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In classic galactosemia (CG) patients, aldose reductase (AR) converts galactose to galactitol. In a phase 1/2, placebo‐controlled study (NCT04117711), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of govorestat were evaluated after single and multiple ascending doses (0.5‐40 mg/kg) in healthy adults (n = 81) and CG patients (n = 14). Levels of govorestat in plasma and cerebrospinal fluid (CSF) and blood levels of galactitol, galactose, and galactose‐1‐phosphate (Gal‐1p) were measured for population PK and PK/PD analyses. Govorestat was well tolerated. Adverse event frequency was comparable between placebo and govorestat. Govorestat PK displayed a 2‐compartment model with sequential zero‐ and first‐order absorption, and no effect of demographic factors. Multiple‐dose PK of govorestat was linear in the 0.5‐40 mg/kg range, and CSF levels increased dose dependently. Elimination half‐life was ∼10 h. PK/PD modeling supported once‐daily dosing. Change from baseline in galactitol was −15% ± 9% with placebo and −19% ± 10%, −46% ± 4%, and −51% ± 5% with govorestat 5, 20, and 40 mg/kg, respectively, thus was similar for 20 and 40 mg/kg. Govorestat did not affect galactose or Gal‐1p levels. In conclusion, govorestat displayed a favorable safety, PK, and PD profile in humans, and reduced galactitol levels in the same magnitude (∼50%) as in a rat model of CG that demonstrated an efficacy benefit on neurological, behavioral, and ocular outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Babble Boot Camp (BBC) is a parent-implemented telepractice intervention for infants at risk for speech and language disorders. BBC uses a teach-model-coach-review approach, delivered through weekly 15-min virtual meetings with a speech-language pathologist. We discuss accommodations needed for successful virtual follow-up test administration and preliminary assessment outcomes for children with classic galactosemia (CG) and controls at age 2.5 years. Method: This clinical trial included 54 participants, 16 children with CG receiving BBC speech-language intervention from infancy, age 2 years, five children receiving sensorimotor intervention from infancy and changing to speech-language intervention at 15 months until 2 years of age, seven controls with CG, and 26 typically developing controls. The participants' language and articulation were assessed via telehealth at age 2.5 years. Results: The Preschool Language Scale-Fifth Edition (PLS-5) was successfully administered with specific parent instruction and manipulatives assembled from the child's home. The GFTA-3 was successfully administered to all but three children who did not complete this assessment due to limited expressive vocabularies. Referrals for continued speech therapy based on PLS-5 and GFTA-3 scores were made for 16% of children who received BBC intervention from infancy as compared to 40% and 57% of children who began BBC at 15 months of age or did not receive BBC intervention, respectively. Conclusions: With extended time and accommodations from the standardized administration guidelines, virtual assessment of speech and language was possible. However, given the inherent challenges of testing very young children virtually, in-person assessment is recommended, when possible, for outcome measurements. [ABSTRACT FROM AUTHOR]

Although PDO Pecorino Sardo is one of the oldest traditional cheeses of Sardinia, Italy, data on its nutritional properties and food safety are lacking. In particular, significant amounts of lactose and galactose may be a health concern for consumers. The primary objective of this study is to quantify, using a validated GC-FID method, the residual lactose and galactose content in "maturo" (i.e., ripened for at least two months) Protected Denomination of Origin (PDO) Pecorino Sardo cheese. A statistically representative sampling from seven dairies distributed throughout Sardinia has been selected for this aim. In addition to lactose and galactose, two of their metabolites (i.e., glucose and tagatose, respectively) and a bioactive polyol like myo-inositol were quantified. The concentration of lactose (mean 26 mg kg−1, range 4–90 mg kg−1) was below the strictest limit set in the European Union (i.e., 100 mg kg−1), while the galactose content was found to be in an amount (mean: 76 mg kg−1, range: 10–200 mg kg−1) that even patients afflicted with severe galactosemia, albeit with some circumspection, could consume this cheese. Ripening (two to four months) had no significant effect on the amount of all analytes, while a slight decrease in galactose levels was observed during the manufacturing season. Finally, the amounts of glucose, tagatose, and myo-inositol are constant in the range of a few tens of mg kg−1. [ABSTRACT FROM AUTHOR]

Abstract Background Classic galactosemia is a rare inherited metabolic disease with long-term complications, particularly in the psychosocial domain. Patients report a lower quality of social life, difficulties in interactions and social relationships, and a lower mental health. We hypothesised that social cognition deficits could partially explain this psychological symptomatology. Eleven adults with galactosemia and 31 control adults participated in the study. We measured social cognition skills in cognitive and affective theory of Mind, and in basic and complex emotion recognition. We explored psychosocial development and mental well-being. Results We found significant deficits on all 4 social cognition measures. Compared to controls, participants with galactosemia were impaired in the 2nd-order cognitive theory of mind, in affective theory of mind, and in basic and complex emotion recognition. Participants with galactosemia had a significant delay in their psychosexual development, but we found no delay in social development and no significant decrease in mental health. Conclusion Social cognition processes seem impaired among our participants with galactosemia. We discuss the future path research may follow. More research is needed to replicate and strengthen these results and establish the links between psychosocial complications and deficits in social cognition.

Abstract Classic galactosemia (CG) arises from loss‐of‐function mutations in the Galt gene, which codes for the enzyme galactose‐1‐phosphate uridylyltransferase (GALT), a central component in galactose metabolism. The neonatal fatality associated with CG can be prevented by galactose dietary restriction, but for decades it has been known that limiting galactose intake is not a cure and patients often have lasting complications. Even on a low‐galactose diet, GALT's substrate galactose‐1‐phosphate (Gal1P) is elevated and one hypothesis is that elevated Gal1P is a driver of pathology. Here we show that Gal1P levels were elevated above wildtype (WT) in Galt mutant mice, while mice doubly mutant for Galt and the gene encoding galactokinase 1 (Galk1) had normal Gal1P levels. This indicates that GALK1 is necessary for the elevated Gal1P in CG. Another hypothesis to explain the pathology is that an inability to metabolize galactose leads to diminished or disrupted galactosylation of proteins or lipids. Our studies reveal that levels of a subset of cerebrosides—galactosylceramide 24:1, sulfatide 24:1, and glucosylceramide 24:1—were modestly decreased compared to WT. In contrast, gangliosides were unaltered. The observed reduction in these 24:1 cerebrosides may be relevant to the clinical pathology of CG, since the cerebroside galactosylceramide is an important structural component of myelin, the 24:1 species is the most abundant in myelin, and irregularities in white matter, of which myelin is a constituent, have been observed in patients with CG. Therefore, impaired cerebroside production may be a contributing factor to the brain damage that is a common clinical feature of the human disease.

Galactosemia, a severe genetic metabolic disorder, results from the absence of galactose-degrading enzymes, leading to harmful galactose accumulation. In this study, we introduce a novel capillary-based surface-enhanced Raman spectroscopy (SERS) sensor for convenient and sensitive galactose detection. The developed sensor enhances SERS signals by introducing gold nanoparticles (Au NPs) onto the surface of silver nanoshells (Ag NSs) within a capillary, creating Ag NSs with Au NPs as satellites. Utilizing 4-mercaptophenylboronic acid (4-MPBA) as a Raman reporter molecule, the detection method relies on the conversion of 4-MPBA to 4-mercaptophenol (4-MPhOH) driven by hydrogen peroxide (H2O2) generated during galactose oxidation by galactose oxidase (GOx). A new SERS signal was observed, which was generated by H2O2 produced when galactose and GOx reacted. Our strategy yielded a quantitative change in the SERS signal, specifically in the band intensity ratio of 998 to 1076 cm−1 (I998/I1076) as the galactose concentration increased. Our capillary-based SERS biosensor provides a promising platform for early galactosemia diagnosis. [ABSTRACT FROM AUTHOR]

Background: Phytobacter diazotrophicus (P. diazotrophicus) is an opportunistic pathogen that causes nosocomial outbreaks and sepsis. However, there are no reports of P. diazotrophicus isolated from human blood in China. Case presentation: A 27-day-old female infant was admitted to our hospital with fever and high bilirubin levels. The clinical features included jaundice, abnormal coagulation, cholestasis, fever, convulsions, weak muscle tension, sucking weakness, ascites, abnormal tyrosine metabolism, cerebral oedema, abnormal liver function, clavicle fracture, and haemolytic anaemia. The strain isolated from the patient's blood was identified as P. diazotrophicus by whole-genome sequencing (WGS). Galactosemia type 1 (GALAC1) was diagnosed using whole-exome sequencing (WES). Based on drug sensitivity results, 10 days of anti-infective treatment with meropenem combined with lactose-free milk powder improved symptoms. Conclusion: P. diazotrophicus was successfully identified in a patient with neonatal sepsis combined with galactosemia. Galactosemia may be an important factor in neonatal sepsis. This case further expands our understanding of the clinical characteristics of GALAC1. [ABSTRACT FROM AUTHOR]

Abstract Background Galactosemia is an autosomal recessive disorder resulting from an enzyme defect in the galactose metabolic pathway. The most severe manifestation of classic galactosemia is caused by galactose-1-phosphate uridylyltransferase (GALT) deficiency, and this condition can be fatal during infancy if left untreated. It also may result in long-term complications in affected individuals. Case presentation This report describes a patient whose initial clinical symptoms were jaundice and liver dysfunction. The patient’s liver and coagulation functions did not improve after multiple admissions and treatment with antibiotics, hepatoprotective and choleretic agents and blood transfusion. Genetic analysis revealed the presence of two variants in the GALT gene in the compound heterozygous state: c.377 + 2dup and c.368G > C (p.Arg123Pro). Currently, the variant locus (c.377 + 2dup) in the GALT gene has not been reported in the Human Gene Mutation Database (HGMD), while c.368G > C (p.Arg123Pro) has not been reported in the Genome Aggregation Database (GnomAD) nor the HGMD in East Asian population. We postulated that the two variants may contribute to the development of classical galactosemia. Conclusions Applications of whole-exome sequencing to detect the two variants can improve the detection and early diagnosis of classical galactosemia and, more specifically, may identify individuals who are compound heterozygous with variants in the GALT gene. Variants in the GALT gene have a potential therapeutic significance for classical galactosemia.

Background: Metabolic liver diseases (MLDs) in children can present with a wide range of clinical features. Aims and Objectives: This study aims to increase the high index of suspicion among physicians and awareness among caregivers regarding early diagnosis of MLD. Materials and Methods: This hospital-based prospective observational study has been conducted in the Paediatric Outpatient Department and Inpatient Department of RG Kar Medical College, Kolkata, over 2 years from 2021 to 2023. A total of 47 children aged up to 12 years were diagnosed as various MLDs who fulfilled inclusion and exclusion criteria were included in the study. Template was generated and analysis was done on SPSS software. Results: The study sample was 47 children with MLDs. Mean age was 4.21±3.81 years. Males: female ratio was approximately 2.35:1. History of consanguinity among parents was present in 23.40% cases which affirmed the autosomal recessive mode of inheritance in most of the MLD. History of sibling deaths was there in 10 cases. The most common symptom was yellowish discoloration 21 (44.68%) followed by abdominal distension 12 (25.53%). There were diverse modes of presentations. The most common presentations were hepatomegaly 47 (100%) and splenomegaly 30 (63.83%). Of 47 MLDs, Wilson disease cases were maximum (27.66%) followed by glycogen storage disease (23.40%). Conclusion: High index of suspicion should be prevalent among physicians for early diagnosis of cases to reduce disease mortality and morbidity.

Abstract 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.

Purpose Health-system pharmacists play a crucial role in monitoring the pharmaceutical pipeline to manage formularies, allocate resources, and optimize clinical programs for new therapies. This article aims to support pharmacists by providing periodic updates on new and anticipated novel drug approvals. Summary Selected drug approvals anticipated in the 12-month period covering the first quarter of 2024 through the fourth quarter of 2024 are reviewed. The analysis emphasizes drugs expected to have significant clinical and financial impact in hospitals and clinics, as selected from 59 novel drugs awaiting US Food and Drug Administration approval. This year's pipeline includes recently added drugs with various indications including oncology, infectious diseases, genetic disorders, and rare diseases. New cellular and gene therapies are rapidly evolving and being studied for several rare diseases and cancers. Conclusion More oncology agents, including gene therapies, oral agents, and monoclonal antibodies, are in the pipeline this year. Additional diseases targeted by new novel drugs, including cellular and gene therapies, are hemophilia, nonalcoholic steatohepatitis, Alzheimer's disease, and rare diseases such as galactosemia and epidermolysis bullosa. [ABSTRACT FROM AUTHOR]

Background: Metabolic liver diseases (MLDs) in children can present with a wide range of clinical features. Aims and Objectives: This study aims to increase the high index of suspicion among physicians and awareness among caregivers regarding early diagnosis of MLD. Materials and Methods: This hospital-based prospective observational study has been conducted in the Paediatric Outpatient Department and Inpatient Department of RG Kar Medical College, Kolkata, over 2 years from 2021 to 2023. A total of 47 children aged up to 12 years were diagnosed as various MLDs who fulfilled inclusion and exclusion criteria were included in the study. Template was generated and analysis was done on SPSS software. Results: The study sample was 47 children with MLDs. Mean age was 4.21±3.81 years. Males: female ratio was approximately 2.35:1. History of consanguinity among parents was present in 23.40% cases which affirmed the autosomal recessive mode of inheritance in most of the MLD. History of sibling deaths was there in 10 cases. The most common symptom was yellowish discoloration 21 (44.68%) followed by abdominal distension 12 (25.53%). There were diverse modes of presentations. The most common presentations were hepatomegaly 47 (100%) and splenomegaly 30 (63.83%). Of 47 MLDs, Wilson disease cases were maximum (27.66%) followed by glycogen storage disease (23.40%). Conclusion: High index of suspicion should be prevalent among physicians for early diagnosis of cases to reduce disease mortality and morbidity. [ABSTRACT FROM AUTHOR]

Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge. Several proposed disease mechanisms are discussed, as well as the time of damage and potential treatment options. Furthermore, we combine data from longitudinal, cross-sectional and retrospective studies with the observations of specialist teams treating this disease to depict the brain disease course over time. Based on current data and insights, the majority of patients do not exhibit cognitive decline. A subset of patients, often with early onset cerebral and cerebellar volume loss, can nevertheless experience neurological worsening. While a large number of patients with CG suffer from anxiety and depression, the increased complaints about memory loss, anxiety and depression at an older age are likely multifactorial in origin. [ABSTRACT FROM AUTHOR]

Introduction: Identifying the underlying etiology of nonfamilial adult-onset progressive cerebellar ataxia is often challenging because neurologists must consider almost all nongenetic and genetic causes of ataxia. Case Presentation: A 39-year-old woman was hospitalized for progressive ataxia with pyramidal and cognitive dysfunction after a right arm shaking and coordination problem deteriorated progressively over 1.5 years. The patient's medical history included amenorrhea, cataracts, developmental delays, consanguinity of the parents, motor coordination issues, and diarrhea and vomiting in infancy. An important finding that enabled us to solve the diagnostic conundrum was the elevated carbohydrate-deficient transferrin levels in the lack of alcohol-related symptoms, which also occur in untreated carbohydrate metabolism disorders, sometimes with ataxia as a leading symptom. The decreased erythrocyte galactose-1-phosphate uridyltransferase (GALT) enzyme activity and the elevated erythrocyte galactose-1-phosphate (Gal-1P) concentration led to the final diagnosis of galactosemia, a rare metabolic disorder. The patient's condition stayed stable with strict adherence to lactose-free and galactose-restricted diets, regular physiotherapy, and speech therapy, despite attempts to control the crippling tremor. Conclusion: This case highlights the importance of considering rare diseases based on unexplained clinical and laboratory findings. Newborn screening does not change the long-term complications of early-treated classical galactosemia. A small percentage of these patients develop ataxia tremor syndrome. [ABSTRACT FROM AUTHOR]

Classic galactosemia is a rare inborn error of metabolism that affects the metabolism of galactose, a sugar derived from milk and derivates. Classic galactosemia is caused by variants of the GALT gene, which lead to absent or misfolded forms of the ubiquitously present galactose-1-phosphate uridylyltransferase enzyme (GALT) driving galactose metabolites to accumulate, damaging cells from neurons to hepatocytes. The disease has different prevalence around the world due to different allele frequencies among populations and its symptoms range from cognitive and psychomotor impairment to hepatic, ophthalmological, and bone structural damage. The practice of newborn screening still varies among countries, dairy restriction treatment is a consensus despite advances in preclinical treatment strategies. Recent clinical studies in Duarte variant suggest dairy restriction could be reconsidered in these cases. Despite noteworthy advances in the classic galactosemia understanding, preclinical trials are still crucial to fully understand the pathophysiology of the disease and help propose new treatments. This review aims to report a comprehensive analysis of past studies and state of art research on galactosemia screening, its clinical and preclinical trials, and treatments with the goal of shedding light on this complex and multisystemic innate error of the metabolism. [ABSTRACT FROM AUTHOR]

Classic galactosemia is an autosomal recessive inherited liver disorder of carbohydrate metabolism caused by deficient activity of galactose-1-phosphate uridylyltransferase (GALT). While a galactose-restricted diet is lifesaving, most patients still develop long-term complications. In this study, we report on a two-week-old female patient who is a compound heterozygote for a known pathogenic variant (p.K285N) and a novel missense variant (p.A303D) in the GALT gene. Segregation analysis showed that the patient inherited the p.K285N pathogenic variant from her father and the p.A303D variant from her mother. A bioinformatics analysis to predict the impact of the p.A303D missense variant on the structure and stability of the GALT protein revealed that it may be pathogenic. Based on this finding, we performed a literature review of all GALT missense variants identified in homozygous and compound heterozygous galactosemia patients carrying the p.K285N pathogenic variant to explore their molecular effects on the clinical phenotype of the disease. Our analysis revealed that these missense variants are responsible for a wide range of molecular defects. This study expands the clinical and mutational spectrum in classic galactosemia and reinforces the importance of understanding the molecular consequences of genetic variants to incorporate genetic analysis into clinical care. [ABSTRACT FROM AUTHOR]

Measurement of galactose level is of clinical significance in terms of galactosemia and galactose intolerance. Especially in newborns, it can have fatal consequences if it is not detected immediately. After diagnosis, galactose should be removed from the diet. Therefore, the determination of galactose in both blood and diet, especially milk and dairy products, is of great importance. In the literature data, the methods developed for galactose determination are time consuming and relatively slow methods that require pre-processing and expensive equipment such as spectrophotometer, chromatography, mass spectrometer. The aim of this study is to develop a fast, specific, inexpensive electrochemical biosensor system for galactose determination.In this study, in which Galactose Oxidase (GaOX) enzyme was used as a biocomponent, a carbon paste electrode containing a ruthenium mediator complex was used as the working electrode. GaOX enzyme was immobilized in the paste structure. The originality of the study is the use of the Ruthenium mediator system used in the paste structure. Electrode construction stages were characterized by cyclic voltammetry (CV) method, while optimization and characterization studies were carried out by means of DP between 0 & 0.9 V and amperometric measurements at 0.5 V. The studies also used a 1 mM p-benzoquinone mediator system in working buffer. As a result of optimization studies, optimum pH was found to be 6.5 and optimum temperature was 30 oC. While the linear detection range of the developed biosensor was found between 0.05- mM, the repeatability was found to be 0.24 mM on average, the standard deviation ± 0.021 and the coefficient of variation (CV%) as 8.3% for 0.25 mM galactose. No interference was observed in the interference effect trial. Sample analysis was made on lyophilized serum and lactose-free milk samples and % recovery was calculated. The use of the Ruthenium mediator complex used in this project in the production of biosensors has been rarely encountered in the literature. However, with this study, it was used for the first time in a galactose biosensor and for the first time with a carbon paste electrode. [ABSTRACT FROM AUTHOR]

Background: Galactosemia 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. Method: NBS 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. Results: From 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. Conclusion: The 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.

This letter discusses two cases of classic galactosemia in infants that presented with pseudohyperglycemia due to interference from a glucometer. The cases highlight the limitations of point-of-care glucometers for diagnosing hyperglycemia and emphasize the need for confirmation using an alternative method, such as a hexokinase assay in the central laboratory. Galactosemia should be considered in the differential diagnosis for infants with pseudohyperglycemia. The letter also mentions the risks of iatrogenic insulin-induced hypoglycemia and the FDA's notification about potentially fatal errors with GDH-PQQ glucose monitoring technology. [Extracted from the article]

Introduction: congenital metabolic diseases (CMD) are a group of disorders caused by a genetic mutation that leads to specific enzymatic dysfunction and can mostly be diagnosed through neonatal screening. Objective: to determine the prevalence of CMD identified by neonatal screening in newborns care for in a Family Medicine Unit in Oaxaca City, Mexico. Material and methods: cross-sectional study carried out with newborns treated in the period 2019 to 2022. The neonatal screening was performed with the Guthrie card and the confirmation of a CME was made by specific diagnostic tests. Prevalence rates are presented in cases per 1,000 newborns. Results: during the study period, 1,859 newborns underwent neonatal screening. Eightyfive newborns had a positive result on the screening, resulting in a prevalence of 45.7 per 1,000 newborns, with hypothyroidism being the most frequent (rate 16.7). Of the 85 with a positive screening, diagnostic confirmation was obtained only in nine patients: seven with adrenal hyperplasia and two with congenital hypothyroidism. Conclusions: in this study, the prevalence of congenital adrenal hyperplasia and congenital hypothyroidism is higher than that previously reported in Mexico, at the national level. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Two siblings showed increased galactose and galactose-related metabolites in neonatal screening. Diagnostic workup did not reveal abnormalities in any of the known disease-causing enzymes involved in galactose metabolism. Using whole-exome sequencing, we identified a homozygous missense variant in PPA1 encoding the cytosolic pyrophosphatase 1 (PPA1), c.557C>T (p.Thr186Ile). The enzyme activity of PPA1 was determined using a colorimetric assay, and the protein content was visualized via western blotting in skin fibroblasts from one of the affected individuals. The galactolytic activity of the affected fibroblasts was determined by measuring extracellular acidification with a Seahorse XFe96 analyzer. PPA1 activity decreased to 22% of that of controls in the cytosolic fraction of homogenates from patient fibroblasts. PPA1 protein content decreased by 50% according to western blot analysis, indicating a reduced stability of the variant protein. The extracellular acidification rate was reduced in patient fibroblasts when galactose was used as a substrate. Untargeted metabolomics of blood samples revealed an elevation of other metabolites related to pyrophosphate metabolism. Besides hyperbilirubinemia in the neonatal period in one child, both children were clinically unremarkable at the ages of 3 and 14 years, respectively. We hypothesize that the observed metabolic derangement is a possible mild manifestation of PPA1 deficiency. Unresolved abnormalities in galactosemia screening might result in the identification of more individuals with PPA1 deficiency, a newly discovered inborn metabolic disorder (IMD). [ABSTRACT FROM AUTHOR]

Background: Classic 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. Methods: A 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). Results: Qualitative 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. Conclusions: These 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. [ABSTRACT FROM AUTHOR]

Introduction: Galactosemia is an inherited disorder caused by mutations in the three genes that encode enzymes implicated in galactose catabolism. Currently, the only available treatment for galactosemia is life-long dietary restriction of galactose/lactose, and despite treatment, it might result in long-term complications.Methods: Here, we present five cases of newborn patients with elevated galactose levels, identified in the context of the newborn screening program. Genetic analysis concerned a next generation sequencing (NGS) methodology covering the exons and adjacent splice regions of the GALT, GALK1, and GALE genes.Results: Our approach led to the identification of eight rare nonsynonymous DNA variants. Four of these variants, namely, p.Arg204Gln and p.Met298Ile in GALT, p.Arg68Leu in GALK1, and p.Ala180Thr in GALE, were already recorded in relevant databases, yet their clinical significance is uncertain. The other four variants, namely, p.Phe245Leu in GALT, p.Gly193Glu in GALK1, and p.Ile266Leu and p.Ala216Thr in the GALE gene, were novel. In silico analysis of the possible effect of these variants in terms of protein function and stability was performed using a series of bioinformatics tools, followed by visualization of the substituted amino acids within the protein molecule. The analysis revealed a deleterious and/or destabilizing effect for all the variants, supported by multiple tools in each case.Discussion: These results, given the extreme rarity of the variants and the specific phenotype of the respective cases, support a pathogenic effect for each individual variant. Altogether, our study shows that targeted NGS methodologies may offer a time- and cost-effective approach for the genetic investigation of galactosemia and can assist in elucidating the complex genetic background of this disorder.

Background: 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. Aim: This study aims to determine the nutrition‐related knowledge, perceptions, practices, and barriers of caregivers related to the therapeutic diet for classical galactosaemia. Methods: 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. Results and Conclusion: Of those who participated, 98% had high levels of dietary knowledge. Caregivers' knowledge scores (x¯ $\bar{{\rm{x}}}$ = 17.9, standard deviation [SD] = 1.7) were positively correlated with educational level (r = 0.383, p = 0.013). High attitudinal scores (x¯ $\bar{{\rm{x}}}$ = 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. Highlights: Following the therapeutic diet for galactosaemia can be arduous for patients and caregivers.Breast milk is contraindicated in infants with classical galactosaemia.Caregivers' negative perceptions and barriers to compliance with the diet should be routinely explored.Exclusion and safety of their child in social settings are major barriers for caregivers.A multidisciplinary treatment approach involving psychological support is warranted. [ABSTRACT FROM AUTHOR]

The article offers information on galactosemia, an inborn error of carbohydrate metabolism caused by the deficiency of galactose-metabolizing enzymes. Topics include the enzymes involved, clinical manifestations, and a case presentation of GALK deficiency with an unreported novel GALK1 variant. The patient presented with cataracts and prolonged jaundice, leading to a lactose-restricted diet.

We present a one-month-old male brought in with diffuse large skin abscesses, failure to thrive, and hepatic failure. His status depreciated rapidly, requiring intensive care unit admission as a result of septic shock and multiple incision and drainage surgeries for skin abscesses. Wound site cultures yielded Staphylococcus aureus and urine culture positive for Candida albicans; however, extensive further investigations for causative infectious versus immune-related etiologies remained unfruitful. Despite broad-spectrum antibiotic, antifungal, and antituberculosis coverage, the child’s condition deteriorated further. Within a month of admission, parents were informed of an abnormal neonatal screening report from the hospital where he was born, as presumptively positive for galactosemia. Feeds were immediately shifted to non-lactose formulation, and diagnosis was then confirmed via genetic testing. Jaundice, coagulopathy, inflammatory markers, and weight gain all steadily improved thereafter, and the child was repatriated for continuity of care. Our case demonstrates a unique disease manifestation of a well-known, often forgotten disorder and reemphasizes the importance of rapid institution of lactose-free formula milk.