3- Hydroxy-3-methylglutaryl CoA lyase deficiency

Figure 20-3. Pathway for the catabolism of leucine. The last step in the pathway is catalyzed by 3-hydroxy-3methyl-CoA lyase, which is deficient in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

Nyhan WL, Barshop BA, Ozand PT 3-Hydroxy-3-methylglutaryl CoA lyase deficiency, in Nyhan WL, Barshop BA, Ozand PT (eds) Atlas of Metabolic Diseases, 2nd edition. Chapman and Half Medical, 2005, pp. 253-258. 

Duran, M., Schutgens, R.B.H., Ketel, A., Heymans, H., Bemtssen, M.W.J., Ketting, D. and Wadman, S.K. (1979), 3-Hydroxy-3-methylglutaryl CoA lyase deficiency Postnatal management following prenatal diagnosis by analysis of maternal urine. J. Pediatr., 95,1004. 

Hydroxy-3-methylglutaryl-CoA lyase deficiency, leading to 3-hydroxy-3-methylglutaric aciduria... 

Despite the prolific literature on this abnormal organic aciduria, there have been only three authenticated cases of 3-hydroxy-3-methylglutaryl-CoA lyase deficiency reported. 

Table 10.3 Organic acid concentrations in urine from a patient with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (after Duran 1978a Schutgens era/., 1978).

These brief reports have been confirmed by a more detailed description of a similar case (Truscott et al, 1979), a girl who died at 5 days of age with hyperammonaemia, and raised plasma glutamine, alanine and lysine. Increased excretion of 3-methylglutaric, 3-methylglutaconic and 3-hydroxy-3-methylglutaric acids (but not of 3-hydroxyisovaleric acid) was observed but at much lower concentrations than those in patients with authentic 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, being 170,463 and 181 mmol mol of creatinine respectively or 20 per cent, 6 per cent and 1 per cent of the concentrations in an authentic patient. Measurement of enzyme activities in cultured fibroblasts showed these to be normal and a primary defect in the urea cycle was suspected ... 

Wang, S. P., Marth, J.D., Oligny, L.L. et al. (1998) 3-Hydroxy-3-methylglutaryl-CoA lyase (HL) gene targeting causes prenatal lethality in HL-deficient mice. Hum. Mo-lec. Genet, 7, 2057-2062. 

The inborn errors of L-leucine catabolism present biochemically with branched-chain amino and/or organic aciduria [1]. These disorders include maple syrup disease (MSD branched-chain a-ketoacid dehydrogenase (BCKD) deficiency), isovaleric acidemia (isovaleryl-coenzyme A (CoA) dehydrogenase deficiency), isolated 3-methylcrotonyl-CoA carboxylase deficiency, the 3-methylglutaconic acidurias (3-methylglutaconyl-CoA hydratase deficiency, Barth syndrome, and other disorders in which the primary defect has not been demonstrated), and 3-hydroxy-3-methylglutaric aciduria (3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency). 

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