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Galactose Toxicity in Animals

Introduction

Galactose is a hexose that differs from glucose only by the configuration of the hydroxyl group at the carbon-4 position. Often present as an anomeric mixture of α-D-galactose and β-D-galactose, this monosaccharide exists abundantly in milk, dairy products and many other food types such as fruits and vegetables [1, 2]. In humans, absorption of galactose from food across the brush border membrane of the proximal jejunum and renal epithelium is mediated by the Na+/glucose co-transporters SGLT1 and SGLT2 [37]. Other sources of galactose include endogenous production and natural turnover of glycolipids and glycoproteins. Using the technique of isotopic labeling, Berry et al. elegantly demonstrated that a 70kg adult male could produce up to 2 grams of galactose per day [810]. Once present inside the cells, β-D-galactose is epimerized to α-D-galactose through the action of a mutarotase [11]. α-D-galactose is subsequently converted to galactose-1-phosphate (gal-1-P) by the enzyme galactokinase (GALK) (E.C. 2.7.1.6). In the presence of galactose-1-phosphate uridylyltransferase (GALT) (E.C. 2.7.7.12), gal-1-P reacts with UDP-glucose to form UDP-galactose and glucose-1-phosphate (Fig. 1). Glucose-1-phosphate produced can enter the glycolytic pathway or react with UTP in the presence of UDP-glucose pyrophosphorylase (UGP) to form a new molecule of UDP-glucose [12]. The other product, UDP-galactose, can act as a galactosyl donor for the biosynthesis of glycoproteins and glycolipids, or be converted back to UDP-glucose by UDP-galactose-4-epimerase (GALE) (E.C. 5.1.3.2) [13, 14]. It is worth mentioning that in addition to UDP-glucose/galactose, human GALE can also recognize UDP-N-acetylgluco/galactosamine [15]. Moreover, gal-1-P can also be dephosphorylated by inositol monophosphatase to form galactose [16]. Because of these reactions and endogenous galactose production, galactose is a non-essential nutrient. GALK, GALT and GALE comprise the evolutionarily conserved Leloir pathway of galactose metabolism [17] (Fig. 1). If the flow of galactose through the Leloir pathway is perturbed either due to congenital deficiency of any of the above-mentioned enzymes or an overwhelming presence of this hexose, toxicity syndromes will be observed. Over the years, there have been dozens of book chapters and reviews on human disorders of galactose metabolism [1829] and experimental galactosemia in animals [3034]. Therefore, the primary goal of this review is not intended to reiterate the known, but to update recent developments in the field and offer our insights into the as yet unknown.

Fig. 1
The galactose metabolic pathway is linked to uridine nucleosides and inositol metabolism [166]

Congenital Disorders of Galactose Metabolism

Inherited deficiencies of GALK, GALT, and GALE activities in humans have all been observed and studied extensively [1829]. The clinical manifestations of each enzyme deficiency, however, differ markedly. For instance, patients with GALK deficiency (MIM 230200) (Type II Galactosemia) have the mildest clinical consequences as they may present only with cataracts [3537]. On the other hand, GALT-deficiency (MIM 230400) (Type I Galactosemia) [38, 39] is potentially lethal and demonstrates long-term, organ-specific complications [40, 41]. GALE-deficiency (MIM 230350) (Type III Galactosemia) has been somewhat controversial with regards clinical manifestations as clinical information is limited, and based mostly on case reports [4244]. Until newborn screening for GALE deficiency is available, the natural history will be unknown. The differences in clinical outcome between GALT and GALK deficiencies reflect the differences in tissue response to the characteristic changes in the levels of galactose metabolites from the respective enzyme deficiencies.

Many reported cases of deficiencies were identified as being caused by missense mutations in the corresponding genes, which resulted in reduced enzyme activities. The genes encoding all three human enzymes have been isolated [4547], and mutations associated with decreased enzymes activities have been reported [4749]. Unlike the GAL genes in the Baker’s yeast [5054], the expression of the three genes in humans has not been examined in great detail. Elsas et al. conducted a functional analysis of the human GALT gene promoter and found that the human GALT gene is regulated in the first −165bp of its promoter region by positive regulators of GALT gene expression, and that a GTCA micro-deletion in a carbohydrate response element explained the functional differences between the D1 and D2 variants of the Duarte N314D mutation in GALT [55]. Recently, Park et al. reported that a novel c.-22T>C mutation in human GALK1 gene promoter is associated with elevated galactokinase phenotype [56]. In contrast to the yeast GAL genes, any up-regulation seen in the human genes observed so far was less than 3-fold. Using rodents as models, several groups noticed that abundant GALT gene expression was found in liver, ovaries, heart, lung and kidneys, while the lowest levels of GALT gene mRNA were detected in testis and skeletal muscle [5759]. In addition, Daude et al. observed that the GALT gene was expressed maximally in the anterior pituitary during the pro-estrous and estrous phases of the estrous cycle [60]. These findings may be relevant to the pathophysiology of primary ovarian insufficiency (POI) in GALT-deficiency galactosemia.

Only human GALK and GALE have been crystallized [61, 62]. Although the human GALT enzyme has not been crystallized, the Escherichia coli GALT crystal was solved by Wedekind et al. [63]. Several laboratories have conducted prolific functional analyses of wild type and mutant human GALT enzymes [6470]. The most common human GALT mutation, Q188R is associated with a poor clinical outcome [7173], while the S135L mutation [7476], has a good outcome only if it is identified and treated in the newborn period with a galactose-restricted diet. Mutations in the GALT gene have ethnic-specific distributions; the Q188R is prevalent in Caucasians of Northern European origin [49], while the S135L is prevalent in patients of African descent [7476]. A 5kb-deletion is found so far exclusively in the Ashkenazi Jewish patients [77]. Similarly, the V94M mutation is associated with the severe, generalized form of GALE-deficiency galactosemia [78], while intermediate phenotypes for GALE deficiency are associated with S81R, T150M and P293L mutations [42, 79]. There are about 20 missense mutations identified in the human GALK1 gene thus far [61], most of which are confined to single families [80], and all but one, A198V, will almost certainly cause cataracts within the first two years of life [81]. The P28T-GALK1 missense mutation is found in people of Roma (Gypsy) descent, likely through a founder effect [82].

Cellular Toxicity of Galactose in Galactosemia – a work in progress

Patients with any type of galactosemia who are on galactose-restricted diet are never truly free from galactose intoxication, as significant amounts of bio-available galactose moieties come from non-dairy foodstuffs [1, 2], endogenous synthesis from UDP-glucose [810], and natural turnover of glycoproteins/glycolipids. At least four mechanisms producing toxicity in human galactosemia at the cellular level are proposed:

(a) Accumulation of toxic metabolites in the blocked Leloir pathway

Since patients with galactosemia are constantly exposed to galactose, they are continually subjected to the potential toxic effects of the intermediates amassed in the blocked Leloir pathway. Accumulation of galactose is seen in all three types of galactosemia, but abnormal accumulation of gal-1-P occurs only in GALT-deficiency and the generalized form of GALE-deficiency [83, 84]. In fact, ingestion of a 60ml-bottle of cow’s milk by GALT-deficient patients results in a rapid accumulation of 10–20mM (18–36mg/100ml) galactose in blood and other tissues [85]. Even on a galactose-restricted diet, such patient’s erythrocytes continue with an intracellular concentration of up to 100–200µM of galactose and gal-1-P [25]. In contrast, GALK-deficient patients also accumulate galactose, galactitol and galactonate, but not ga1-1-P. GALK-deficient patients manifest neither acute toxicity syndrome nor chronic complications such as POI, ataxia and growth failure as seen in the GALT-deficiency. Since the only difference is the elevated gal-1-P, gal-1-P must be the major, if not sole, pathogenic agent for these organ specific failures in GALT-deficiency. Indeed, retrospective studies showed that the median gal-1-P level is the best predictor for the development of POI and dyspraxic speech in GALT-deficiency galactosemia [72, 73]. Additionally, gal-1-P accumulation inhibited cellular growth in the model system Saccharomyces cerevisiae [8689]. Yet, despite reports that gal-1-P potentially interferes with enzymes such as phosphoglucomutase [89, 90], glycogen phosphorylase [91], UDP-glucopyrophosphorylase [9295], and inositol monophosphatase [16, 95, 96], the in vivo target(s) for gal-1-P toxicity have not been confirmed in humans. Pourci and coworkers proposed that gal-1-P might not be toxic, because when adding 2.5mM inosine to the growth medium of GALT-deficient fibroblasts, these cells grew in the presence of 5mM galactose, despite the accumulation of significant amount gal-1-P [97]. We suggest that the added inosine might have overcome or suppressed the toxic effects of the gal-1-P in fibroblasts.

To date, there are no well-controlled human studies that correlate between GALT mutations and gal-1-P levels, as the latter vary with the degree of dietary compliance and the level of individual’s GALK1 gene expression. One can, therefore, only assume that more gal-1-P will be accumulated in patients with more deleterious GALT mutations.

(b) Accumulation of toxic products of alternate galactose catabolism

If galactose is not metabolized efficiently, whether due to a block in the Leloir pathway, excess galactose will be catabolized by alternate pathways to form (a) galactitol and (b) galactonate (Fig.1) [25, 36, 84, 98]. Galactitol cannot be further metabolized, and is predominantly excreted in the urine [25]. Yet, some galactitol accumulates in lens fibers and other tissues. Galactonate is metabolized via the pentose phosphate shunt, and it remains unclear whether the accumulated galactonate is toxic [25]. Recent observations dispute the traditional view of the intracellular osmotic effect of galactitol on lens epithelial cell permeability with consequent cell death and cataract formation in both GALK- and GALT-deficient patients [99101]. Kubo and colleagues suggested that cataract formation is caused by free radical production [102, 103]. These investigators proposed that the concentration of galactitol in the target tissues might not be high enough to evoke significant osmotic stress. Instead, they showed that excess galactose resulted in activation of aldose reductase in producing galactitol, thus depleting NADPH and leading to lowered glutathione reductase activity. As a result, hydrogen peroxide or other free radicals accumulate causing serious oxidative damage to the cells. Change in redox potential in red blood cells has also been reported by Berry et al. in their study of galactonate formation in Type I Galactosemia [104]. In addition to accumulation in lens, high galactitol concentrations are found by MRS in brains of GALT-deficient patients with pseudotumor cerebri [105, 106]. It remains unclear whether this plays a role in the long-term cerebellar dysfunctions and/or mental retardation subsequently seen in these patients.

However, even if galactitol/galactonate metabolism plays a synergistic role with gal-1-P in the pathophysiology of GALT- and GALE-deficiency, it by no means diminishes the pathogenic role played by increased gal-1-P.

(c) Deficiency of UDP-galactose (and UDP-glucose) with implications in protein glycosylation and galactosylation

The Leloir pathway emphasizes the uridylation of gal-1-P. For each molecule of glucose-1-phosphate produced, one molecule of UDP-glucose and one molecule of gal-1-P are consumed, and one molecule of UDP-galactose is formed without energy expenditure (Fig. 1). UDP-glucose can come from epimerization of UDP-galactose or the pyrophosphorylase reaction (Fig. 1). Therefore, the production of glucose-1-phosphate from each gal-1-P molecule can take place at the expense of UDP-galactose formation, and does not necessarily result in a net gain of glucose-1-phosphate if UDP-glucose used originates from the pyrophosphorylase reaction (Fig. 1). In the latter case, UDP-galactose, not glucose-1-phosphate, is the net product of the conversion. It is thus logical to assume that if the galactose metabolic pathway is blocked, it will lead to a potential deficit of UDP-galactose [107]. Since UDP-galactose is a galactosyl donor in glycoproteins/glycolipids biosynthesis, UDP-galactose deficiency can theoretically impair the production of these macromolecules. Yet some investigators suggested that even if the Leloir pathway were blocked at the GALT reaction, UDP-galactose could be formed via the epimerization of UDP-glucose in the presence of GALE (Fig. 1). Still, we and others found that high level of gal-1-P competed with glucose-1-phosphate for the enzyme UDP-glucose pyrophosphorylase (UGP) in vitro [9295]. As the UGP reaction is necessary to produce UDP-glucose (Fig. 1), we found that the natural inhibition of this enzyme in GALT-deficient fibroblasts by gal-1-P lead to reduced availability of UDP-glucose and UDP-galactose [93]. Such decline in UDP-glucose availability would further jeopardize the formation of UDP-galactose from the GALE reaction, and this in turn would lead to the production of abnormal glycoproteins and glycolipids. Several groups have identified aberrantly galactosylated glycoproteins such as serum transferrins, lysozomal enzymes, and circulating follicle stimulating hormone (FSH) in GALT-deficient patients [108111]. At first glance, the oligosaccharide chains of the circulating glycoproteins were found to be deficient in their penultimate galactose and terminal sialic acids [108111], suggesting galactosemia is a secondary congenital disorders of glycosylation (CDG) characterized by galactose deficiency of glycoproteins and glycolipids (processing defect or CDG-II). However, a more in-depth study published recently by Sturiale et al. showed the perturbation of N-linked glycosylation in galactosemia is more complex than originally thought. The authors showed that in untreated galactosemia, there was also a partial deficiency of whole glycans of serum transferrin associated with increased fucosylation and branching as seen in genetic glycosylation assembly defects (CDG-I). It thus suggested that galactosemia is a secondary "dual" CDG causing a processing as well as an assembly N-glycosylation defect [112].

It should be noted that UDP-galactose deficiency has also been observed in mouse cells with defects in the Golgi UDP-galactose translocator (UGT) [113, 114]

(d) Perturbation of inositol metabolism

Wells and Wells reported decreased free and lipid-bound inositol in the tissues of both GALT-deficient patients [115] and galactose-intoxicated rats [116]. Recently, over-expression of human inositol monophosphatase was found to overcome galactose toxicity in GALT-deficient yeast cells [95]. Furthermore, gal-1-P competitively inhibited human inositol monophosphatase [117]. These recent findings suggest a pathogenic role of reduced inositol pools in GALT-deficiency.

These proposed mechanisms for gal-1-P toxicity are not mutually exclusive. For instance, it is possible that the loss of sialic acids in some of the glycoproteins detected under GALT-deficiency resulted from both UDP-galactose deficiency [107, 118] and from excess galactitol formation [119]. Similarly, myo-inositol deficiency could be due to both excess galactitol accumulation [30] and inhibition of inositol phosphatases by excess gal-1-P [117].

Organ-specific Toxicities in Classic (Type I) Galactosemia

GALK-deficient patients manifest only cataracts. They do not have failures of liver, brain, ovary and growth seen in GALT-deficiency. Reports of patients with generalized GALE-deficiency suggested a phenotype similar to that of GALT-deficiency. Thus, we will focus on Type I Galactosemia in this section. Consequent to newborn screening programs [120, 121], most cases of GALT-deficiency are now diagnosed before acute manifestations of the disease advance from prolonged neonatal jaundice to end-stage liver failure. However, very little is known about the pathophysiology of the acute, life-threatening syndromes, including hepatotoxicity [25, 26].

Concerning long-term complications, neurological disorders [122127] and POI [72, 128154] have long been subjects of intense research. More recently osteoporosis [151, 155160] and skeletal muscle weakness were recognized [161, 162]. To date, studies of organ toxicities in GALT deficiency have been mostly descriptive with little known about the precise pathogenic mechanisms. For instance, depletion of Purkinje cells is observed in the cerebellum [122], but nothing is known about the cause for their reduction in number, or why Purkinje cells are more susceptible to galactose toxicity than others in cerebellum. POI associated with hypergonadotrophic hypogonadism has a prevalence of 85% among galactosemic females, and on-going research focused mainly on the followings: (1) Does the pathophysiology occur during the prenatal and/ or postnatal period [141, 145]? (2) Do galactose and/or its metabolites induce apoptosis of ovarian tissues (follicles and granulosa cells) [135, 137]? (3) Does UDP-galactose deficiency decrease viability and function of ovarian tissues [140]? (4) Does aberrant glycosylation of FSH (and LH) molecules impede maturation of follicles [111]? (5) Does aberrant glycosylation adversely affect migration of germ cells [146, 147]? To date, these inquiries have not provided a uniform theory for the cause of POI. For example, there is no solid evidence for prenatal damaging effects of galactose upon ovarian tissues, as Levy et al. reported normal histological findings of ovaries in a female galactosemic patient who died of sepsis [163]. Such anecdotal observations suggest that galactose and/or its metabolites exert their toxicities upon follicles after birth. Indeed, some patients with severe GALT mutations with low MSH, high FSH and LH have conceived, with or without exogenous FSH treatment [144, 149, 154].

Animal Models for Galactosemia and Experimental Hypergalactosemia

One major obstacle in delineating the organ toxicity for GALT-deficiency galactosemia is the lack of an animal model that recapitulates patient symptoms. Leslie and coworkers constructed GALT-knockout mice [164, 165]. When these mice were fed with a high galactose diet (40% galactose by weight), they showed mildly elevated levels of cellular gal-1-P (~30% of the level seen in untreated human patients), galactitol and galactose. Moreover, they remained symptom-free and the female mice were fertile. The fact that these mice accumulated significant levels of gal-1-P suggested that the Leloir pathway of galactose metabolism remained the predominant route of galactose metabolism in these animals. The investigators noted that galactitol was excreted at only 10% of humans with GALT deficiency and considered the low aldose reductase to be protective of organ failure in GALT deficient mice. These authors did not consider the possibility that the target(s) of galactose toxicity in human galactosemic patients could be absent in rodents, or the likelihood that these toxicity targets in mice are less susceptible to the toxic galactose metabolites. We recently identified a human gene called ARHI (aplysia ras homolog I) as a new a target of galactose toxicity in galactosemic patients [166]. We found that this gene was over-expressed in cultured dermal fibroblasts from patients with no GALT genes [77]. When these cells (and controls with GALT) were challenged with galactose, ARHI was increased 10-fold over a 24-hour period [166] in the GALT-deficient cells. Interestingly, over-expression of the ARHI transgene in a normal mouse model caused failure of folliculogenesis, loss of Purkinje cells in the cerebellar cortex, and stunted growth [167], all prevalent clinical complications seen in GALT-deficient patients [25]. Even more significant is that this gene is evolutionarily lost in rodents [168], which may explain why the GALT-knockout mice did not show the expected organ-specific failures [164, 165].

Other investigators of Classic Galactosemia have routinely “poisoned” normal rodents or cell models with excess galactose to create ‘experimental hypergalactosemia’, and although some of these studies offered interesting insights [135, 137, 141, 142, 145, 169172], one must recognize that ‘experimental hypergalactosemia’ does not perturb any genes in the Leloir pathway. This model is reminiscent of rodent models for human type 2 diabetes mellitus by stressing with excess glucose to examine the effect of exaggerated polyol pathway activity on the target tissues as an analogy for human, organ-specific complications [33, 173180]. With normal insulin responses, these rodent models had little analogy to type 2 human diabetes [30, 181, 182]. Recently, ‘experimental hypergalactosemia’ has been used to study aging in wild type fruitfly Drosophila melanogaster [183] and age-related neuronal changes in mice [184187], both of which suggested the involvement of oxidative stress. It is therefore, unclear to what extent that one can extrapolate the results obtained in ‘experimental hypergalactosemia’ to studies of GALT-deficiency galactosemia in humans. Fridovich-Keil’s group recently observed that loss of Drosophila GALT (DgalT) or GALE (DgalE) genes recapitulated significant aspects of the acute human phenotype of galactosemia (http://crisp.cit.nih.gov), and therefore, proposed a new D. melanogaster model for Classic Galactosemia. This new genetic model may help advance our understanding of the role of Leloir pathway in organ function in eukaryotes.

A GALK1-knockout mouse model for galactokinase deficiency has been constructed, but surprisingly, the GALK1-knockout mice did not form cataracts even when fed a high galactose diet [188]. Introduction of a human aldose reductase transgene into these animals resulted in cataract formation in the first postnatal day. No GALE-knockout mouse models have been reported.

Advances in Clinical Management for Galactosemia

Few advances in the clinical management of GALK, GALT and GALE deficiency have been made in recent years. GALK deficiency is detected in newborn screening programs that screen for elevation of galactose. It should be considered in such cases, as well as in cases of neonatal bilateral cataracts [35, 189, 190], which can occur as early as 4 weeks after birth [191]. Laboratory studies will confirm galactosuria, increased urinary galactitol [37, 192]. GALK activity in erythrocytes will be low, while GALT activity in erythrocytes will be normal. Intervention includes (ga-) lactose restriction, and cataract extraction if needed [193]. Mutation studies for GALK1 gene are clinically available.

The most important advance in treating GALT deficiency galactosemia has come from public health based newborn screening and the concept of prediction, intervention and prevention of this autosomal recessive inherited disorder. All states in the USA now screen for GALT deficiency in newborns using dried blood on filter paper either for the GALT enzyme or for total galactose concentrations (galactose plus gal-1-P). Immediate follow-up with direct measurement of gal-1-P and galactose-1-P uridylyltransferase in erythrocytes from whole blood and change of breast or milk formula to soy-based formulas have enabled prevention of liver failure, cataracts, and lethal E. coli sepsis. Further analysis of the GALT gene for mutations aids in developing a long term prognosis, and is clinically available. Severe mutations such as the Q188R, K285N and 5kb-deletion may still develop ataxia, POI, speech dyspraxia and osteoporosis. Recent therapies are aimed at preventing these chronic disabilities and in maintaining the gal-1-P in patients at as low a level as possible. Nutrition is important to provide adequate calories from non-galactose containing foods, to supplement with Vitamin D and Calcium to prevent osteoporosis [159], and to anticipate POI/estrogen deficiency, and provide exogenous sources if needed [152, 154]. Assessment of gal-1-P concentration in erythrocytes in intervals can help determine dietary compliance. Some women with galactosemia have conceived despite having primary amenorrhea [144, 149, 154]. These case reports provide anecdotal evidence that ovarian pathology involves failure of follicle maturation, but the presence of immature ovarian follicles. As discussed above, most evidence supports a primary role of excess gal-1-P in the pathophysiology of galactosemia and the most exciting new approach to treatment would be to develop a non-toxic, enzyme-specific inhibitor of galactokinase to reduce gal-1-P accumulation [27, 194196]. A recent report documenting significant abnormalities on cerebral PET scans in patients with GALT deficiency may lead to further developments in imaging and management of this condition [197]. Finally, clinical management of partial GALT deficiency, especially patients with a D/G biochemical phenotype, has been a topic of interest, at least up to age 5 years [198]. Ficicioglu and coworkers, however, showed that clinical and development outcomes in D/G galactosemics are good independent of any dietary treatment [199].

Reports of patients with generalized GALE deficiency suggest a phenotype comparable to that of GALT deficiency, but also with significant infantile hypotonia, mental deficiency and sensorineural hearing loss in a few cases [78, 200205]. Acquired dysmorphic features have been described, as well as splenomegaly and contractures [204]. At least one patient was reported to have normal ovarian function [78]. GALE deficiency may be detected in newborn screening programs that screen for elevation of galactose [200, 202, 204]. It should be considered in such cases, as well in cases that resemble Classic Galactosemia [78, 201]. Laboratory studies will confirm galactosuria; GALT activity in erythrocytes will be normal, while GALE activity will be reduced. Intervention includes (ga-)lactose restriction. Mutation studies for GALE are clinically available.

Looking to the future

Due to the relatively benign nature of GALK deficiency and the severe effects of GALT-/GALE-deficiencies, it is reasonable to assume that GALT-/GALE- deficiencies will continue to dominate the research field of galactosemia. It is also clear that early dietary treatment for GALT-deficiency fails to prevent the chronic complications and negatively affect the health-related quality of life of galactosemic patients [126, 206210]. Several of us have recognized the specific toxicity of accumulated galactose-1-phosphate in human GALT-deficiency. Therefore a rational and unique approach to therapy would be to reduce the accumulation of gal-1-P by inhibiting the GALK enzyme with specific, non-toxic, low molecular weight compound [27, 194196]. To date, our group has screened different chemical compound libraries composed of about 50,000 small molecules with diverse structural scaffolds for their inhibitory properties against activity of purified GALK. Thus far, we have identified nearly 150 small molecules (or hits) that inhibit human GALK activity in vitro at the level of 86.5% or more [195]. We have selected 34 compounds for further characterization, and results so far are promising (Fig. 2).

Fig. 2
Thirty-four selected human GALK inhibitors [195]

In addition to the much-needed research for improved therapy, there is also great need to advance our understanding of the pathophysiology of this condition. Are the toxic effects of GALT-deficiency initiated in utero or post-natally? Are there dual effects? What are the toxicity targets of gal-1-P in vivo? Why are some organs more susceptible to galactose toxicity? The answers will not only dictate the treatment options, but also uncover new tissue-specific therapeutic targets.

Lastly, human GALT- and GALE- deficiencies represent natural models for the study of single gene effects on a pleiotrophic phenotype with perturbation of an essential metabolic pathway. In fact, all hypotheses concerning pathogenic mechanisms listed above implicated many other cellular processes such as inositol metabolism and protein glycosylation, further indicating the time is ripe to study human galactose metabolism and the disorders associated with it from the Systems Biology perspective [211, 212].

Acknowledgements

We acknowledge that we could not have completed this manuscript without the outstanding contributions made by our scientific and clinical colleagues, as well as patient volunteers. Grant support to Kent Lai includes NIH 5 R01 HD054744-02 and NIH 1 R03 MH085689-01.

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