peak in periodicity of changes in drawing speed or direction in the 4-8 Hz range. We observed a highly significant difference (P < .001) in RMS scores between cases and controls, with almost 51% of cases showing at least 1 of 4 spirals scoring outside the 95th percentile for controls. The corresponding prevalence for controls was 10%. Similarly, more than 35% of cases, and almost 14% of controls, showed at least 1 of 4 spirals with a tremor amplitude above the 95th % cutoff for controls. Our results both confirm and extend what is known about hand fine motor control deficit among children and adults with CG and establish digital assessment as a useful approach to quantify this outcome.
| S-EPMC8627187 | biostudies-literature
Project description:Classic galactosemia is a potentially lethal disorder that results from profound impairment of galactose-1-phosphate uridylyltransferase (GALT). Despite decades of research, the underlying pathophysiology of classic galactosemia remains unclear, in part owing to the lack of an appropriate animal model. Here, we report the establishment of a Drosophila melanogaster model of classic galactosemia; this is the first whole-animal genetic model to mimic aspects of the patient phenotype. Analogous to humans, GALT-deficient D. melanogaster survive under conditions of galactose restriction, but accumulate elevated levels of galactose-1-phosphate and succumb during larval development following galactose exposure. As in patients, the potentially lethal damage is reversible if dietary galactose restriction is initiated early in life. GALT-deficient Drosophila also exhibit locomotor complications despite dietary galactose restriction, and both the acute and long-term complications can be rescued by transgenic expression of human GALT. Using this new Drosophila model, we have begun to dissect the timing, extent and mechanism(s) of galactose sensitivity in the absence of GALT activity.
| S-EPMC2931538 | biostudies-literature
Project description:Food allergies are an increasingly public health problem, affecting up to 10% of children and causing a significant burden on affected patients, resulting in dietary restrictions, fear of accidental ingestion and related risk of severe reactions, as well as a reduced quality of life. Currently, there is no specific cure for a food allergy, so the only available management is limited to strict dietary avoidance, education on prompt recognition of symptoms, and emergency treatment of adverse reactions. Several allergen specific- and nonspecific-therapies, aiming to acquire a persistent food tolerance, are under investigation as potential treatments; however, to date, only immunotherapy has been identified as the most promising therapeutic approach for food allergy treatment. The aim of this review is to provide an updated overview on changes in the treatment landscape for food allergies.
| S-EPMC6571952 | biostudies-literature
Project description:The current management of vitiligo remains challenging; however, different strategies can be proposed to patients with a good efficacy in many cases. First, it is important to identify patients in the active phase of the disease because treatment should start as soon as possible to halt its progression. For patients with a stable disease, the treatment strategy is now well-stratified and is based on a combination of phototherapy (natural or in a cabin) and topical immunomodulatory agents. Surgical treatments are useful for localized and stable vitiligo, as well as for segmental vitiligo. Depigmentation remains indicated in very extensive forms. The recent approval of topical ruxolitinib cream in both the US and Europe brings new approaches for the management of vitiligo and paves the way for the development of new topical or oral targeted drugs.
| S-EPMC10824325 | biostudies-literature