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TitleOrganic Acids in Man: Analytical Chemistry, Biochemistry and Diagnosis of the Organic Acidurias
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Page 1

Organic Acids in Man
Analytical Chemistry, Biochemistry and Diagnosis
of the Organic Acidurias

Page 2

Organic Acids in Man
Analytical Chemistry, Biochemistry and
Diagnosis of the Organic Acidurias




M.R.e. Clinical Research Centre,
Harrow, UK



Page 265

256 . Organic acids in human metabolic diseases

gross accumulation, some is also metabolized to 3-hydroxyisovaleric acid (Fig.
10.12). Isovaleryl-CoA is conjugated with glycine by the action of glycine
N-acylase which shows a high affinity in vitro for isovaleryl-CoA as substrate
(Bartlett and Gompertz, 1974). The activity of the enzyme is apparently
increased because of the accumulation of isovaleryl-CoA, and this in turn
appears to stimulate increase of the glycine pool for acylglycine formation, with
isovalerylglycine being formed in preference to hippuric acid (benzoylglycine)
(Ando et at., 1971). The oxidation of glycine and its conversion into serine,
however, are normal (Ando et at., 1971), and this has been explained on the
basis of separate glycine pools for acylglycine formation and for serine
synthesis and glycine oxidation (Tanaka, 1975). Although endogenous glycine
synthesis must be greatly increased to supply the requirements for isovaleryl-
CoA conjugation, most patients show normal blood glycine concentrations,
although in some cases a mild hyperglycinaemia may occur (Guibaud et at.,
1973). This may be explained on the basis of the high affinity of glycine
N-acylase for isovaleryl-CoA, in contrast to disorders such as propionic
acidaemia and methylmalonic aciduria, where the affinities of the enzyme for
the corresponding substrates are much lower and in which low urinary
acylglycine concentrations and gross hyperglycinaemia are observed (Chapter


Isovaleryl-CoA + Defect



Isovaleric acid



3-Hydroxyisovaleric acid

Fig. 10.12 Metabolism of isovaleryl-CoA in isovaleric acidaemia (isovaleryl-CoA
dehydrogenase deficiency).

Page 266

Branched-chain amino acid metabolism . 257

During more acute episodes the excretion of 3-hydroxyisovaleric acid in-
creases. This metabolite is also observed in urine from patients with 3-methyl-
crotonylglycinuria and tends to characterize that disorder (Section 10.3.2), but
its occurrence is due to different mechanisms in the different diseases. In
isovaleric acidaemia, the supply of glycine is exceeded by the accumulation of
isovaleryl-CoA during periods of increased leucine catabolism (for example,
high protein intake, infections); the isovaleryl-CoA is hydrolysed to free
isovaleric acid which accumulates in turn in the tissues and body fluids. The free
isovaleric acid is then oxidized to 3-hydroxyisovaleric acid and is excreted into
the urine. The accumulation of isovaleric acid during these periods exacerbates
the severity of the disease and produces the acute episodes observed. The
isovaleric acid is believed to be oxidized by an w-1 oxidation process (Tanaka et
al., 1968), which occurs simultaneously with w-oxidation of fatty acids in liver
(Den, 1965). This is supported to some extent by the finding of low concentra-
tions of methylsuccinic acid in urine, which had been stored for several years,
from a patient with isovaleric acidaemia (Baerlocher et al., 1973).

The association of the increased severity of symptoms observed in patients
with isovaleric acidaemia during acute attacks with the accumulation of free
isovaleric acid is explained on the basis of the known encephalopathic action of
short-chain and particularly five-carbon fatty acids (White and Samson, 1956;
Samson et al., 1956; Teychenne et al., 1976). Isovaleric acid is neurotoxic and
produces coma in experimental animals, with electroencephalographic
changes such as pronounced increases in~slow-wave electrical activity paral-
leling the increase in concentration in the cerebrospinal fluid (Teychenne et al.,
1976). The data obtained support the hypothesis that the coma occurring
during acute attacks in patients with isovaleric acidaemia is directly due to the
accumulation of free isovaleric acid, and it has been suggested that this occurs
by interference with neuronal membrane function rather than by biochemical
disturbances such as uncoupling of oxidative phosphorylation (Walker et al.,
1970; Tanaka, 1975). Thus the concept of preventing such attacks by dietary
glycine supplementation to conjugate the excess isovaleric acid would appear

The specific nature of the disease and of the en~yme defect is demonstrated
by the characteristic metabolites that accumulate in the absence of cor-
responding metabolites of other branched-chain amino acids. Isovaleryl-CoA
dehydrogenase is specifically inhibited by hypoglycin (2-aminomethylene-
cyclopropylpropionic acid), in the absence of inhibition of isobutyryl-CoA
dehydrogenase and only moderate impairment of 2-methylbutyryl-CoA
dehydrogenase activity (Tanaka et al., 1971). Isovaleryl-CoA dehydrogenase
has also been said to have been isolated from rat liver mitochondria as a
separate enzyme from straight-chain acyl-CoA dehydrogenase (Sherratt et al.,
1975). This, together with the observation of a patient with proposed isolated
deficiency of butyryl-CoA dehydrogenase (Tanaka et al., 1977), has indicated
the separate existence of these dehydrogenases and hence of the identity of

Page 529

522 Index

Titrimetric determination, of organic acids, 4
Total ion current chromatogram, 93
Toxins, xenobiotic, 350, 372
Transplantation, as treatment, 234-5

deficiencies of, 315

artificial amino acid mixtures in, 240
biotin in multicarboxylase deficiency, 259,

biotin in pyruvate carboxylase deficiency,

cell and organ transplantation in, 234, 235
cystamine in pyroglutamic aciduria, 406
by dietary protein restriction, 240, 252, 259,

of disorders of pyruvate metabolism and the

tricarboxylic acid cycle, 392-3, 394
with enzymes, 233-5
glycine in isovaleric acidaemia, 252
low phenylalanine/tyrosine diet in, 422, 429,

of metabolic diseases, 4, 6, 229-35
peritoneal dialysis, 279, 299
pyridoxine (vitamin B6) in oxaluria, 412
of pyruvate carboxylase deficiency, 395
of tyrosinaemia, 429,434
vitamin B12 (cobalamin), 317, 319

Trennzahl value in gas chromatography, 58
Tricarboxylate transporter, mitochondrial, 384
Tricarboxylic acid cycle, 3, 4, 16, 17,40,41

disorders of, 390-4
Tricarboxylic acid cycle acids, 28, 36, 52, 53, 54,


and acid-base balance, 163
and diet, 163
and methyIcitrate, 305
in non-ketotic dicarboxylic aciduria, 372-4
in Reye's syndrome, 374

Trichloroacetic acid
as deproteinizing agent, 24
as artefact in urine, 193

Triglyceridaemia (hyper), in glucose-6-
phosphatase deficiency, 396

medium chain, 357, 361
in propionic acidaemia, 311

Trihydroxypentonic acids, see Deoxypentonic

Trimethoprim, in phenylketonuria
heterozygote detection, 428

Trimethylamino-3-hydroxybutyric acid, see L-

TrimethyIchlorosilane (TMCS), 34, 35, 38, 68,

Trifluoroacetylation, 35, 68
Trihydroxybutanoic acids, see Erythronic and

Threonic acids

Trimethylanilinium hydroxide, in methylation,

N-Trimethylsilyl acetamide, 36
N-O-bis (Trimethylsilyl) acetamide (BSA), 36,

Trimethylsilylation, 15,22,34,35,36,38,65,

Trimethylsilyl derivatives, 18,30,34,35,43,


mass spectra, 115-27
Trimethylsilyl esters-TMS ethers, 27, 35, 66,

of volatile acids, 130, 134

Trimethylsilyl ether-methyl esters, 32, 34, 35,

mass spectra, 113
Trimethylsilylimidazole (TSIM), 36, 38, 134
O-Trimethylsilyloxime, see Oxime, O-TMS
Trimethylsilylquinoxalinols, 43, 44, 60, 67, 71,

mass spectra, 126-7

N-Trimethylsilyltrifluoroacetamide, 36
N,O-bis (Trimethylsilyl) trifluoroacetamide

(BSTFA), 36, 38
Tubular, see Renal tubular
Tyramine, 426, 436
Tyrosinaemia ('type 1'; McKusick 27670),2,

inheritance of, 431
methioninaemia in, 429
prenatal diagnosis, 224
in Quebec, 431
retardation in, 429
treatment, 429

Tyrosinaemia type II, see Tyrosine
aminotransferase deficiency

Tyrosine, 169
corneal crystals of, 434
metabolic disorders of, 428-36

Tyrosine aminotransferase deficiency
(oculocutaneous tyrosinaemia)
(McKusick 27 660),428,431, 432-{i

inheritance of, 434
mental retardation in, 431, 434
treatment of, 434

Tyrosinosis, 2, 216, 428
'Medes' (McKusick 27 670),434
'Oregon type', see Tyrosine

aminotransferase deficiency
Tyrosyluria, neonatal (McKusick 27650),


UDP-glucose dehydrogenase (EC,

Ultrafiltration, for deproteinization, 24

Page 530

in amniotic fluid, 202, 223
and diet, 192
in normal urine, 175
renal retention of, 332

Urea, 14
in amniotic fluid, 199,223

Urea cycle
defects, 279

Uricaemia (hyper)
in glucose-6-phosphatase deficiency, 396
in methyl malonic aciduria, 317
in succinyl CoA; 3-Keto acid CoA

transferase deficiency, 332
Urine, 2, 3, 4,11,12,15,17,18,20,21,56, 162

collection, 12
early morning, in screening, 162
foetal, 223
24-h and timed collections, 11, 162, 182
maternal, in prenatal diagnosis, 227, 278
preservatives, 12, 194
storage, 15
transport of specimens, 12, 13

Urine odour
'cats' urine, 258
maple syrup, 240
'musty', 422
'sweaty feet', 250, 274, 353, 354

Urocanase deficiency, 419
urocanic aciduria, 219, 419

Uronic acids, 78
oxime-TMS derivatives, mass spectra, 123

UV oscillographic recorder, 93

n-Valeric acid, 66, 188,189
methyl ester, mass spectrum, 109

n-Valeryl CoA, 297
n-Valerylglycine, 73, 75
Valinaemia (hyper) (McKusick 27710),239
Valine load test, 250, 284
L-Valine metabolism, 70, 239, 286
'Valine toxic'-intermittant branched-chain

keto aciduria, 241
Valproic acid, see Dipropylacetic acid

Index 523

in isovaleric acidaemia, 250
in 2-methylacetoacetic aciduria, 283, 285
in non-ketotic dicarboxylic aciduria, 369
see also Jamaican vomiting sickness

Vanillic acid
gas chromatography, 68
in normal urine, 175

Vanillin, 68
Vanilmandelic acid, 69

methyl ester, gas chromatography, 68
in newborn urine, 183, 184
in normal urine, 164, 175

Venepuncture, 23

methyl ester, mass spectrum, 114
Vitamin B6 , see Pyridoxine
Vitamin B12

deficiency, 212, 318, 324
-dependent mutase, 296
malabsorption, 312, 315
structure, 313
and vegetarian diets, 318, 322, 324
see also Cobalamin

'Vitamin B12 metabolic defect' , 316
Vitamin C, see Ascorbate

acids, 38, 129, 131, 135, 187,301,318
alcohols, aldehydes, ketones, 129
neutral compounds, 129,131

Volatilization, 19,20,128

Wall-coated open tubular (WCOT) columns,
see Gas-liquid chromatography

Werdnig-Hoffmann's disease (McKusick

XAD resins, XAD 2, XAD 7, 16
Xenobiotic toxins, 350, 372
X-linked recessive inheritance, 356
Xylitol metabolism, 173
L-Xylonic acid, 76,173, 175

Zellweger's syndrome (McKusick 23940),338
and respiratory chain disorders, 398

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