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Molecular Genetics and Metabolism 2022Despite many decades of research involving both human subjects and model systems, the underlying pathophysiology of long-term complications in classic galactosemia (CG)... (Review)
Review
Despite many decades of research involving both human subjects and model systems, the underlying pathophysiology of long-term complications in classic galactosemia (CG) remains poorly understood. In this review, intended for those already familiar with galactosemia, we focus on the big questions relating to outcomes, mechanism, and markers, drawing on relevant literature where available, attempting to navigate inconsistencies where they appear, and acknowledging gaps in knowledge where they persist.
Topics: Humans; Galactosemias; Models, Biological; UTP-Hexose-1-Phosphate Uridylyltransferase
PubMed: 35882174
DOI: 10.1016/j.ymgme.2022.07.005 -
Orphanet Journal of Rare Diseases Mar 2022Classic Galactosemia is a rare, autosomal recessive disease in which galactose is not metabolized properly due to severe deficiency/absence of the galactose-1-phosphate...
BACKGROUND
Classic Galactosemia is a rare, autosomal recessive disease in which galactose is not metabolized properly due to severe deficiency/absence of the galactose-1-phosphate uridylyltransferase (GALT) enzyme, converting to an aberrant and toxic metabolite, galactitol. Newborn screening and timely galactose-restricted diet can resolve acute symptoms and decrease fatalities. However, despite this, significant chronic, progressive morbidities remain which have a real impact upon daily life. To better understand the burden of disease, 20 in-depth qualitative interviews were undertaken with adult patients (n = 12), and their caregivers (n = 8), enrolled in the ACTION-Galactosemia trial, part of a clinical program designed to investigate the safety and efficacy of AT-007 (govorestat) in reducing toxic galactitol and long-term clinical outcomes in Classic Galactosemia.
RESULTS
Interviews revealed the substantial burden of Classic Galactosemia on patients and families. Most adults were not able to live independently, and all required support with day-to-day activities. Short- and long-term memory difficulties and tremors were identified as the most frequently experienced and challenging symptoms. Other difficulties such as fine motor skills and slow/slurred speech contribute to the significant impact on daily activities, affecting ability to communicate and interact with others. Symptoms were first noticed in early childhood and worsened with age. Classic Galactosemia impacted all areas of daily functioning and quality of life, leading to social isolation, anxiety, anger/frustration and depression. This demonstrates the significant burden of disease and challenges associated with Classic Galactosemia.
CONCLUSIONS
The impact on both patients and caregivers underscores the severity of the unmet medical need and the importance of pharmacological intervention to halt or prevent disease progression. Any treatment that could reduce symptoms or slow functional decline would ease the burden of this condition on patients and caregivers.
Topics: Adult; Caregivers; Child, Preschool; Cost of Illness; Galactosemias; Humans; Infant, Newborn; Quality of Life; UTP-Hexose-1-Phosphate Uridylyltransferase
PubMed: 35346295
DOI: 10.1186/s13023-022-02287-9 -
Journal of Inherited Metabolic Disease Apr 2011Primary or premature ovarian insufficiency (POI) is the most common long-term complication experienced by girls and women with classic galactosemia; more than 80% and... (Review)
Review
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.
Topics: Adolescent; Adult; Animals; Child; Epigenesis, Genetic; Escherichia coli; Female; Follicle Stimulating Hormone; Galactose; Galactosemias; Humans; Ovary; Primary Ovarian Insufficiency; Puberty; Sepsis
PubMed: 20978943
DOI: 10.1007/s10545-010-9221-4 -
International Journal of Neonatal... Oct 2021The Leloir pathway, which consists of highly conserved enzymes, metabolizes galactose. Deficits in three enzymes in this pathway, namely galactose-1-phosphate... (Review)
Review
The Leloir pathway, which consists of highly conserved enzymes, metabolizes galactose. Deficits in three enzymes in this pathway, namely galactose-1-phosphate uridylyltransferase (GALT), galactokinase (GALK1), and UDP-galactose-4'-epimerase (GALE), are associated with genetic galactosemia. We recently identified patients with galactosemia and biallelic variants in , encoding galactose epimerase (GALM), an enzyme that is directly upstream of GALK1. GALM deficiency was subsequently designated as type IV galactosemia. Currently, all the published patients with biallelic variants were found through newborn screening in Japan. Here, we review GALM deficiency and describe how we discovered this relatively mild but not rare disease through the newborn screening system in Japan.
PubMed: 34842598
DOI: 10.3390/ijns7040068 -
Orphanet Journal of Rare Diseases Feb 2020Despite early diagnosis and treatment, Classical Galactosemia (CG) patients frequently develop long-term complications, such as cognitive impairment. Available...
BACKGROUND
Despite early diagnosis and treatment, Classical Galactosemia (CG) patients frequently develop long-term complications, such as cognitive impairment. Available literature primarily reports on general intellectual abilities and shows a substantially lower Full Scale Intelligence Quotient (FSIQ) in CG patients than in the general population. Both problems in social functioning as well as internalizing problems are often reported in CG patients. The combination of intelligence, cognitive functioning, behavior and social functioning has not been studied systematically in CG patients.
METHODS
To determine if CG patients demonstrate a specific neuropsychological and psychosocial profile, we investigated intelligence, functioning on multiple cognitive domains, behavior and social functioning with a comprehensive neuropsychological test battery and questionnaires (self- and proxy-reported).
RESULTS
The data of 48 patients, aged 4-47 years are reported. FSIQ ranged from 45 to 103 (mean 77 ± 14). A negative correlation between age and FSIQ was demonstrated (p = 0.037) which resulted directly from the inclusion of four young 'milder' patients detected by newborn screening (NBS) with an expected better clinical outcome. Compared to normative data, patients had significantly lower but highly variable scores on all cognitive domains, especially on tests requiring mental speed. In the context of the FSIQ, 43% of the cognitive test results exceeded IQ based expectations. Overall, the patients' scores on social functioning were in the normal range but internalizing problems were frequently reported. In our cohort, an early initiation of dietary treatment due to NBS or family screening did not result in a more favorable neuropsychological outcome.
CONCLUSIONS
In this study, we demonstrated that as a cohort, CG patients have a below average intelligence and impaired cognitive functioning without a distinctive neuropsychological profile. The effect of age on neurocognitive functioning should be assessed in longitudinal studies. Social functioning was not impaired, but patients may be at risk for internalizing problems. Considering the large variability in cognitive, behavioral and social functioning and the finding that cognitive outcomes may exceed IQ based expectations, an individual evaluation and follow-up is warranted in all CG patients to ensure timely support if needed.
Topics: Cognition; Galactosemias; Humans; Infant, Newborn; Intelligence; Neuropsychological Tests; Psychosocial Functioning
PubMed: 32033562
DOI: 10.1186/s13023-019-1277-0 -
Journal of Inherited Metabolic Disease May 2020Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an...
Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactose-restricted diet, fails to prevent long-term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long-term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal-1-P is not the sole pathophysiological agent responsible for the phenotype observed in galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)-hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. galactokinase (GALK) inhibitors, UDP-glucose pyrophosphorylase (UGP) up-regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in galactosemia. Promising co-adjuvant therapies include antioxidant therapy and UGP up-regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets.
Topics: Animals; Disease Models, Animal; Galactokinase; Galactose; Galactosemias; Genotype; Humans; Oxidative Stress; Phenotype; UDPglucose 4-Epimerase; UTP-Hexose-1-Phosphate Uridylyltransferase
PubMed: 31808946
DOI: 10.1002/jimd.12202 -
Indian Journal of Ophthalmology Feb 2014Natural eye lens is a crystalline substance to produce a clear passage for light. Cataract is opacity within the clear lens of the eye and is the dominant cause of... (Review)
Review
Natural eye lens is a crystalline substance to produce a clear passage for light. Cataract is opacity within the clear lens of the eye and is the dominant cause of socio-medical problem i.e., blindness worldwide. The only available treatment of cataract is surgery. However, insufficient surgical facilities in poor and developing countries and post-operative complications inspire researchers to find out other modes of treatment for cataract. In this review, an attempt has been made to appraise various etiological factors of cataract to make their perception clear to build up counterpart treatment. Present study is an assortment of various available literatures and electronic information in view of cataract etiopathogenesis. Various risk factors have been identified in development of cataracts. They can be classified in to genetic factors, ageing (systemic diseases, nutritional and trace metals deficiencies, smoking, oxidative stress etc.), traumatic, complicated (inflammatory and degenerative diseases of eye), metabolic (diabetes, galactosemia etc.), toxic substances including drugs abuses, alcohol etc., radiation (ultraviolet, electromagnetic waves etc.) are implicated as significant risk factors in the development of cataract.
Topics: Aging; Cataract; Humans; Lens, Crystalline; Risk Factors
PubMed: 24618482
DOI: 10.4103/0301-4738.121141 -
International Journal of Molecular... Dec 2023Classic galactosemia is an autosomal recessive inherited liver disorder of carbohydrate metabolism caused by deficient activity of galactose-1-phosphate... (Review)
Review
Classic galactosemia is an autosomal recessive inherited liver disorder of carbohydrate metabolism caused by deficient activity of galactose-1-phosphate uridylyltransferase (GALT). While a galactose-restricted diet is lifesaving, most patients still develop long-term complications. In this study, we report on a two-week-old female patient who is a compound heterozygote for a known pathogenic variant (p.K285N) and a novel missense variant (p.A303D) in the gene. Segregation analysis showed that the patient inherited the p.K285N pathogenic variant from her father and the p.A303D variant from her mother. A bioinformatics analysis to predict the impact of the p.A303D missense variant on the structure and stability of the GALT protein revealed that it may be pathogenic. Based on this finding, we performed a literature review of all missense variants identified in homozygous and compound heterozygous galactosemia patients carrying the p.K285N pathogenic variant to explore their molecular effects on the clinical phenotype of the disease. Our analysis revealed that these missense variants are responsible for a wide range of molecular defects. This study expands the clinical and mutational spectrum in classic galactosemia and reinforces the importance of understanding the molecular consequences of genetic variants to incorporate genetic analysis into clinical care.
Topics: Female; Humans; Galactose; Galactosemias; Mutation; Mutation, Missense; UTP-Hexose-1-Phosphate Uridylyltransferase
PubMed: 38139222
DOI: 10.3390/ijms242417388 -
Indian Pediatrics Aug 2016Suspecting metabolic liver disease in an infant or young child with acute liver failure, and a protocol-based workup for diagnosis is the need of the hour. (Review)
Review
CONTEXT
Suspecting metabolic liver disease in an infant or young child with acute liver failure, and a protocol-based workup for diagnosis is the need of the hour.
EVIDENCE ACQUISITION
Data over the last 15 years was searched through Pubmed using the keywords Metabolic liver disease and Acute liver failure with emphasis on Indian perspective. Those published in English language where full text was retrievable were included for this review.
RESULTS
Metabolic liver diseases account for 13-43% cases of acute liver failure in infants and young children. Etiology remains indeterminate in very few cases of liver failure in studies where metabolic liver diseases were recognized in large proportion. Galactosemia, tyrosinemia and mitochondrial disorders in young children and Wilsons disease in older children are commonly implicated. A high index of suspicion for metabolic liver diseases should be kept when there is strong family history of consanguinity, recurrent abortions or sibling deaths; and history of recurrent diarrhea, vomiting, failure to thrive or developmental delay. Simple dietary modifications and/or specific management can be life-saving if instituted promptly.
CONCLUSION
A high index of suspicion in presence of red flag symptoms and signs, and a protocol-based approach helps in timely diagnosis and prompt administration of lifesaving therapy.
Topics: Child; Child, Preschool; Humans; Infant; Infant, Newborn; Liver Failure, Acute; Liver Transplantation; Metabolic Diseases
PubMed: 27395834
DOI: 10.1007/s13312-016-0913-1 -
Survey of Ophthalmology 1988Galactosemia is a disorder caused by a deficiency of any one of three possible enzymes involved in the metabolism of galactose: galactokinase, transferase or epimerase.... (Review)
Review
Galactosemia is a disorder caused by a deficiency of any one of three possible enzymes involved in the metabolism of galactose: galactokinase, transferase or epimerase. Any single deficient enzyme can result in cataract through the accumulation of galactitol in the lens. The ophthalmologist may play an important role in this disease, since early recognition of cataract development followed by the initiation of a galactose-free diet may lead to clearing of lenticular opacities. The clinical and laboratory findings that distinguish the three enzyme deficiency disorders of galactosemia are discussed. The biochemical genetics of each enzyme also are reviewed, along with the recent evidence linking heterozygous galactokinase deficiency and presenile cataract.
Topics: Animals; Cataract; Female; Galactokinase; Galactose; Galactosemias; Genes; Humans; Methods; Molecular Biology; Pregnancy; Pregnancy Complications; UDPglucose 4-Epimerase; UTP-Hexose-1-Phosphate Uridylyltransferase
PubMed: 3043741
DOI: 10.1016/0039-6257(88)90095-1