Glutaric aciduria type II (multiple acyl-CoA dehydrogenase deficiency) (McKusick 23168) is an inherited metabolic disease associated clinically with severe hypoglycaemia, metabolic acidosis, hepatomegaly, hypotonia, neurological symptoms and death in the neonatal period. Biochemically it is characterised by increased urinary excretion of several organic acids, particularly glutarate, 2-hydroxyglutarate, 3-hydroxyisovalerate, adipate and other dicarboxylic acids, and isovalerylglycine and other acylgtycines. Pathologically, there is fatty infiltration of the liver and heart and a number of cases have been described in which grossly enlarged polycystic kidneys occur together with severe dysmorphic features. We report here prenatal diagnosis for severe neonatal dysmorphic glutaric aciduria type II using both chemical analysis of amniotic fluid supernatant with quantitative selected ion monitoring (SIM) on GC-MS and also enzymology on cultured amniocytes. Affected and unaffected fetuses have been correctly predicted with results being duplicated in three independent laboratories.
PROPOSITUS AND CASE HISTORYThe parents are unrelated and in their twenties. During the mother's first pregnancy (1982), a raised ~-fetoprotein (AFP) at 17 weeks' gestation led to referral: amniocentesis yielded fluid with a normal AFP and amniocytes showed a normal 46,XY karyotype. Repeat renal scans showed the very slow development of moderate cystic changes and the pregnancy continued to term. At term a 2.58 kg boy was delivered normally. He developed pallor and respiratory distress at 30 min with rapidly developing severe metabolic acidosis. He showed dysmorphic features including a large head (circumference 36 cm), deepset eyes, sunken nasal bridge, wide mouth, abnormal tragus, coronal hypospadias and prominent heels. Kidneys were easily palpable and there was an odour of'sweaty feet'. The baby died at 50 h and histology of kidneys showed a medulla replaced by dilated tubular cysts, primitive ducts and blurring of the cortico-medullary junction. GC-MS of urine showed a raised glutaric acid (5230mmol tool creatinine-1), adipic acid (407 mmol mot-i) and 3-hydroxyisovateric acid (340mmolmol-1), consistent with a diagnosis of glutaric aciduria type II (Dr J. Leonard, Institute of Child Health, London). GC-MS of stored amniotic fluid supernatant at the CRC and QCMH showed greatly increased concentrations of glutaric acid and 2-hydroxyglutaric acid (Table 1), confirming the diagnosis and providing the basis for future prenatal diagnosis by direct chemical analysis.
METHODSOrganic acids were extracted from amniotic fluid using DEAE Sephadex and glutarate quantified by selected ion monitoring (SIM) on GC-MS of the trimethylsilyl (TMS) ester against a 3-methylglutarate internal standard added to the fluid before extraction or by addition of the internal standard, lyophilisation and direct preparation of n-butyl esters. 2-Hydroxyglutarate was quantified as the TMS derivative against a C24-hydrocarbon internal standard using a response factor deter...
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