Barbara S. Miles

Glutaric aciduria; A “new” disorder of amino acid metabolism☆

Abstract Studies are reported on two siblings with a neurodegenerative disorder, glutaric aciduria and glutaric acidemia. The glutaric aciduria was increased by oral administration of l -lysine, which is metabolized through glutaryl-CoA, and decreased by lowering protein intake. The metabolism of [1,5-14C] glutaryl-CoA was deficient in the peripheral leukocytes of the patients. The results are compatible with an inherited deficiency of glutaryl-CoA dehydrogenase. It is speculated, but not proved, that the biochemical abnormality is causally related to the central nervous system dysfunction.

A syndrome resembling lathyrism associated with iminodipeptiduria

Abstract A patient with abnormalities of skeleton, eyes, ears and cardiovascular system, associated with iminodipeptiduria and bound hydroxyprolinuria, is described. Analysis of dermal collagen indicated decreased intermolecular cross linking, and electron microscopy of vascular collagen in the spleen disclosed abnormalities similar to those observed in lathyritic animals. These findings suggest that the clinical picture in this patient may represent a condition in man analogous to lathyrism in animals.

Human glycerol kinase deficiency with hyperglycerolemia and glyceroluria

Abstract Two brothers with a previously unidentified syndrome of severe osteoporosis and neuromuscular disease have elevated concentrations of glycerol in serum and urine. A deficiency of glycerol kinase in leukocytes of both patients is described.

Glutaric aciduria; Presence of glutaconic and β-hydroxyglutaric acids in urine☆

Abstract The urine from two siblings with glutaric aciduria has been found to contain abnormally high amounts of β-hydroxyglutaric and glutaconic acids. This strongly suggests that the enzymic block in these patients, which previously has been shown to exist in one of the two steps between glutaryl-CoA and glutaconyl-CoA, is in the decarboxylation of glutaconyl-CoA to crotonyl-CoA. Furthermore, the presence of these two metabolites in urine makes it likely that the postulate of glutaryl-CoA dehydrogenase and glutaconyl-CoA decarboxylase in mammals being one enzyme is not correct.

4-Hydroxycyclohexane-1-carboxylic acid: An unusual compound isolated from the urine of children with suspected disorders of metabolism

1. An unknown compound has been isolated in the acidic fraction of urine samples taken from several children suspected of having metabolic disorders. 2. This unknown has been characterized using a gas chromatograph/mass spectrometer/computer system. Both the high and low resolution mass spectra have been determined and a structure proposed. 3. Authentic samples were synthesized and compared to the unknown and a final proof of structure is presented. The compound, 4-hydroxycyclohexane-1-carboxylic acid, is suspected to come from a dietary source but the actual genesis will be determined in future work.

Hydroxylysinemia; a disorder due to a defect in the metabolism of free hydroxylysine.

Abstract Studies are reported on a patient with free hydroxylysinemia and hydroxylysinuria. The results indicate the metabolism of appreciable quantities of free hydroxylysine in normal children, and are compatible with a defect in this catabolic pathway in the patient. Although the precise location of the metabolic block is not proved, it is suggested to lie at the level of hydroxy- l -lysine kinase.

Methylmalonic/β-hydroxy-n-valeric aciduria due to methylmalonyl-Coa mutase deficiency

A patient with methylmalonic and beta-hydroxy-n-valeric aciduria, apparently due to deficiency of methylmalonyl-CoA mutase, is described. The excretion of beta-hydroxy-n-valerate did not parallel that of beta-hydroxypropionate and methylmalonate but was observed, together with beta-keto-n-valerate, only during ketosis. beta-Hydroxy-n-valerate excretion thus correlates primarily not with the pool size of propionyl-CoA but with that of acetyl-CoA, and may occur during ketosis in any disorder causing accumulation of propionyl-CoA.

The treatment of maple syrup urine disease

Summary The early management of 3 infants with maple syrup urine disease is described with particular reference to variations in daily requirements for branched-chain amino acids. The use of a new dry base mix consisting of a dextrimaltose-corn oil-mineral mix, an iron-vitamin mix, and an amino acid mix as a formula base has facilitated earlier home management of these patients.

GLYCEROIURIA, PSYCHOMOTOR RETARDATION, SPASTICITY DYSTROPHIC MYOPATHY, AND OSTEOPOROSIS IN A SIBSHIP

We have identified two brothers who appear to represent a previously undescribed disease. Their clinical problems include poor somatic growth (less than 3rd percentile), moderately severe psychomotor retardation, generalized spasticity, a non-paralytic esotropia, severe generalized osteoporosis resulting in pathologic fractures, and a “wizzened” facial appearance. At ages 18 months and 4 years there is no evidence of a degenerative course. There is no demonstrable renal, thyroid, parathyroid or nutritional problem. Histochemical studies of muscle demonstrate a strikingly dystrophic process. Routine and EM studies of bone show nonspecific osteoporosis. Gas chromatography-mass spectroscopy of urine indicates elevated glycerol concentrations in both patients.In a survey of an institutionalized, mentally retarded population, four patients were noted to excrete glycerol in their urine (Ann. Med. Exp. Fenn. 45:90, 1967). Three exhibited spasticity but no additional clinical information was presented. Our patients appear to represent a previously unrecognized, apparently genetic syndrome, characterized by psychomotor retardation, spasticity, dystrophic myopathy, osteoporosis, and glyceroluria.

ORGANIC ACIDURIA FOLLOWING EXTENSIVE SMALL BOWEL RESECTION

Routine screening has identified two patients with striking organic aciduria after extensive small bowel resection. JK, a 5 ½ yo male, underwent resection of all but 21 cm of small bowel at 3 days of age because of necrosis secondary to midgut volvulus and subsequently has had recurrent acidemic episodes. TK, a 5 yo female, was left with 15 cm of jejunum following mesenteric artery thrombosis at 15 months. Both have experienced episodes of progressive abdominal distention, colonic ileus, and CNS depression. Urinary lactate (JK only), glutarate, propionate, β-hydroxyphenylacetate and β-phenyllactate were elevated. White blood cell glutaryl-CoA dehydrogenase activity in JK was normal. Serum prostaglandin E and F were significantly elevated in JK. Absorption of organic acids from stool has been reported and these patients illustrate that this may become quantitatively significant following small bowel resection. The data also suggest that the addemia of short bowel may not be solely due to bicarbonate wasting. Our patients demonstrate that gastroenterologic disorders constitute a previously unrecognized etiology to be differentiated from inborn enzymatic errors associated with glutaric aciduria. Dietary restriction, oral bicarbonate, catharsis, and inhibitors of prostaglandin synthesis may play a role in treatment of this disorder.