Galactose - a key source of energy and a crucial structural element in complex molecules - is particularly important for early human development. However, galactose metabolism might be important not only for fetal and neonatal development but also for adulthood, as evidenced by the inherited disorders of galactose metabolism. The purpose of this review is to summarize the current evidence of galactose metabolism in health and disease. The biological importance of galactose goes beyond its importance as a nutrient and a metabolite. Galactose has been selected by evolutionary pressure to exert also a crucial structural role in macromolecules. Additionally, galactose has recently been reported as beneficial in a number of diseases, particularly in those affecting the brain. Galactose is crucial for human metabolism, with an established role in energy delivery and galactosylation of complex molecules, and evidence for other roles is emerging.

Classical galactosemia (CG) is an inborn error of galactose metabolism. Evidence‐based guidelines for the treatment and follow‐up of CG are currently lacking, and treatment and follow‐up have been demonstrated to vary worldwide. To provide patients around the world the same state‐of‐the‐art in care, members of The Galactosemia Network (GalNet) developed an evidence‐based and internationally applicable guideline for the diagnosis, treatment, and follow‐up of CG. The guideline was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. A systematic review of the literature was performed, after key questions were formulated during an initial GalNet meeting. The first author and one of the working group experts conducted data‐extraction. All experts were involved in data‐extraction. Quality of the body of evidence was evaluated and recommendations were formulated. Whenever possible recommendations were evidence‐based, if not they were based on expert opinion. Consensus was reached by multiple conference calls, consensus rounds via e‐mail and a final consensus meeting. Recommendations addressing diagnosis, dietary treatment, biochemical monitoring, and follow‐up of clinical complications were formulated. For all recommendations but one, full consensus was reached. A 93 % consensus was reached on the recommendation addressing age at start of bone density screening. During the development of this guideline, gaps of knowledge were identified in most fields of interest, foremost in the fields of treatment and follow‐up.

Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients. Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018. Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome. This study describes the natural history of classic galactosemia based on the hitherto largest data set.

Classic galactosemia is a rare inherited disorder of galactose metabolism caused by deficient activity of galactose‐1‐phosphate uridylyltransferase (GALT), the second enzyme of the Leloir pathway. It presents in the newborn period as a life‐threatening disease, whose clinical picture can be resolved by a galactose‐restricted diet. The dietary treatment proves, however, insufficient in preventing severe long‐term complications, such as cognitive, social and reproductive impairments. Classic galactosemia represents a heavy burden on patients’ and their families’ lives. After its first description in 1908 and despite intense research in the past century, the exact pathogenic mechanisms underlying galactosemia are still not fully understood. Recently, new important insights on molecular and cellular aspects of galactosemia have been gained, and should open new avenues for the development of novel therapeutic strategies. Moreover, an international galactosemia network has been established, which shall act as a platform for expertise and research in galactosemia. Herein are reviewed some of the latest developments in clinical practice and research findings on classic galactosemia, an enigmatic disorder with many unanswered questions warranting dedicated research.

Neurite orientation dispersion and density imaging (NODDI) enables more specific characterization of tissue microstructure by estimating neurite density (NDI) and orientation dispersion (ODI), two key contributors to fractional anisotropy (FA). The present work compared NODDI- with diffusion tensor imaging (DTI)-derived indices for investigating white matter abnormalities in a clinical sample. We assessed the added value of NODDI parameters over FA, by contrasting group differences identified by both models. Diffusion-weighted images with multiple shells were acquired in a group of 8 healthy controls and 8 patients with an inherited metabolic disease. Both standard DTI and NODDI analyses were performed. Tract based spatial statistics (TBSS) was used for group inferences, after which overlap and unique contributions across different parameters were evaluated. Results showed that group differences in NDI and ODI were complementary, and together could explain much of the FA results. Further, compared to FA analysis, NDI and ODI gave a pattern of results that was more regionally specific and were able to capture additional discriminative voxels that FA failed to identify. Finally, ODI from single-shell NODDI analysis, but not NDI, was found to reproduce the group differences from the multi-shell analysis. To conclude, by using a clinically feasible acquisition and analysis protocol, we demonstrated that NODDI is of added value to standard DTI, by revealing specific microstructural substrates to white matter changes detected with FA. As the (simpler) DTI model was more sensitive in identifying group differences, NODDI is recommended to be used complementary to DTI, thereby adding greater specificity regarding microstructural underpinnings of the differences. The finding that ODI abnormalities can be identified reliably using single-shell data may allow the retrospective analysis of standard DTI with NODDI.