Current and Future Treatments for Classic Galactosemia

Delnoy, Britt; Coelho, Ana Daniela; Rubio‐Gozalbo, M. Estela

doi:10.3390/jpm11020075

Cited by 28 publications

(21 citation statements)

References 141 publications

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“…Accumulation of toxic galactitol appears to be the primary and driving factor in acute and long-term complications. Although other contributing factors have been postulated, including impaired glycosylation, altered gene expression, oxidative stress, and endoplasmic reticulum stress [ 6 , 7 ], none of them has been conclusively demonstrated to have a critical role in Classic Galactosemia. Thus, even patients with early diagnosis and strict dietary adherence can experience early onset and progression of the symptoms of Classic Galactosemia as well as long-term complications [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Qualitative interviews with adults with Classic Galactosemia and their caregivers: disease burden and challenges with daily living

Randall¹,

Sutter

Wang³

et al. 2022

Orphanet J Rare Dis

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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.

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Section: Introductionmentioning

confidence: 99%

Qualitative interviews with adults with Classic Galactosemia and their caregivers: disease burden and challenges with daily living

Randall¹,

Sutter

Wang³

et al. 2022

Orphanet J Rare Dis

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show abstract

“…Altogether, this evidence reinforces the need for establishing exogenous galactose (galactose from food) tolerance and its relationship with long-term complication [31,67]. On the other hand, variations in the complications of individuals with the same genotype suggest the influence of other factors, such as epigenetic mechanisms, on glycosylation or signaling pathways such as unfolded protein response (UPR), inositol and inflammation [49], for which the research has been aimed at evaluating management alternatives beyond diet [11,68].…”

Section: Dairy Productsmentioning

confidence: 65%

Advances and Challenges in Classical Galactosemia. Pathophysiology and Treatment

Cornejo

Morales

et al. 2022

J. inborn errors metab. screen.

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Classical galactosemia is caused by the genetic deficiency of galactose-1-phosphate-urydyl-transferase resulting in clinical symptoms development during the first weeks of life including jaundice, hypotonia, lethargy, emesis, hepatomegaly, among others. Currently, dietary restriction of galactose is considered the standard for classical galactosemia management. For several years, severe dietary galactose restriction was considered necessary, implying restriction not only of dairy products, but also fruits, vegetables, legumes, and viscera. Such management failed to improve or prevent the appearance of long-term complications, by contrast, such restrictive approach may lead to nutritional deficiencies development. Thus, the last consensus suggests guidelines that are more flexible. In addition, the lack of knowledge regarding the physiopathology of the disease, and the toxicity threshold of the metabolites accumulated, make even more difficult to propose novel and more effective therapeutic approaches. This review summarizes the current state of knowledge regarding classical galactosemia in terms of physiopathology, long-term complications, newborn screening and genetic variants and their implications on galactosemia treatment, summed to the challenges that researchers working on this disease must address in future studies including the analysis of galactose content in foods, galactose tolerance threshold and search for novel therapeutic targets.

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“…Whether AR inhibitors are able to address extraocular symptoms (e.g., cognitive symptoms, subfertility) remains to be established. Moreover, the potential effect of blocking the galactose conversion to galactitol (e.g., galactonate increase) remains to be elucidated [ 73 ].…”

Section: Treatmentmentioning

confidence: 99%

Galactosemia: Biochemistry, Molecular Genetics, Newborn Screening, and Treatment

et al. 2022

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Galactosemia is an inborn disorder of carbohydrate metabolism characterized by the inability to metabolize galactose, a sugar contained in milk (the main source of nourishment for infants), and convert it into glucose, the sugar used by the body as the primary source of energy. Galactosemia is an autosomal recessive genetic disease that can be diagnosed at birth, even in the absence of symptoms, with newborn screening by assessing the level of galactose and the GALT enzyme activity, as GALT defect constitutes the most frequent cause of galactosemia. Currently, galactosemia cannot be cured, but only treated by means of a diet with a reduced content of galactose and lactose. Although the diet is able to reverse the neonatal clinical picture, it does not prevent the development of long-term complications. This review provides an overview of galactose metabolism, molecular genetics, newborn screening and therapy of galactosemia. Novel treatments for galactosemia currently being investigated in (pre)clinical studies and potentially able to prevent long-term complications are also presented.

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Current and Future Treatments for Classic Galactosemia

Cited by 28 publications

References 141 publications

Qualitative interviews with adults with Classic Galactosemia and their caregivers: disease burden and challenges with daily living

Qualitative interviews with adults with Classic Galactosemia and their caregivers: disease burden and challenges with daily living

Advances and Challenges in Classical Galactosemia. Pathophysiology and Treatment

Galactosemia: Biochemistry, Molecular Genetics, Newborn Screening, and Treatment

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