Galactose-restricted Diet Research Articles

Health and well-being of maturing adults with classic galactosemia.

Long-term outcomes in classic galactosemia (CG) have been studied previously, but all prior studies have relied on cohorts of patients that were small in number, or heavily skewed toward children and young adults, or both. Here, we extend what is known about the health and well-being of maturing adults with CG by analyzing the results of anonymous custom surveys completed by 92 affected individuals, ages 30-78, and 38 unaffected sibling controls, ages 30-79. The median age for patients was 38.5 years and for controls was 41 years. These study participants hailed from 12 different countries predominantly representing Europe and North America. Participants reported on their general life experiences and outcomes in seven different domains including: speech/voice/language, cognition, motor function, cataracts, bone health, psychosocial well-being, and gastrointestinal health. We also queried women about ovarian function. Our results indicated a prevalence of long-term complications across all outcome domains that aligned with levels previously reported in younger cohorts. Given the sample size and age range of participants in this study, these findings strongly suggest that the adverse developmental outcomes commonly linked to CG are not progressive with age for most patients. We also tested four candidate modifiers for possible association with each of the outcomes followed, including: days of neonatal milk exposure, rigor of dietary galactose restriction in early childhood, current age, and home continent. We observed no associations that reached even nominal significance, except for the following: cataracts with neonatal milk exposure (p = 2.347e-04), cataracts with age (p = 0.018), and bone health with home continent (p = 0.03).

Whole-body galactose oxidation as a robust functional assay to assess the efficacy of gene-based therapies in a mouse model of Galactosemia

Despite the implementation of life-saving newborn screening programs and a galactose-restricted diet, many patients with Classic Galactosemia develop long-term debilitating neurological deficits and primary ovarian insufficiency. Previously, we showed that administration of human GALT mRNA predominantly expressed in the GalT gene-trapped mouse liver augmented the expression of hepatic GALT activity, which not only decreased galactose-1 phosphate (gal-1P) in the liver, but also peripheral tissues. Since each peripheral tissue requires distinct methods to examine the biomarker and/or GALT effect, this highlights the necessity for alternative strategies to evaluate the overall impact of therapies. In this study, we established that whole-body galactose oxidation (WBGO) as a robust, non-invasive, and specific method to assess the in vivo pharmacokinetic and pharmacodynamic parameters of two experimental gene-based therapies that aimed to restore GALT activity in a mouse model of Galactosemia. While our results illustrated the long-lasting efficacy of AAVrh10-mediated GALT gene transfer, we found that GALT mRNA therapy that target the liver predominantly is sufficient to sustain WBGO. The latter could have important implications in the design of novel targeted therapy to ensure optimal efficacy and safety.

Twelve-year review of galactosemia newborn screening in Taiwan: Evolving methods and insights

BackgroundGalactosemia was introduced into Taiwan's routine newborn screening (NBS) program in 1985. This study presents a 12-year experience, emphasizing disease diagnosis and screening performance. MethodNBS for galactosemia utilized dried blood spot samples taken 48–72 h post-delivery, with total galactose (TGal) level as the primary marker. Newborns with critical TGal levels were referred immediately, while those with borderline TGal underwent a recall test. GALT activity measurement was applied simultaneously as the second-tier marker. Further confirmatory tests, such as whole exome sequencing (WES), were conducted upon referral. ResultsFrom January 1st, 2011, to December 31st, 2022, 51 cases were identified from 817,906 newborns. Of these, nine individuals had persistently elevated TGal. Diagnoses included one case of GALT deficiency, one of GALM deficiency, and seven of GALE deficiencies. Notably, the classic galactosemia patient (GALT deficiency) presented with extreme high TGal and was referred to the hospital for diet management immediately. All affected patients were instructed to adopt a galactose-restricted diet. By the median age of 2.5 years, all exhibited normal development and liver function. ConclusionThe incidence of classical galactosemia and its variants is extremely low in Taiwan. Incorporating WES into NBS has improved our ability to detect various galactosemia forms, enriching our understanding of the genetic underpinnings. While these newly discovered forms often present with milder initial elevations in TGal, specific biochemical investigations and regular monitoring are essential to understanding the long-term implications and outcomes.

Neuropsychological stability in classical galactosemia: A pilot study in 10 adult patients.

Classical galactosemia (CG) is an autosomal recessive disorder of galactose metabolism. Despite early initiation of a galactose-restricted diet, patients develop long-term complications including cognitive impairment. There is an ongoing debate whether the cognitive impairment in CG is stable throughout life or progresses with age. Earlier cross-sectional and longitudinal studies regarding intelligence suggest stability, but longitudinal neuropsychological studies focusing on specific cognitive functions are limited. Therefore, the aim of this study is to assess cognitive change over time in adult CG-patients. Ten adult patients with normal to borderline intelligence (mean age 33 years, range 22-49; IQ≥70 or independent work- or living situation) were assessed twice with a mean time interval of 3 years and 9 months (range 1023-1575 days). The neuropsychological assessments covered information processing speed, executive functioning, verbal fluency, and visuospatial functioning. Results showed that there was no significant decline or improvement in test scores on all neuropsychological measures except a decline on the Trail Making Test-A (p = 0.048). However, this group-level difference was subject to "regression to the mean" and was not endorsed by significant change in test scores measuring the same cognitive domain. Moreover, no specific pattern of reliable change (RCI > -1.96) was present on specific measures or within individual patients. This explorative study performed in 10 adult CG-patients with normal to borderline intelligence revealed no cognitive change on several cognitive domains. This implies that the subset of adults with a normal to borderline IQ in their early and middle adulthood are cognitively stable.

Grip strength in patients with galactosemia and in a galactose-1-phosphate uridylyltransferase (GALT)-null rat model.

Classic galactosemia (CG) and clinical variant galactosemia (CVG) are allelic inborn errors of metabolism that result from profound deficiency, and near-profound deficiency, respectively, of galactose-1-P uridylyltransferase (GALT). Despite early detection and lifelong dietary restriction of galactose, which is the current standard of care, most patients with CG/CVG grow to experience a range of long-term developmental and other complications. One of the less well-understood complications of CG/CVG is decreased hand grip strength, as reported by Potter et al. (2013). Here, we confirm this phenotype in an independent cohort of 36 cases (4-18 years) and 19 controls (4-17 years), and further demonstrate that the grip strength deficit observed in cases may be secondary to growth delay. Specifically, we found that when grip strength of cases and controls in a new cohort recruited in 2022 was plotted by weight, rather than age, the difference between cases and controls for both sexes disappeared. Reanalyzing data from the original 2013 cohort, we found that differences in weight accounted for grip strength differences between cases and controls in girls and young women, but not in boys and young men. Finally, we tested whether a GALT-null rat model of CG also showed a grip strength deficit-it did-and again the difference between GALT-null and wild-type rats associated with differences in body mass. Combined, these results confirm that GALT deficiency is associated with a grip strength deficit in both young patients with CG/CVG and GALT-null rats, and further demonstrate that this phenotype may be secondary to growth delay, and therefore not evidence of a muscle abnormality.

Long-term complications in classic galactosemia are not progressive

Classic galactosemia (CG) is a potentially lethal genetic disorder that results from profound deficiency of galactose-1-P uridylyltransferase. Despite early detection and life-long dietary restriction of galactose, which is the current standard of care, many patients with CG grow to experience a range of long-term developmental complications that can include difficulties with speech/voice/language, cognitive, motor, and psychosocial outcomes, among other problems. That these complications are common in CG is well-documented, but whether they are also progressive has been a point of controversy for decades. Here, we addressed the question of whether long-term outcomes in CG are progressive by analyzing a robust data set in each of 4 ways. First, we compared cross-sectional Vineland-3 Adaptive Behavior Scales scores for 101 cases and 65 unaffected sibling controls and found no evidence of consistently declining scores with age. Second, we analyzed longitudinal Vineland-3 subdomain scores for 45 cases and 34 controls to see if individual participants demonstrated developmental gains (positive slope) or losses (negative slope) over time. The changes in most growth scale value (GSV) scores, which are not normed, were positive for both cases and controls <10y, and either positive or near zero for participants ≥10y. In contrast, the slopes of most v-Scale scores, which are normed, were negative for many cases <10y, indicating that these children, while gaining milestones, were gaining them at a slower pace than their counterparts in the reference population. Third, we analyzed medical records from 76 cases, assigning ordinal scores for complications and gathering the quantitative results of relevant formal assessments where available. Both cross-sectional and longitudinal analyses of both ordinal and formal assessment scores confirmed that outcomes were mostly stable, albeit with some ups and downs in isolated cases. Finally, we analyzed data collected via custom family-response surveys from 124 cases and 67 controls regarding each participant's perceived symptom severity over time. Among cases, the percentages of respondents reporting worsening symptoms over time for speech, cognitive, motor, and psychosocial outcomes were 0.8%, 6.6%, 5.2%, and 9.8%, respectively. Among controls, the corresponding percentages were 0.0%, 1.5%, 1.5%, and 6.5%, respectively. These results provide compelling evidence that long-term developmental complications are not progressive for a majority of patients with CG.

Understanding the patient experience of Classic Galactosemia in pediatric and adult patients: increased disease burden, challenges with daily living, and how they evolve over time

BackgroundClassic Galactosemia (CG) is a rare, autosomal recessive condition. Newborn screening and a timely galactose-restricted diet can resolve acute symptoms and decrease fatalities, but significant chronic, progressive morbidities remain and significantly impact daily life. The objective of this study was to better understand the burden of disease in children and adults with CGs and describe how morbidities evolve over time.MethodsA total of 49 individuals with CG from the United States (US) were included in the qualitative surveys (13 adults [9 self-reported] and 36 pediatric patients). Fifteen follow-up interviews were conducted with 5 adults and 10 caregivers, discussing 17 individuals with CG overall (2 caregivers each discussed 2 children).ResultsQualitative survey and interview data demonstrated the substantial burden of CG. Difficulties in a wide range of functions were experienced, which included: speech articulation; language and communication; cognition, memory and learning; emotions; and social interactions. Most difficulties appeared in childhood and persisted or worsened with age. Most adults did not live independently. Others lived semi-independently and experienced many daily challenges and required support. Caregivers also described the burden of caring for someone with CG and spoke about the impact this has on their day-to-day life, work, and relationships.ConclusionsThese findings demonstrate the pronounced and persistent burden of disease encountered by individuals with CG, and that the condition has a significant impact on the quality of life of caregivers.

Novel GALT variations and genetic spectrum in Turkish population with the correlation of genotype and phenotype.

Classic galactosemia (OMIM#230400) is an autosomal recessive inborn error of carbohydrate metabolism caused by a deficiency of the galactose-1-phosphate-uridyl-transferase enzyme encoded by the GALT gene. Even though a galactose-restricted diet efficiently resolves the acute complications, it is insufficient to prevent long-term complications regarding speech defects, intellectual functioning, premature ovarian failure, cataract, hepatomegaly, dysarthria, ataxia, and tremor. Seventy-seven patients who were genetically diagnosed with classic galactosemia were included in this cohort. Identified novel variants were classified based on their predicted effect on the GALT function. Further, potential genotype-phenotype correlations were investigated via statistical analysis. In total, 18 different sequence variants were identified, including four novels (c.200delG/p.(Arg67Profs* 19), c.533T>G/ p.(Met178Arg), c.708_709delGT/p.(Ser236Argfs* 30), c.467C>A/p.(Ser156* )). Jaundice was the most common short-term finding with 80% (61/77). Even with early diagnosis, intellectual disability is encountered with 36% (27/74) of the long-term complications. Patients with biallelic missense variants have a significantly higher prevalence of cataracts (OR: 17.9). Longitudinal observations showed attenuation of cataracts and hepatomegaly. This study has shown the GALT variation spectrum of the Turkish population with a 30-year retrospective cohort, submitting a significant contribution to the genotype/phenotype correlation in galactosemia. This study also highlights the cost-effective importance of Sanger sequencing in the diagnosis of single-gene metabolic diseases.

Gas Chromatography with Flame-Ionization Detection-Based Analysis of Sugar Contents in Korean Agricultural Products for Patients with Galactosemia.

Patients with galactosemia accumulate galactose in their bodies, requiring a lifelong galactose-restricted diet. Therefore, accurate information on the galactose content in commercial agro-food resources is essential. The HPLC method generally used for sugar analysis has low separation and detection sensitivity. Here, we sought to establish an accurate analytical method for determining the galactose content in commercial agro-food resources. To that aim, we employed gas chromatography with flame-ionization detection to detect trimethylsilyl-oxime (TMSO) sugar derivatives (concentration: ≤0.1 mg/100 g). The galactose content in 107 Korean agro-food resources reflecting intake patterns was then analyzed. The galactose content in steamed barley rice was 5.6 mg/100 g, which was higher than that in steamed non-glutinous and glutinous rice. Moist-type and dry-type sweet potatoes, blanched zucchini, and steamed Kabocha squash had high galactose content (36.0, 12.8, 23.1, and 61.6 mg/100 g, respectively). Therefore, these foods are detrimental to patients with galactosemia. Among fruits, avocado, blueberry, kiwi, golden kiwifruit, and sweet persimmon had galactose contents of ≥10 mg/100 g. Dried persimmon had 132.1 mg/100 g and should therefore be avoided. Mushrooms, meat, and aquatic products showed low galactose content (≤10 mg/100 g), making them safe. These findings will help patients to manage their dietary galactose intake.

Caregivers' nutrition-related knowledge, perceptions, practices and barriers regarding the therapeutic diet for classical galactosaemia.

Classical galactosaemia is a life-threatening disorder of carbohydrate metabolism, and the primary treatment is a lifelong galactose-restricted diet commenced in infancy. Adherence to restrictive diets can be burdensome for patients and their families; however, little is known about the impact on caregivers. This study aims to determine the nutrition-related knowledge, perceptions, practices, and barriers of caregivers related to the therapeutic diet for classical galactosaemia. An online survey was conducted among 98 eligible members of the Galactosaemia Support Group using a novel questionnaire. Descriptive and inferential analyses were performed using Microsoft Excel 2021 and Stata/MP (version 17.0), respectively. Forty-three caregivers participated in the study. RESULTSANDCONCLUSION: Of those who participated, 98% had high levels of dietary knowledge. Caregivers' knowledge scores ( = 17.9, standard deviation [SD] = 1.7) were positively correlated with educational level (r = 0.383, p = 0.013). Highattitudinal scores ( = 32.5, SD = 5.5) obtained by most caregivers (65%) revealed an overall positive attitude towards the galactosaemia diet. Negative perceptions of being unable to feed their child breast milk (49%) were apparent, and this perception was positively correlated with caregivers' intention to feed their child breast milk (r = 0.450, p = 0.003). Caregivers' concerns about the safety of their child in social settings (79%) and feeling that their child was excluded in social settings (49%) were clear barriers. A multidisciplinary approach to galactosaemia management is warranted, with healthcare interventions focusing on addressing caregivers' negative perceptions and barriers related to the diet to enable tailored support and facilitate lifelong compliance.

Lactose and Galactose Content in Spanish Cheeses: Usefulness in the Dietary Treatment of Patients with Galactosaemia.

In galactosaemia, a strict galactose-free diet is necessary to prevent or resolve acute symptoms in infants. However, because the body produces up to 10 times more galactose than is found in a galactose-restricted diet, excessively restrictive diets should be avoided in children and adults to prevent nutritional deficiencies. Since cheese is a nutritional source of the calcium necessary for bone health, the latest international guidelines on the management of classical galactosaemia (2017) allow the consumption of cured cheeses with less than 25 mg of galactose/100 g and recommend that each country verifies the adequacy of the cheeses, since most mature cheeses do not always have a lower galactose content. In total, 32 cheese samples were purchased (19 Spanish and 13 international cheeses), and their lactose and galactose contents were analysed using ion chromatography with pulsed amperometric detection (IC-PAD). Five Spanish cheeses contained less than 25 mg of galactose/100 g: García Baquero semi-cured cheese; Hacendado, Gran Reserva and Mahón cured cheeses; and García Baquero Reserva 12-month cured cheese. In addition, eight international cheeses were confirmed as suitable: Comté, Gouda, Gruyere, Maasdam, Parmigiano, Edam, Emmental, and some samples of Cheddar. In addition to the well-known low-galactose Swiss and Dutch cheeses, according to the current results, five Spanish cheeses can be safely consumed. The greater availability of types of cheese favours better bone health in patients with galactosaemia.

CO168 Adaptive Behaviors Over Time in Children and Young Adults With Classic Galactosemia

Prior studies have documented that patients with classic galactosemia (CG) are at increased risk for developmental deficits despite early detection and rigorous dietary restriction of galactose. However, whether these complications progress over time has not been confirmed. Here, we explore this question using both cross-sectional and longitudinal analyses.

Early postnatal alterations in follicular stress response and survival in a mouse model of Classic Galactosemia

Primary ovarian insufficiency is characterized by accelerated loss of primordial follicles, which results in ovarian failure and concomitant menopause before age 40. About 1–3% of females in the general population are diagnosed with POI; however, greater than 80% of females with the inherited disease Classic Galactosemia will develop POI. Classic Galactosemia is caused by mutations in the GALT gene encoding the enzyme galactose-1 phosphate uridylyltransferase. While dietary restriction of galactose is lifesaving in the neonatal period, the development of complications including primary ovarian insufficiency is not mitigated. Additionally, the pattern(s) of follicle loss have not been completely characterized. The chronic accumulation of aberrant metabolites such as galactose-1-phosphate and galactitol are suspected culprits in the development of the sequelae, yet the mechanisms remain elusive.Our group uses a GalT gene-trapped mouse model to study the pathophysiology of primary ovarian insufficiency in Classic Galactosemia. We recently showed that differences in the Integrated Stress Response pathway occur in mutant ovaries that likely contribute to their primary ovarian insufficiency phenotype. Using immunofluorescent staining of histological sections of ovaries at progressive ages, we saw evidence of altered Integrated Stress Response activity in granulosa cells and primordial oocytes consistent with accelerated primordial follicle growth activation, aberrant DNA damage and/or repair, and increased cellular stress/death. Overall, our findings indicate that abnormal Integrated Stress Response in the Classic Galactosemia model ovary results in accelerated primordial follicle growth activation, sometimes referred to as “burnout.” These aberrant early events help further clarify when/how the primary ovarian insufficiency phenotype arises under galactosemic conditions.

A multinational study of acute and long-term outcomes of Type 1 galactosemia patients who carry the S135L (c.404C> T) variant of GALT.

Patients with galactosemia who carry the S135L (c.404C > T) variant of galactose-1-P uridylyltransferase (GALT), documented to encode low-level residual GALT activity, have been under-represented in most prior studies of outcomes in Type 1 galactosemia. What is known about the acute and long-term outcomes of these patients, therefore, is based on very limited data. Here, we present a study comparing acute and long-term outcomes of 12 patients homozygous for S135L, 25 patients compound heterozygous for S135L, and 105 patients homozygous for two GALT-null (G) alleles. This is the largest cohort of S135L patients characterized to date. Acute disease following milk exposure in the newborn period was common among patients in all 3 comparison groups in our study, as were long-term complications in the domains of speech, cognition, and motor outcomes. In contrast, while at least 80% of both GALT-null and S135L compound heterozygous girls and women showed evidence of an adverse ovarian outcome, prevalence was only 25% among S135L homozygotes. Further, all young women in this study with even one copy of S135L achieved spontaneous menarche; this is true for only about 33% of women with classic galactosemia. Overall, we observed that while most long-term outcomes trended milder among groups of patients with even one copy of S135L, many individual patients, either homozygous or compound heterozygous for S135L, nonetheless experienced long-term outcomes that were not mild. This was true despite detection by newborn screening and both early and life-long dietary restriction of galactose. This information should empower more evidence-based counseling for galactosemia patients with S135L.

Multi-omics in classical galactosemia: Evidence for the involvement of multiple metabolic pathways.

Classical galactosemia (CG) is one of the more frequent inborn errors of metabolism affecting approximately 1:40.000 people. Despite a life-saving galactose-restricted diet, patients develop highly variable long-term complications including intellectual disability and movement disorders. The pathophysiology of these complications is still poorly understood and development of new therapies is hampered by a lack of valid prognostic biomarkers. Multi-omics approaches may discover new biomarkers and improve prediction of patient outcome. In the current study, (semi-)targeted mass-spectrometry based metabolomics and lipidomics were performed in erythrocytes of 40 patients with both classical and variant phenotypes and 39 controls. Lipidomics did not show any significant changes or deficiencies. The metabolomics analysis revealed that CG does not only compromise the Leloir pathway, but also involves other metabolic pathways including glycolysis, the pentose phosphate pathway, and nucleotide metabolism in the erythrocyte. Moreover, the energy status of the cell appears to be compromised, with significantly decreased levels of ATP and ADP. This possibly is the consequence of two different mechanisms: impaired formation of ATP from ADP possibly due to reduced flux though the glycolytic pathway and trapping of phosphate in galactose-1-phosphate (Gal-1P) which accumulates in CG. Our findings are in line with the current notion that the accumulation of Gal-1P plays a key role in the pathophysiology of CG not only by depletion of intracellular phosphate levels but also by decreasing metabolite abundance downstream in the glycolytic pathway and affecting other pathways. New therapeutic options for CG could be directed towards the restoration of intracellular phosphate homeostasis.

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

BackgroundClassic 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.ResultsInterviews 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.ConclusionsThe 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.

OP005: AT-007 significantly reduces toxic galactitol in ACTION-galactosemia kids - the 1st therapeutic interventional clinical trial in children with classic galactosemia

Classic Galactosemia (CG) is a rare, autosomal recessive disease where galactose is not metabolized properly due to severe deficiency or absence of the GALT enzyme (galactose-1-phosphate uridyl transferase). At abnormally high levels, galactose becomes an aberrant substrate for the enzyme aldose reductase, resulting in conversion to an abnormal and toxic metabolite, galactitol. Newborn screening and implementation of a galactose-restricted diet has reduced newborn acute symptoms and significantly decreased fatalities. However, despite early dietary intervention, children continue to develop significant morbidities in speech, cognition, behavior, and motor function, which have been shown to progressively worsen with age, as well as cataracts and primary ovarian insufficiency in females. AT-007 is an oral CNS penetrant aldose reductase inhibitor, which prevents conversion of galactose to toxic galactitol, that is in development for the treatment of CG. Reduction in circulating galactitol by AT-007 has been shown to halt the progression of disease in a rat model of Galactosemia. ACTION-Galactosemia Kids is a sequential, two-part, randomized double-blind, placebo-controlled study evaluating the clinical benefit, safety, pharmacokinetics and pharmacodynamics of AT-007 in pediatric patients with CG. Patients were randomized 2:1 to AT-007 or placebo. Disease demographics, genetic variant, and patient history were assessed at baseline. Additionally, functional tests of speech, motor function, cognition and behavior were performed at baseline for all patients enrolled in the clinical study. The primary biomarker study endpoint was reduction in plasma galactitol over a minimum of 30 days of treatment with the target dose of AT-007 vs placebo. Baseline and 30-day plasma galactitol levels were drawn under fasted conditions and evaluated via a validated liquid chromatography-mass spectrometry assay. Baseline galactitol correlation with disease severity was evaluated via a linear model incorporating baseline speech, cognition, behavior and motor skills assessments. Forty-seven patients ranging in age from 2 to 17, were enrolled at 3 US clinical sites in ACTION-Galactosemia Kids across three predefined age groups (2-6 years old; 7-12 years old; 13-17 years old). The patients were predominantly White (98%), had a mean age of 9 and 51% were female/49% male. The most common baseline disease characteristics included learning disorders (∼50%), apraxia (∼40%), anxiety (∼35%), vitamin deficiency (∼30%), tremor (∼20%) and ataxia (∼20%). All the female patients older than 12 had primary ovarian insufficiency. Additionally, ∼10% of the patients suffered from seizures and ∼5% had early onset cataracts. Baseline disease and demographic characteristics were balanced across the placebo and AT-007 treatment groups. Galactitol levels at baseline correlated with total disease severity in this pediatric patient population (p=0.004). Treatment with AT-007 resulted in a 40.2% reduction in galactitol, which was significant when compared with patients on placebo (p<0.001). The reduction in toxic galactitol was consistent among age and dose groups and was not associated with changes in galactose or galacose-1-phosphate (Gal-1p). AT-007 was safe and well tolerated. The biomarker results from ACTION-Galactosemia Kids demonstrates that treatment with AT-007 resulted in a significant reduction of the toxic metabolite galactitol, a biomarker that correlated with disease severity, in pediatric patients with Classic Galactosemia. Treatment of pediatric Galactosemia patients age 2 to 17 with AT-007 was safe and well tolerated.

Neonatal GALT gene replacement offers metabolic and phenotypic correction through early adulthood in a rat model of classic galactosemia

Classic galactosemia (CG) results from profound deficiency of galactose‐1‐P uridylyltransferase (GALT). Despite early detection by newborn screening and lifelong dietary restriction of galactose, most patients grow to experience a range of long‐term complications. Recently, we developed and characterized a GALT‐null rat model of CG and demonstrated that AAV9‐hGALT, administered by tail vein injection to neonatal pups, dramatically improved plasma, liver, and brain galactose metabolites at 2 weeks posttreatment. Here we report a time‐course study of GALT restoration in rats treated as neonates with scAAV9‐hGALT and harvested at 8, 14, 30, and 60 days. Cohorts of rats in the two older groups were weaned to diets containing either 1% or 3% of calories from galactose. As expected, GALT activity in all treated animals peaked early and then diminished over time, most notably in liver, ostensibly due to dilution of the nonreplicating episomal vector as transduced cells divided. All treated rats showed dramatic metabolic rescue through 1 month, and those weaned to the lower galactose diet showed continued strong metabolic rescue into adulthood (2 months). Prepubertal growth delay and cataracts were both partially rescued by treatment. Finally, we found that UDP glucose pyrophosphorylase (UGP), which offers a metabolic bypass around missing GALT, was 3‐fold more active in brain samples from adult rats than from young pups, offering a possible explanation for the improved ability of older GALT‐null rats to metabolize galactose. Combined, these results document promising metabolic and phenotypic efficacy of neonatal GALT gene replacement in a rat model of classic galactosemia.

Advances and Challenges in Classical Galactosemia. Pathophysiology and Treatment

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.

β-Galactosidase therapy can mitigate blood galactose elevation after an oral lactose load in galactose mutarotase deficiency.

Galactose mutarotase (GALM) deficiency (MIM# 618881), also known as type IV galactosemia, is caused by biallelic pathogenic variants of GALM. Cataracts are observed in patients with GALM deficiency as well as in other conditions associated with high levels of blood galactose and can be prevented by consuming a galactose-restricted diet or formula. Galactose restriction is the only known treatment for GALM deficiency and other types of galactosemia. We incidentally found that β-galactosidase might reduce blood galactose levels caused by lactose loading in GALM deficiency. Consequently, we investigated the effectiveness of β-galactosidase in decreasing the level of blood galactose in three patients with GALM deficiency. We performed two lactose loading tests per case: one with and one without β-galactosidase. The add-on administration of β-galactosidase significantly mitigated blood galactose elevations after lactose loading. Although urine galactitol was mildly elevated in all patients with GALM deficiency, β-galactosidase did not prevent increased levels of urine galactitol during the loading tests. No adverse events, including cataracts, were observed during or after the tests. Therefore, β-galactosidase could be a potential novel treatment agent for blood galactose elevation caused by lactose in patients with GALM deficiency. The effectiveness of β-galactosidase could possibly result in loosening of the galactose dietary restrictions or treatment for patients with GALM deficiency.