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Galactosaemia is characterised by enzymatic deficiencies affecting galactose metabolism, most frequently the enzyme galactose-1-phosphate uridyl transferase (GALT), resulting in the accumulation of galactose-1-phosphate. In Europe, the disease affects approximately one newborn in 35 000. The clinical signs appear during the first days of life and include refusal to feed, vomiting, jaundice, lethargy, hepatomegaly, oedema and ascites. If left untreated, the condition evolves rapidly towards hepatic and renal failure with septicaemia due to gram negative Escherichia coli bacteria. Nuclear cataract develops after several days or weeks and rapidly becomes irreversible. Galactosaemia is an autosomal recessive condition caused by point mutations. Three enzyme deficiencies involving the galactose metabolic pathway have been associated with the condition: galactokinase (GALK) deficiency, uridine diphosphate (UDP) galactose-4-epimerase deficiency, and most commonly, galactose 1 phosphate uridyl transferase (GALT) deficiency. The gene encoding GALT has been localised to 9p13. Diagnosis relies on detection of galactose-1-phosphate accumulation in erythrocytes (spot test), determination of a deficiency in one of the enzymes in the galactose metabolic pathway and identification of the gene mutation. Postnatal diagnosis is systematic in some countries. In utero testing may be offered to galactosaemic parents. To date, the only treatment available is a galactose-free diet. Despite this regime, neurological complications (decreasing IQ with age, verbal dyspraxia, myelin disorders) and hypergonadotropic hypogonadism (ovary dysfunction, very high levels of FSH and LH) appear during childhood. UDP-galactose deficiency and/or accumulation of galactose-1-phosphate in utero may result in deficient galactosylation of glycoproteins (including FSH) and glycolipids (galactolipides in myelin) thus causing the complications. In addition, aberrant galactosylation may also contribute to alterations in function of the galactosylated molecules. The galactose-free diet may allow partial biosynthesis of carbohydrate chains for some glycoproteins. Research concerning the classic forms of galactosaemia is essentially targeted towards developing therapeutic strategies aiming to prevent the neurological and endocrinal manifestations. These strategies revolve around limiting the accumulation of galactose and its derivatives and developing a treatment capable of stimulating secondary metabolic pathways that could metabolise the toxic derivatives of galactose and increase the level of UDP-galactose, which is necessary for the glycosylation of proteins and lipids. |