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Mini Review - (2024)Volume 8, Issue 3
Galactosemia confers long-term Central Nervous System (CNS) complications and other difficulties in most affected individuals, despite newborn screening and dietary galactose restriction allowing survival into adulthood. These complications include speech, cognition, motor, and behavioral deficits, as well as cataracts and ovarian insufficiency in women. Endogenous synthesis of galactose far exceeds the level achieved through a galactose-restricted diet, limiting the long-term benefits of dietary control. Thus, an urgent medical need exists for those with this disorder. Although our understanding of Galactosemia has evolved over the last two decades, its pathophysiology has not been fully elucidated. Proposed causes of the complex symptomatology include newborn galactose exposure, nonadherence to the galactose-restricted diet, and Galactose-1-phosphate (Gal-1p) accumulation. However, none of these have been shown to account for the long-term complications of disease. Galactitol, an abnormal metabolite found in the blood of individuals with both Galactokinase (GALK) and Galactose-1-phosphate uridyltransferase (GALT) deficiencies, is a critical pathogenic cause of these complications. Galactitol is a toxic metabolite of galactose, produced by the enzyme aldose reductase only in the presence of excess galactose and is not found in healthy individuals. Several lines of evidence support the galactitol hypothesis of galactosemia-associated CNS complications, including animal models and clinical findings in individuals with galactosemia. Understanding the role of galactitol may provide a pathway to preserve CNS function in galactosemia.
Galactokinase; Galactose; Neuropsychological; Pathogenesis; Galactosemia
Galactosemia is a lifelong disease
Galactosemia is a multi-system disorder caused by a genetic inability to metabolize the sugar galactose [1]. Galactosemia is associated with acute life-threatening complications in the newborn period and chronic long-term complications that impact quality of life and day-to-day functioning [2-4]. While dietary restriction of galactose initiated during the early neonatal period usually prevents the severe acute features of galactosemia, a continued restricted diet fails to prevent neurological complications and premature ovarian insufficiency in women [5]. Endogenous synthesis of galactose by the body is higher than the amount of galactose consumed in food on a galactosemia diet [6-9]. There are currently no approved therapies to prevent the long-term complications of galactosemia. Govorestat is a novel, highly selective, brain penetrant aldose reductase inhibitor recently shown to lower galactitol level in patients with classic galactosemia [10].
Neuropsychological complications
Long-term neuropsychological complications associated with galactosemia include developmental delays, speech and language delay and/or deficits, suboptimal intellectual functioning, gross and fine motor difficulties, behavioral abnormalities, and psychiatric disorders (depression and anxiety) [11-13]. Some case studies suggest progressive worsening of symptoms [14,15]. A recent cross-sectional analysis of 19 children with galactosemia explored the relationship between functioning and age, using ageappropriate standardized tests to assess neuropsychological domains of speech, cognition, motor skills and behavior [16]. All children were adherent to a strict galactosemia diet initiated at birth and had access to typical supportive services, including speech therapy, learning support and occupational therapy. Symptoms in younger children appeared to be less severe than symptoms in later childhood and adolescence in all domains. However, longitudinal studies are lacking to confirm the observation from the recent cross-sectional analysis [16].
The neuropsychological complications associated with galactosemia impact quality of life and day-to-day functioning, and create a substantial burden of care [17-19]. Speech deficits, speech production (verbal apraxia) and word-finding difficulties are the speech elements most often affected in individuals with galactosemia. These types of language deficits impair effective communication and comprehension [13,20-22]. Poor cognitive functioning also affects educational attainment and independent living [23,24]. Psychosocial and behavioral abnormalities, including psychiatric disorders and adaptive behavior, may result in isolation and dependence on a parent or caregiver throughout adulthood [17,18,23]. Motor skill deficiencies can impact performance in the early school years, including activities such as writing and drawing and may restrict opportunities for adult employment in physical occupations [4,13,25,26]. Thus, the impact of galactosemia extends beyond quality of life, with adults generally unemployed and relying heavily on caregivers or assisted living facilities [17,27].
Pathogenesis of galactosemia
Exposure to galactose in the newborn period was thought to be responsible for early manifestations of galactosemia and that symptoms would resolve with removal of galactose from the diet [28]. However, many children who were never acutely exposed to galactose at birth (because of an older sibling with galactosemia or prenatal identification via genetic testing) experienced speech delay and cognitive deficits, suggesting that other factors, rather than exposure to galactose in the newborn period, are responsible for the long-term complications [29]. Non-adherence to the galactose-restricted diet was also proposed as the cause of learning deficits or other symptoms [30,31]. However, studies have demonstrated that endogenous galactose production exceedes the amount of galactose ingested in young children, casting doubt on this hypothesis [9,32-34].
Deficiency of Galactose-1-phosphate uridyltransferase (GALT) is the primary biochemical abnormality in classic galactosemia. The resulting accumulation of Gal-1p, which is the substrate for GALT, has been thought to impact protein glycosylation in multiple organs, including the brain. The hypothesis concerning abnormal glycosylation has been proposed as a contributing factor to the underlying CNS complications in this disorder. The elevation of Gal-1p has not been proven to be responsible for CNS damage. In vitro mechanistic studies with excess Gal-1p have failed to demonstrate a toxic effect, and protein glycosylation defects detected in older children and adults with classic galactosemia have not been shown to correlate with the long-term complications [35,36].
Galactonate is another compound involved in galactose metabolism and could, in principle, be considered in the pathology of galactosemia. Galactonate is formed via conversion of galactose by the enzyme galactose dehydrogenase. However, individuals with galactosemia have normal levels of galactose dehydrogenase and are able to convert galactose to galactonate efficiently. Although endogenous production of galactose may lead to increased flux of galactose to galactonate, galactonate itself is a non-reactive, nontoxic metabolite. Furthermore, it does not accumulate in blood and tissues because it can easily be metabolized or directly excreted in urine [37,38].
Role of Galactitol in galactosemia
Recent evidence suggests galactitol may be the most important metabolite associated with complications in galactosemia. Galactitol is formed by conversion of galactose to a reduced sugar alcohol by the enzyme, aldose reductase-a reaction that only occurs at very high galactose concentrations and does not occur in healthy people [39-40]. Healthy people (without galactosemia) do not have measurable levels of galactitol in blood or tissues [41,42]. Galactitol (like other reduced sugar alcohols) is highly toxic and its accumulation intracellularly is associated with osmotic dysregulation, oxidative damage, and disturbances in redox potential in neurons [7,8,43,44].
A relevant evidence on the role of galactitol in causing neurological damage was derived from a study of patients with Galactokinase (GALK) deficiency. Unlike patients with GALT deficiency, GALK-deficient patients do not produce Gal-1p. However, they do have elevated levels of galactitol and many patients show neuropsychological deficits similar to those seen in GALT-deficient patients, pointing towards a role of galactitol, rather than Gal-1p, in the pathogenesis of galactosemia [36,45].
Animal models provide additional support to the role of galactitol in brain function. Deletion of GALK in GALT-null Drosophila reduced Gal-1p levels but did not prevent functional deficits [46]. GALT-null rats, which display elevated levels of galactose, galactitol and Gal-1p, display similar CNS complications as humans with Galactosemia, including learning, cognition and motor issues [47]. However, GALT-null mice, which display elevated galactose and Gal-1p levels but not elevated galactitol (because mice express very low levels of aldose reductase compared with rats and humans) do not display any CNS complications [48,49]. Treatment of the GALT-null rat model with an aldose reductase inhibitor decreased galactitol levels (without lowering elevated Gal-1p and galactose levels) and prevented CNS symptoms of disease (as well as cataracts) [50].
Elevated galactitol has been detected in the brains of children with classic galactosemia and it has been proposed that galactitol may be responsible for CNS complications such as pseudotumor cerebri reported in both patients with classic galactosemia and GALK deficiency [51-57].
Recent clinical data from a cross-sectional analysis of 47 children with classic galactosemia revealed a correlation between plasma galactitol levels and measures of speech/language, cognitive, motor and behavioral difficulties [58].
Thus, evidence is leading to a focus on galactitol and its role in complications associated with Galactosemia. Although galactitol levels are high in blood and tissues throughout the body in individuals with Galactosemia, damage and long-term complications are most pronounced in tissues with low cellular turnover, such as the brain and ovaries in females [13].
Govorestat is a novel, highly selective, brain penetrant aldose reductase inhibitor recently shown to lower galactitol level in patients with classic galactosemia [10].
Galactosemia significantly affects CNS function, as well as emotional well-being and quality of life. Speech, cognition, motor skills and behavior are impaired in most individuals. Dietary restriction, while essential to prevent the acute symptoms of galactosemia, does not prevent long-term complications. Pharmacological inhibition of galactitol formation provides a compelling opportunity to prevent the troubling long-term consequences for patients.
RP, EB and SS are all employees and shareholders of Applied Therapeutics.
SS and RP drafted the initial manuscript and critically reviewed and revised the draft manuscript. SW, JM, EB reviewed and revised the draft manuscript. All authors provided final approval of the draft for submission. All authors agree to be accountable for the accuracy and integrity of the work.
This research did not receive any specific grant from funding agencies.
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Citation: Perfetti R, Waisbren SE, Mink JW, Bailey E, Shendelman S (2024) Towards an Advanced Understanding of the Pathogenesis of CNS Complications Associated with Galactosemia: Targeting Galactitol for Pharmacological Intervention with Govorestat, a Novel Aldose-Reductase Inhibitor. J Pharma Reports. 08: 220.
Received: 23-Jul-2024, Manuscript No. JPR-24-33138; Editor assigned: 26-Jul-2024, Pre QC No. JPR-24-33138 (PQ); Reviewed: 12-Aug-2024, QC No. JPR-24-33138; Revised: 19-Aug-2024, Manuscript No. JPR-24-33138 (R);; Published: 26-Aug-2024 , DOI: 10.35248/JPR.24.08.220
Copyright: © 2024 Perfetti R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.