Three inborn errors of galactose metabolism are known, one for each step in the Leloir pathway of galactose conversion to glucose. The first, galactokinase deficiency, is discovered either through newborn screening for hypergalactosemia, or by the chance finding of reducing substance in urine, or by selective urine screening for galactose in infants or older persons examined for nuclear cataracts. In the undiagnosed newborn drinking milk, cataracts develop insidiously within a few weeks as the only clinical manifestation. Galactose-galactitol-glucose diabetes is the only chemical sign. Diagnosis is made by enzyme assay on blood cells or fibroblasts. For treatment, milk and milk products are eliminated from the diet. In transferase deficiency or galactosemia, the second step in the Leloir pathway is blocked. In most developed countries, this defect is discovered through newborn screening, and the more serious clinical symptoms are avoided by prompt treatment. Infants who remain undiagnosed develop symptoms and signs of liver and kidney failure and succumb to sepsis. Survivors develop cataracts and mental impairment. Diagnosis is suggested by the presence of reducing substance in the urine of the fed newborn, and it is made by enzyme assay on blood cells, a liver biopsy specimen, or fibroblasts. Lifelong exclusion of all galactose from the diet is stipulated, but difficult to achieve. Partial transferase deficiency is more frequent than the complete defect. It is treated by a less-than-complete removal of dietary galactose, usually restricted to the first few months of life. The third defect of the Leloir pathway, epimerase deficiency, occurs in both a benign mild form and a severe and crippling form. Both are discovered through newborn screening, using methods sensitive to galactose-1-phosphate and are diagnosed by enzyme assay on blood cells or fibroblasts. Infants with the mild form do not seem to require treatment. The two documented severe cases showed clinical features reminiscent of untreated galactosemia; their dietary treatment proved difficult and unsatisfactory.

Disorders of Galactose Metabolism

We used event-related potentials (ERPs) and gamma band oscillatory responses (GBRs) to examine whether intermodal attention operates early in the auditory, visual, and tactile modalities. To control for the effects of spatial attention, we spatially coregistered all stimuli and varied the attended modality across counterbalanced blocks in an intermodal selection task. In each block, participants selectively responded to either auditory, visual, or vibrotactile stimuli from the stream of intermodal events. Auditory and visual ERPs were modulated at the latencies of early cortical processing, but attention manifested later for tactile ERPs. For ERPs, auditory processing was modulated at the latency of the Na (29 msec), which indexes early cortical or thalamocortical processing and the subsequent P1 (90 msec) ERP components. Visual processing was modulated at the latency of the early phase of the C1 (62-72 msec) thought to be generated in the primary visual cortex and the subsequent P1 and N1 (176 msec). Tactile processing was modulated at the latency of the N160 (165 msec) likely generated in the secondary association cortex. Intermodal attention enhanced early sensory GBRs for all three modalities: auditory (onset 57 msec), visual (onset 47 msec), and tactile (onset 27 msec). Together, these results suggest that intermodal attention enhances neural processing relatively early in the sensory stream independent from differential effects of spatial and intramodal selective attention.

Intermodal auditory, visual, and tactile attention modulates early stages of neural processing

Cataracts (opacities of the lens) are frequent in the elderly, but rare in paediatric practice. Congenital cataracts (in industrialized countries) are mainly caused by mutations affecting lens development. Much of our knowledge about the underlying mechanisms of cataractogenesis has come from the genetic analysis of affected families: there are contributions from genes coding for transcription factors (such as FoxE3, Maf, Pitx3) and structural proteins such as crystallins or connexins. In addition, there are contributions from enzymes affecting sugar pathways (particularly the galactose pathway) and from a quite unexpected area: axon guidance molecules like ephrins and their receptors. Cataractous mouse lenses can be identified easily by visual inspection, and a remarkable number of mutant lines have now been characterized. Generally, most of the mouse mutants show a similar phenotype to their human counterparts; however, there are some remarkable differences. It should be noted that many mutations affect genes that are expressed not only in the lens, but also in tissues and organs outside the eye. There is increasing evidence for pleiotropic effects of these genes, and increasing consideration that cataracts may act as early and readily detectable biomarkers for a number of systemic syndromes.

/pdf/clinical-and-experimental-advances-in-congenital-and-2766wpbxv2.pdf

Clinical and experimental advances in congenital and paediatric cataracts

Molecular Structure of Human Galactokinase: IMPLICATIONS FOR TYPE II GALACTOSEMIA

The conversion of beta-D-galactose to glucose 1-phosphate is accomplished by the action of four enzymes that constitute the Leloir pathway. Galactokinase catalyzes the second step in this pathway, namely the conversion of alpha-D-galactose to galactose 1-phosphate. The enzyme has attracted significant research attention because of its important metabolic role, the fact that defects in the human enzyme can result in the diseased state referred to as galactosemia, and most recently for its utilization via ‘directed evolution’ to create new natural and unnatural sugar 1-phosphates. Additionally, galactokinase-like molecules have been shown to act as sensors for the intracellular concentration of galactose and, under suitable conditions, to function as transcriptional regulators. This review focuses on the recent X-ray crystallographic analyses of galactokinase and places the molecular architecture of this protein in context with the extensive biochemical data that have accumulated over the last 40 years regarding this fascinating small molecule kinase.

Galactokinase: structure, function and role in type II galactosemia.

Summary Galactokinase deficiency is an inborn error in the first step of galactose metabolism. Its major clinical manifestation is the development of cataracts in the first weeks of life. It has also been suggested that carriers of the deficiency are predisposed to presenile cataracts developing at age 20–50 years. Newborn screening data suggest that the gene frequency is very low worldwide but is higher among the Roma in Europe. Since the cloning of the galactokinase gene (GK1) in 1995, only two disease-causing mutations, both confined to single families, have been identified. Here we present the results of a study of six affected Romani families from Bulgaria, where index patients with galactokinase deficiency have been detected by the mass screening. Genetic linkage mapping placed the disease locus on 17q, and haplotype analysis revealed a small conserved region of homozygosity. Using radiation hybrid mapping, we have shown that GK1 is located in this region. The founder Romani mutation identified in this study is a single nucleotide substitution in GK1 resulting in the replacement of the conserved proline residue at amino acid position 28 with threonine (P28T). The P28T carrier rate in this endogamous population is ∼5%, suggesting that the mutation may be an important cause of early childhood blindness in countries with a sizeable Roma minority.

A Founder Mutation in the GK1 Gene Is Responsible for Galactokinase Deficiency in Roma (Gypsies)

During a study of hereditary motor and sensory neuropathy-Lom in Bulgaria, a previously unrecognized neurological disorder was encountered, mainly in Wallachian Gypsies, who represent a relatively recent genetic isolate. The disorder has been termed the congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome to emphasize its salient features. Fifty individuals from 19 extended pedigrees were identified and examined clinically and electrophysiologically. At least 1 patient from each family was admitted to the hospital in Sofia for full investigation. Pedigree analysis indicates autosomal recessive inheritance. The disorder is recognized in infancy by the presence of congenital cataracts and microcorneas. A predominantly motor neuropathy beginning in the lower limbs and later affecting the upper limbs develops during childhood and leads to severe disability by the third decade. Associated neurological features are a moderate nonprogressive cognitive deficit in most affected individuals together with pyramidal signs and mild chorea in some. Accompanying nonneurological features include short stature, characteristic facial dysmorphism, and hypogonadotrophic hypogonadism. Nerve conduction studies suggest a hypomyelinating/demyelinating neuropathy, confirmed by nerve biopsy. The CCFDN syndrome is thus a pleomorphic autosomal recessive disorder displaying a combination of neurological and nonneurological features.

Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan gypsies: Clinical and electrophysiological observations

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A Founder Mutation in the GK1 Gene Is Responsible for Galactokinase Deficiency in Roma (Gypsies)

Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan gypsies: Clinical and electrophysiological observations