Galactose Metabolism in a Patient with Hereditary Galactokinase Deficiency

Abstract

Abstracf. "he ability of a galactokinase deficient patient to metabolize galactose, galactitol and galactonate was quantitated. In galactokinase deficiency, converaion of galactose to C02 is minimal. Apparently the defect is extemive. involving all tissues. Galactitol and galactonate, injected intravenously, were not metabolized. The adminiitration of C-1 and C-2 labelled galactose resulted in 1 C 0 , excretory patterm similar to that observed in uridyltransferaae deficient mutanta. The different fatea of C-1 and C-2 observed in this galactokixwm deficient patient give eup rt to the existence of a direct oxidative pathway for ga&ose. Galactonate. although preeent in urine during the period of observation following injection of radioactive galactose failed to become labelled.

Involvement of endoplasmic reticulum stress in a novel Classic Galactosemia model

“…Faced with the lack of overt galactose toxicity in the GALTknockout mouse model [15][16][17], researchers nonetheless proposed that galactose-1-phosphate (gal-1-p) plays a major role in causing acute toxicity syndrome and chronic complications [44][45][46]. It has been recognized that patients with inherited deficiency of galactokinase (GALK) do not accumulate gal-1-p in their tissues, nor manifest either the acute toxicity syndrome or chronic complications seen in the GALT-deficient patients [3,10,47,48]. Yet the in vivo toxicity target(s) of gal-1-p have been elusive.…”

“…Since GALK-deficient patients do not accumulate gal-1-p in their tissues [3,10], researchers have long proposed that gal-1-p plays a significant role in the pathogenesis of Classic Galactosemia [11][12][13][14]. Yet the in vivo targets of this presumably toxic intermediate have never been identified.…”

Galactose toxicity in animals

“…If galactose is not metabolized efficiently, whether due to a block in the Leloir pathway, excess galactose will be catabolized by alternate pathways to form (a) galactitol and (b) galactonate (Fig.1) [25, 36, 84, 98]. Galactitol cannot be further metabolized, and is predominantly excreted in the urine [25].…”

Use of Site-Directed Mutagenesis in the Diagnosis, Prognosis and Treatment of Galactosemia

“…Accumulation of gal-1P is regarded as a major, if not sole, factor for the chronic complications seen in patients with Classic Galactosemia, as suggested by both clinical observation and experimental results from yeast models. Patients with inherited deficiency of GALK, who do not accumulate gal-1P, do not experience the brain and ovary complications seen in GALT-deficient patients (Gitzelmann et al, 1974;Gitzelmann 1975;Stambolian et al, 1986). While gal7 (i.e, GALT-deficient) mutant yeast stops growing upon galactose challenge, a ga17 ga11 double mutant strain (i.e, GALT-and GALK-deficient) is no longer sensitive to galactose Hawthorne, 1964, 1966).…”