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  • Familial hyperlysinemia is an autosomal recessive disease caused by a defect in the bifunctional protein α-aminoadipic semialdehyde synthase. The two associated enzyme activities, lysine-ketoglutarate reductase and saccharopine dehydrogenase, normally initiate the degradation of lysine by removal of the ε amino group. In familial hyperlysinemia, both activities are reduced to 10 percent of normal or less, causing hyperlysinemia and lysinuria, frequently accompanied by a relatively mild saccharopinuria. The condition appears to be benign. A variant, saccharopinuria, has been described in which 30 percent of lysine-ketoglutarate activity was retained and the saccharopine dehydrogenase activity was undetectable. Saccharopinuria was prominent, exceeding the associated lysinuria. Experience with the variant is too limited to know if this metabolic abnormality causes disease.

  • Removal of the α amino group of lysine constitutes a minor pathway for lysine degradation in most tissues, with pipecolic acid as a product. Hyperpipecolatemia is regularly observed in familial hyperlysinemia as an overflow phenomenon. It is also a common concomitant of Zellweger syndrome, as the result of a defect in peroxisome formation and the consequent deficiency of L-pipecolic acid oxidase activity. A convincing example of a patient with hyperpipecolatemia as a primary defect has not been reported. The hyperpipecolatemia in Zellweger syndrome becomes manifest after the major symptoms are already evident, suggesting that it is not a significant contributing factor.


This chapter is devoted to inherited metabolic diseases of the first enzymatic steps in lysine degradation. Familial hyperlysinemia and saccharopinuria are the most prominent and most clearly elucidated abnormalities. Hyperpipecolatemia has received considerable attention and also will be discussed briefly. Sporadic reports of hyperlysinemia of uncertain etiology and lysinuria in the absence of hyperlysinemia will not be considered. The latter generally results from transport defects, often as part of a dibasic amino acid transport defect, and is discussed in Hartnup Disorder


Lysine is an essential six-carbon dibasic amino acid.1L-Lysine uptake into cells is generally efficient. Saturable and unsaturable transport systems have been described, as well as a sodium-independent carrier of the y+ type that is specific for L-lysine.2,3 In common with other amino acids, an excess of lysine beyond that needed for protein synthesis is degraded through the Krebs cycle after removal of amino groups, yielding energy. Early workers in intermediary metabolism noted that the keto acid of lysine could not replace the amino acid in the diet and correctly concluded that lysine did not participate in classic transamination. The initial steps in the degradation of lysine remained uncertain, however, until relatively recently.

Saccharopine Pathway

It is now recognized that the major pathway for the degradation of lysine involves transfer of the ε amino group to α-ketoglutarate through the stable intermediate saccharopine.4-6 The end result of transamination is thereby achieved, although by a different mechanism. Two enzymatic steps ...

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