Brain function in classic galactosemia, a galactosemia network (GalNet) members review

Abstract

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.

Keywords: brain; classic galactosemia; cognitive problems; galactose; movement disorders; neurodevelopment; neuropsychiatry.

FIGURE 1

Galactose metabolism and CG pathophysiology. (A) The first step of the Leloir pathway involves the conversion of β-D-galactose to its stereoisomer α-D-galactose by galactose mutarotase (GALM). Then, α-D-galactose is phosphorylated to α-D-galactose-1-phosphate (Gal-1-P) by galactokinase (GALK1). Galactose-1-phosphate uridylyltransferase (GALT) catalyzes the 2-step reaction through which Gal-1-P and UDP-glucose are converted to α-D-glucose-1-phosphate and UDP-galactose. Finally, UDP-galactose 4′-epimerase (GALE) mediates the interconversion of UDP-galactose (UDP-gal) and UDP-glucose (UDP-glc). This enzyme is crucial to maintain the steady state UDP-galactose/UDP-glucose ratio in different cells, playing an important role in glycoconjugate formation. Accumulation of α-D-galactose due to GALT deficiency leads to the formation of galactitol and galactonate, mediated by aldose reductase (AR) and galactose dehydrogenase (GALDH), respectively. Additionally, Gal-1-P can be converted into UDP-Gal via the action of UDP-glucose pyrophosphorylase (UGP); however its affinity is much lower when compared to the main substrate, Glc-1-P. Except for GALK1, the enzymes in this pathway can work in both directions, depending on the substrate levels and energy demand of the cell. Please note that there are only two enzymes in humans that are capable of converting Gal-1-P to UDP-galactose, the GALT enzyme and the UGP enzyme. Additionally, while UGP is bidirectional in nature, the reaction usually goes in the direction of Glc-1-P to UDP-Glc because PPi is rapidly hydrolyzed. (B) The accumulation of toxic metabolites, aberrant glycosylation, myo-inositol deficiency, endoplasmic reticulum (ER) stress and oxidative stress, and signaling pathway alterations all seem implicated in the pathophysiological cascade elicited in CG. Increased levels of Gal-1-P can inhibit inositol monophosphatase (IMPase1), which converts L-myo-inositol-1-phosphate to free myo-inositol, thereby limiting the intracellular myo-inositol concentration. Accumulation of galactitol generates osmotic stress which may result in decreased transcription of the myo-inositol cotransporter SMIT1, further aggravating the intracellular myo-inositol deficiency. The myo-inositol deficiency and subsequent alterations in inositide signaling can impair calcium homeostasis and cause ER stress, which is associated with apoptosis and downregulation of PI3K/Akt signaling. Gal-1-P and aberrant glycosylation may also contribute to ER stress. Lastly, the role of epigenetics and modifier genes also needs to be considered in CG pathology. Dotted lines represent associations that are still under debate. (C) Classic Galactosemia (CG) patients can suffer from brain pathology in multiple domains, i.e., cognition, neurology, neuropsychology, neuropsychiatry and neuro-imaging.