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Disorders of galactose, pentose, and pyruvate metabolism 

Disorders of galactose, pentose, and pyruvate metabolism

Chapter:
Disorders of galactose, pentose, and pyruvate metabolism
Author(s):

T.M. Cox

DOI:
10.1093/med/9780199204854.003.120303_update_001

Update:

Galactosaemia—(1) Description of gene-expression profiling and proteomic studies that give new insights into pathophysiology and pathology. (2) Expanded discussion of matters related to fertility in women, and of general prognosis.

Substantial updating of sections on (1) epimerase deficiency; (2) pentosuria—new genetic information; (3) treatment of pyruvate dehydrogenase deficiency; (4) diagnosis and treatment of pyruvate decarboxylase deficiency.

Updated on 28 Nov 2013. The previous version of this content can be found here.
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date: 23 April 2017

Inborn errors of galactose metabolism

Galactose is principally found as free lactose in dairy products; the sugar moiety also occurs as a dietary component in glycoproteins and complex lipids. Three inborn errors of galactose metabolism are recognized:

Galactokinase deficiency (‘galactose diabetes’)—a very rare condition which impairs the assimilation of dietary galactose that is normally initiated by phosphorylation, principally in the liver; the free sugar and its metabolites, galactonic acid and galactitol, appear in plasma and the urine. Conversion of galactose to osmotically active galactitol in tissues causes premature cataracts and occasionally pseudotumor cerebri in infants. The abnormalities may be ameliorated by early institution of a galactose- and lactose-free diet.

Galactose 1-phosphate uridylyltransferase deficiency (classical galactosaemia)—the most important disorder, with an overall estimated frequency of 1 in 47 000 births. High concentrations of galactose in the plasma and tissues lead to aberrant glycosylation of glycoproteins and other glycoconjugates, including lipids. The clinical features are diverse and the pathogenesis remains ill understood. The principal manifestations are a bacteriocidal defect associated with neonatal E. coli sepsis. There is failure to thrive and—in older patients—growth retardation, mental retardation, and hepatomegaly, which without dietary treatment may cause cirrhosis. Disease of the proximal kidney tubule causes the renal Fanconi syndrome and osteomalacia. The diagnosis is made by plasma galactose, galactose 1-phosphate, and red-cell transferase determinations in blood spots obtained after birth. Visceral disease and stunting are mitigated by institution of a lactose- and galactose-free diet, but ovarian failure leading to premature menopause and osteoporosis is common in young girls and women. Ovarian failure is frequent and occurs irrespective of dietary exclusion therapy. Prompt institution of an appropriate diet allows survival into late adult life, but disabling neurological manifestations persist.

Uridine diphosphate-4-epimerase deficiency—a rare but largely harmless disorder, is usually discovered at neonatal screening for galactosaemia.

Pentosuria

Essential pentosuria is an asymptomatic autosomal recessive disorder of glucuronate metabolism (principally affecting Ashkenazi Jews) caused by deficiency of hepatic xylitol dehydrogenase which causes the daily appearance of several grams of l-xylulose in the urine.

Disorders of pyruvate metabolism

Deficiency of the pyruvate dehydrogenase complex is the most common inherited disorder which causes lacticacidaemia. Hereditary defects affect the five principal components of this macromolecular complex, most often producing deficiency of the E1α‎ subunit, which is inherited as an X-linked character. Presentation is with overwhelming neonatal acidosis; moderate lactic acidosis with progressive neurological features; or—in male children and young adults—an indolent neurological course without overt acidosis but with episodes of cerebellar ataxia induced by carbohydrate administration.

Pyruvate carboxylase is a biotin-dependent gluconeogenic enzyme deficiency that mainly causes lactate/pyruvate acidosis with a necrotizing encephalopathy resembling Wernicke’s encephalopathy. Hypoglycaemia may complicate intercurrent infections and starvation.

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