An Updated Review of the Long-Term Neurological Effects of Galactosemia

Ridel, Keith R.; Leslie, Nancy; Gilbert, Donald L.

doi:10.1016/j.pediatrneurol.2005.02.015

Cited by 102 publications

(83 citation statements)

References 83 publications

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“…5 Despite early dietary management, chronic complications such as intellectual deficits, ataxia, speech dyspraxia, premature ovarian insufficiency (POI) and decreased bone mineralization occur in many adults. [10][11][12][13][14][15][16][17][18][19] Different cell and animal models have been utilized to understand the pathogenic mechanisms of the acute neonatal lethality and the long-term complications associated with Classic Galactosemia. Early genetic studies in the yeast Saccharomyces cerevisiae showed that GALT-deficient mutant yeasts are sensitive to galactose in growth medium; but disruption of galactokinase (GALK) function in these yeasts reversed their galactose sensitivity.…”

Section: Introductionmentioning

confidence: 99%

Subfertility and growth restriction in a new galactose-1 phosphate uridylyltransferase (GALT) - deficient mouse model

et al. 2014

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The first GalT gene knockout (KO) mouse model for Classic Galactosemia (OMIM 230400) accumulated some galactose and its metabolites upon galactose challenge, but was seemingly fertile and symptom free. Here we constructed a new GalT genetrapped mouse model by injecting GalT gene-trapped mouse embryonic stem cells into blastocysts, which were later implanted into pseudo-pregnant females. High percentage GalT gene-trapped chimera obtained were used to generate heterozygous and subsequently, homozygous GalT gene-trapped mice. Biochemical assays confirmed total absence of galactose-1 phosphate uridylyltransferase (GALT) activity in the homozygotes. Although the homozygous GalT gene-trapped females could conceive and give birth when fed with normal chow, they had smaller litter size (P ¼ 0.02) and longer time-to-pregnancy (P ¼ 0.013) than their wild-type littermates. Follicle-stimulating hormone levels of the mutant female mice were not significantly different from the age-matched, wild-type females, but histological examination of the ovaries revealed fewer follicles in the homozygous mutants (P ¼ 0.007). Administration of a high-galactose (40% w/w) diet to lactating homozygous GalT gene-trapped females led to lethality in over 70% of the homozygous GalT gene-trapped pups before weaning. Cerebral edema, abnormal changes in the Purkinje and the outer granular cell layers of the cerebellum, as well as lower blood GSH/GSSG ratio were identified in the galactose-intoxicated pups. Finally, reduced growth was observed in GalT gene-trapped pups fed with normal chow and all pups fed with high-galactose (20% w/w) diet. This new mouse model presents several of the complications of Classic Galactosemia and will be useful to investigate pathogenesis and new therapies.

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Section: Introductionmentioning

confidence: 99%

Subfertility and growth restriction in a new galactose-1 phosphate uridylyltransferase (GALT) - deficient mouse model

et al. 2014

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“…Research to date suggests that differential developmental outcomes observed in the disorder are not related to conditions during the neonatal (e.g., age at diagnosis and restriction of galactose intake or severity of neonatal crisis) or postnatal period [e.g., adherence to diet] (Cleary et al 1995;Bosch 2011). Rather, developmental outcome may be influenced by prenatal conditions (Fridovich andWalter 2008, Potter et al 2008;Berry and Elsas 2011) such as harmful intrauterine levels of galactitol causing early but static neural injury (Ridel et al 2005). Exposure to galactose in the neonatal period may magnify the galactose toxicity in individual children (Berry and Elsas 2011).…”

Section: Discussionmentioning

confidence: 99%

“…GAL is the result of an inborn deficiency of the enzyme galactose-1-phosphate uridyltransferase [GALT] (Bosch 2006). Approximately one child in 53,000 in the United States is born with the disorder (Ridel et al 2005). Intervention for galactose toxicity is the implementation of a galactoserestricted diet (Hughes et al 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Heterogeneity of developmental abilities and attainment is evident across individuals with GAL (Doyle et al 2010), but neither genetic nor biochemical measures predict or explain the heterogeneous outcomes for children (Ridel et al 2005). Given the currently inexplicable outcomes for children with GAL, Bosch et al (2004) have suggested that a focus of ongoing care should be aimed at supporting children to attain the best achievable quality of life (Bosch et al 2004).…”

Section: Introductionmentioning

confidence: 99%

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Differential Phonological Awareness Skills in Children with Classic Galactosemia: A Descriptive Study of Four Cases

et al. 2012

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Educational achievement, which for individuals with the metabolic disorder classic galactosemia (GAL) is significantly lower than in the wider population, correlates with self-reported quality of life. Phonological awareness skills underpin the development of literacy, and although literacy is a key contributor to successful academic outcomes, no study to date has investigated phonological awareness skills in children with GAL. This study investigated phonological awareness (PA) in four school-aged children with the disorder, two of whom were siblings. Age range for the children was 7 years 7 months to 9 years 2 months. Each child was assessed with the Phonological Awareness criterionreferenced subtest from the Clinical Evaluation of Language Fundamentals-Fourth Edition. Included in the data for analysis was each child's performance measures obtained from their most recent assessment of cognitive and lexical development. A number of descriptive analyses were undertaken on the data. One child, who met her age criterion for PA, had cognitive and lexical development skills in the average range. The remaining three children failed to meet their age criteria. Although these three children presented with clinically similar cognitive and lexical development skills, disparate PA skills were identified. The PA skills of one of the sibling pair were notably more advanced than his older sibling. The limitations of relying on behavioural test results in children with GAL to predict those most at risk of reduced skill development are discussed in terms future research directions.

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“…Consumption of fruits and vegetables containing galactose is still a controversy [Bosch, 2006]; however, endogenous production of galactose may account for elevated galactose metabolites in galactosemic patients under strict diets [Berry et al, 1993;Segal, 1998]. Despite treatment, patients with classical galactosemia may experience long-term complications such as cognitive and developmental delays, and ovarian failure [Fishler et al, 1980;Friedman et al, 1989;Waggoner et al, 1990;Leslie et al, 1992;Waggoner and Buist, 1993;Kaufman et al, 1995;Lewis et al, 1995;Nelson, 1995;Leslie, 2003;Ridel et al, 2005]. Consequently, the speed at which diagnosis and treatment are implemented may influence the long-term outcome of a galactosemic patient.…”

Section: Introductionmentioning

confidence: 99%