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. 

Urine collected at 4 and 16 days after clinical onset showed abnormal organic acids on thin-layer chromatography, and further investigations using gas chromatography and mass spectrometry demonstrated high concentrations of 

3-hydroxyisovaleric acid (2450 mg per g of creatinine), 3-methylglutaric acid (1190 mg per g of creatinine), 3-methylglutaconic acid (10140 mg per g of creatinine) and 3-hydroxy-3-methylglutaric acid (18490 mg per g of creatinine). 

The urine from the second patient (Duran etaly 1978a) has been re-analysed using DEAE-Sephadex extraction, and the chromatograms obtained are shown in Fig. 10.20, together with peak identifications made by mass spectrometry. The peak marked X in the chromatogram shown by Duran etal. (1978a) (Fig. 10.19 peak 2) has been identified as 5-hydroxyhexanoic (5-hydroxycaproic) acid (Chalmers and Lawson, 1979). 

Duran et al. (1979a) also further confirmed the autosomal recessive mode of inheritance by demonstrating enzyme activities in leucocytes from the parents intermediate between the normal activities and the absent activity in the patient s leucocytes. 

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Isovaleric acidemia Glutaric acidemia type II 3-Hydroxy-3-methylglutaric aciduria... 

Sweaty feet Isovaleric acid Isovaleric acidemia 3-Hydroxy-3-methylglutaric aciduria MAD... 

Methylglutaric acid n.d n d. n.d n.d. n.d. 3-Methyl-glutaconic acidurias (6) 3-hydroxy-3-methylglutaric aciduria (6)... 

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). 

Hydroxy-3-methylglutaric aciduria 3-Methylglutaconic, 3-hydroxy-3-methylglutaric, 3-hydroxyiso-valeric and 3-methylglutaric acids 3-Hydroxy-3-methylglutaryl-CoA lyase (EC 4.1.3.4) 10.3.4... 

Fig. 10.17 Chromatogram of organic acids extracted using ethyl acetate from the urine of a patient with 3-hydroxy-3-methylglutaric aciduria separated as their trimethylsilyl derivatives on 6 per cent Apiezon N on Chromosorb W (DMCS) (80-100 mesh) using temperature programming from 80 C to 250°C at 6°C min Peak identifications are 1, 3-hydroxyisovalerate 2, 3-methylglutarate 3 and 4, 3-methylglutaconate peaks 5, 3-hydroxy-3-methylglutarate. (Redrawn with modifications from Faull et al, 1976b)...

Fig. 10.21 Concentrations of metabolites of L-leucine in the urine of a woman at risk for 3-hydroxy-3-methylglutaric aciduria and carrying an affected foetus. (Reproduced from Duran et al., 1979, by permission, The C. V. Mosby Co.)...

Faull, K.F., Bolton, P.D., Halpem, B., Hammond, J. and Danks, D.M. (1976b), The urinary organic acid profile associated with 3-hydroxy-3-methylglutaric aciduria. Clin. Chim. Acta, 73,553. 

Wysocki, S.J. andHahnel, R. (1976a), 3-Hydroxy-3-methylglutaric aciduria Deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase. Clin. Chim. Acta, 71,349. 

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