The Neuropathology of Galactosemia

Haberland, Catherine; Perou, Maurice; Brunngraber, Eric G.; Hof, Hildegard

doi:10.1097/00005072-197107000-00009

Cited by 69 publications

(25 citation statements)

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“…The authors suggested that the abnormal signal intensity might be due to a primary abnormality in the biochemical structure of myelin secondary to deficient galactocerebrosides. Histopathological and biochemical examination in an untreated adult patient revealed low galactocerebroside levels, supporting this idea (Haberland et al 1971). Later studies continued to observe WM abnormalities (Crome 1962; Wang et al 2001; Otaduy et al 2006; Hughes et al 2009), and links with affected myelination (Böhles et al 1986; Widhalm et al 2002).…”

Section: Introductionmentioning

confidence: 59%

White matter microstructure pathology in classic galactosemia revealed by neurite orientation dispersion and density imaging

Timmers

Zhang

Bastiani

et al. 2014

J of Inher Metab Disea

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White matter abnormalities have been observed in patients with classic galactosemia, an inborn error of galactose metabolism. However, magnetic resonance imaging (MRI) data collected in the past were generally qualitative in nature. Our objective was to investigate white matter microstructure pathology and examine correlations with outcome and behaviour in this disease, by using multi-shell diffusion weighted imaging. In addition to standard diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging (NODDI) was used to estimate density and orientation dispersion of neurites in a group of eight patients (aged 16–21 years) and eight healthy controls (aged 15–20 years). Extensive white matter abnormalities were found: neurite density index (NDI) was lower in the patient group in bilateral anterior areas, and orientation dispersion index (ODI) was increased mainly in the left hemisphere. These specific regional profiles are in agreement with the cognitive profile observed in galactosemia, showing higher order cognitive impairments, and language and motor impairments, respectively. Less favourable white matter properties correlated positively with age and age at onset of diet, and negatively with behavioural outcome (e.g. visual working memory). To conclude, this study provides evidence of white matter pathology regarding density and dispersion of neurites in these patients. The results are discussed in light of suggested pathophysiological mechanisms.

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Section: Introductionmentioning

confidence: 59%

White matter microstructure pathology in classic galactosemia revealed by neurite orientation dispersion and density imaging

Timmers

Zhang

Bastiani

et al. 2014

J of Inher Metab Disea

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“…A linear relationship, however, ai. (6) of deranged glycoproteins in a galactosemic brain and the exists between them in galactosemic cells as shown by linear recent report of Dobbie et al (7) of an abnormal galactose to regression analysis (y = 9.75 + 94.5x, R2 = 0.73).…”

Section: Resultsmentioning

confidence: 92%

“…This defective synthesis would result from the observed low concentrations of UDPgalactose in red cells, cultured fibroblasts, and liver biopsies of galactosemic patients (5). Indeed, Haberland et al (6), in 197 1, reported an abnormal pattern of glycoproteins in the brain of a galactosemic patient. Dobbie et al (7) recently found that the galactose to mannose ratio is abnormally low in a hydrolysate of the cultured fibroblasts of galactosemic patients, supporting the idea of defective galactosylation in these cells.…”

Section: Abbreviationsmentioning

confidence: 99%

Abnormal Galactosylation of Complex Carbohydrates in Cultured Fibroblasts from Patients with Galactose-1-Phosphate Uridyltransferase Deficiency

et al. 1992

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ABSTRACT. An abnormality in galactosylation of complex carbohydrates may be important in the pathogenesis of the long-term complications of classic (galactose-lphosphate uridyltransferase-deficient) galactosemia. The ability of nine galactosemic fibroblast preparations to be galactosylated with a purified galactosyltransferase was measured as an indicator of vacant sites where galactose would normally reside. The amount of galactose transferred to cell protein from galactosemic patients was significantly higher than that transferred to a group of seven controls (p < 0.005). Galactosyltransferase activity of the galactosemic cell preparation toward N-acetylglucosamine was also significantly higher than normal (p < 0.01), and there was a linear relationship between these two parameters in galactosemic but not normal cells. These findings suggest that there is defective galactosylation of galactosemic cell complex carbohydrates and that such cells increase their galactosyltransferase levels in an attempt to compensate for the defect. Defective galactosylation may be implicated as an etiologic factor in complications observed in galactosemic patients even when treated with galactose-restricted diets. (Pediatr Res 31: 508-511, 1992) Abbreviations UDPgalactose, uridine diphosphogalactose UDPglucose, uridine diphosphoglucose OPCA, olivopontocerebellar atrophy Although dietary restriction of galactose has been the basis for treatment of classical galactosemia for over 50 years (I), the longterm efficacy of this approach has been seriously questioned. A survey of over 300 patients indicates that even well-treated patients whose galactose restriction was initiated at birth have developmental delay, speech abnormalities, and ovarian failure in females (2). Older galactose-restricted patients have developed an ataxia syndrome (3).Two theories have been proposed, both involving the sugar nucleotide UDPgalactose, to explain the presence of the complications seen despite the absence of dietary galactose. Gitzelmann et al. (4) (7) recently found that the galactose to mannose ratio is abnormally low in a hydrolysate of the cultured fibroblasts of galactosemic patients, supporting the idea of defective galactosylation in these cells. To test the latter hypothesis, we studied the galactosylation state of glycoproteins in cultured fibroblasts by determining the extent to which cellular glycoproteins would serve as galactose acceptors when extracts were incubated with a purified galactosyltransferase. The rationale for this approach was that an impairment of galactosylation would result in a greater number of glycoprotein oligosaccharides being terminated in N-acetylglucosamine. Normally, galactose is linked to N-acetylglucosamine in the biosynthesis of the carbohydrate moieties of glycoproteins by a galactosyltransferase (Fig. 1). We reasoned that if we incubated cell extracts with radiolabeled UDPgalactose and purified galactosyltransferase, radioactive galactose would be transferred to terminal N-acetylglucosamine sites (Fig. 1)....

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“…Studies on galactosemic patients’ brains have reported structural abnormalities, such as cerebral and cerebellar atrophy, and white matter abnormalities possibly due to altered myelination (Crome 1962; Haberland et al 1971; Hughes et al 2009; Koch et al 1992; Krabbi et al 2011; Lo et al 1984; Nelson et al 1992; Wang et al 2001). A recent study on the white matter microstructure in galactosemic patients revealed increased neurite dispersion (i.e., less organized axons) and lower neurite density (Timmers et al 2015b).…”

Section: Pathophysiology and Long-term Outcomementioning

confidence: 99%

Sweet and sour: an update on classic galactosemia

Coelho

Rubio-Gozalbo

Vicente

et al. 2017

J of Inher Metab Disea

108

125

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Classic galactosemia is a rare inherited disorder of galactose metabolism caused by deficient activity of galactose-1-phosphate uridylyltransferase (GALT), the second enzyme of the Leloir pathway. It presents in the newborn period as a life-threatening disease, whose clinical picture can be resolved by a galactose-restricted diet. The dietary treatment proves, however, insufficient in preventing severe long-term complications, such as cognitive, social and reproductive impairments. Classic galactosemia represents a heavy burden on patients’ and their families’ lives. After its first description in 1908 and despite intense research in the past century, the exact pathogenic mechanisms underlying galactosemia are still not fully understood. Recently, new important insights on molecular and cellular aspects of galactosemia have been gained, and should open new avenues for the development of novel therapeutic strategies. Moreover, an international galactosemia network has been established, which shall act as a platform for expertise and research in galactosemia. Herein are reviewed some of the latest developments in clinical practice and research findings on classic galactosemia, an enigmatic disorder with many unanswered questions warranting dedicated research.

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The Neuropathology of Galactosemia

Cited by 69 publications

References 0 publications

White matter microstructure pathology in classic galactosemia revealed by neurite orientation dispersion and density imaging

White matter microstructure pathology in classic galactosemia revealed by neurite orientation dispersion and density imaging

Abnormal Galactosylation of Complex Carbohydrates in Cultured Fibroblasts from Patients with Galactose-1-Phosphate Uridyltransferase Deficiency

Sweet and sour: an update on classic galactosemia

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