Ingeborg Krieger

Therapeutic effects of glycine in isovaleric acidemia.

Extract: The effect of glycine administration on acute leucine loading (125 mg/kg) was tested in a patient with isovaleric acidemia. Serum isovaleric acid at 1 ¾ hr after the leucine loading alone was elevated to 5.60 mg/100 ml and urinary isovalerylglycine excretion was 9.90 mg/mg creatinine/24 hr. When the same amount of leucine was given with glycine (250 mg/kg) serum isovaleric acid was only 0.93 mg/100 ml. Unfortunately, urine was collected for only 12 hr after the leucine-glycine loading. However, the amount of urinary isovalerylglycine was 26.2 mg/mg creatinine in this period. In the following experiments in which a meal containing 80 mg leucine/kg was given, serum isovaleric acid was elevated to 1.14 and 1.01 mg/100 ml at 3 hr and 6 hr after the loading, respectively. How-ever, serum isovaleric acid was only 0.53 and 0.79 mg/100 ml at 3 and 6 hr, respectively, when the identical mean was given with 2 g glycine.The effect of long term glycine administration (250 mg/kg/24hr) was also tested. It did not prevent two ketotic episodes which were caused by infections. However, the duration of clinical symptoms such as vomiting and a large anion gap in the acute episodes were much shorter with rectal glycine administration. The patients linear growth and weight gain during glycine administration was much belter than that in the pretreatment period.Speculation: In isovaleric acidemia, isovaleryl-CoA is not oxidized because of an inborn deficiency of isovaleryl-CoA dehydrogenase activity. The leucine loading tests and clinical response to oral glycine in this patient suggest that exogenously administered glycine enhanced the conjugation of glycine with isovaleryl-CoA, thus preventing accumulation of free isovaleric acid, a toxic substance. With glycine administration, mitochondrial glycine concentration seems to be elevated to a level at which faster reaction velocity of glycine-N-acylation of isovaleryl-CoA is attained. Thus, glycine administration appears to be an effective therapeutic method in the management of acute ketoacidotic episodes in this disease. However, chronic administration failed to prevent ketoacidotic episodes which were induced by infections.

Acrodermatitis enteropathica without hypozincemia: therapeutic effect of a pancreatic enzyme preparation due to a zinc-binding ligand.

The clinical course and intestinal absorption studies of a female infant who developed diarrhea after cessation of breast feeding, mood changes, and intermittently had mild perioral and perianal rashes are described. She showed a partial response to a pancreatic enzyme preparation which was attributed to its content of a zinc-binding ligand, picolinic acid. Complete recovery occurred on pharmacologic doses of zinc. Exacerbation occurred twice upon withdrawal of the oral zinc medication. The zinc concentrations of plasma and intestinal mucosa were normal.

Gyrate Atrophy of the Choroid and Retina: Early Findings

Examination of two sisters ages 2 years 10 months and 6 years four months with gyrate atrophy of the choroid and retina provided an opportunity for detailed clinical investigation. Although the chorioretinal lesions were confined to the peripheral retina in the older case and were quite minimal in the younger case, there was electroretinographic evidence of marked involvement of the cone and rod systems. These cases offer an opportunity to assess an arginine restricted diet in preventing the progress of the disease.

Cerebrospinal fluid glycine in nonketotic hyperglycinemia. Effect of treatment with sodium benzoate and a ventricular shunt

In three infants with nonketotic hyperglycinemia, glycine was increased three-to fourfold in plasma, 13- to 28-fold in lumbar spinal fluid, and was higher yet in ventricular fluid. Oral sodium benzoate lowered cerebrospinal fluid (CSF) glycine by greater than 40%, but did not change the abnormal plasma: CSF ratio. An adult control, made hyperglycinemic with oral glycine, had a normal plasma: CSF ratio. Treatment of one patient with sodium benzoate from birth did not prevent mental retardation; the degree of brain stem depression was a function of CSF glycine in another patient. The persistance of glycine elevation in CSF, although therapy maintained normal concentration in plasma, appears to be caused by overproduction in brain and limitation of the high-capacity lumbar spinal reabsorptive mechanism. Treatment through lowering of CNS glycine by use of a ventricular shunt was explored.

Energy metabolism in infants with growth failure due to maternal deprivation, undernutrition, or causes unknown: II. Relationship between nitrogen balance, weight gain, and postprandial excess heat production**

Infants with growth failure and malnutrition were found to have an increase in postprandial heat production during the recovery phase. The magnitude of the increase showed a high degree of correlation with the rate of weight gain.

Food Restriction as a Form of Child Abuse in Ten Cases of Psychosocial Deprivation Dwarfism

Ten children with a psychosocial deprivation syndrome had linear growth failure, retarded bone age, a voracious and bizarre appetite, and behavior abnormalities which were a consequence of maternal rejection. Direct and indirect evidence suggests that their food had been persistently restricted by mothers who abused the children physically and had personality traits characteristic of such mothers. Most of the children had a low IQ. Weight recovery occurred regularly in the hospital and in three cases in the home, providing food was not restricted. Diagnosis was difficult because ravenous appetites and abnormal stools suggested malabsorption in seven cases; however, histories, absorption tests, and weight recovery which occurred despite temporary persistence of abnormal stools indicated that malabsorption was not the primary cause of malnutrition. Deviant be havior and abnormal stools were used to rationalize frustration and food restriction. Intensive psychotherapy of the mother is necessary.

A postural sign in the sensory deprivation syndrome in infants

Historical data and prolonged observation of 35 children with growth failure, malnutrition, developmental retardation, and behavioral disturbances indicated that 21 had been deprived of sensory stimulation. A preferred posture and tonic immobility of the arms was observed with increased frequency (52.6 per cent) in the infants with the sensory deprivation syndrome (SDS). The posture appears to have diagnostic significance in infants over 5 months of age who show growth failure, certain behavioral abnormalities, and no other signs of central nervous system disease than development retardation. It is probably a manifestation of cerebral function at a subcortical level directly related to prolonged lack of sensory input.

Inhibition of Bone Marrow Stem Cell Growth In Vitro by Methylmalonic Acid: a Mechanism for Pancytopenia in a Patient with Methylmalonic Acidemia

Summary: A 7-week-old infant with methylmalonic acidemia had pancytopenia and hypoplastic bone marrow. The patient responded to large doses of vitamin B12 treatment, and within 3 wk, the blood counts and bone marrow cellularity returned to normal. To understand the mechanism of marrow depression in this infant, we examined the effect of the patients plasma and methylmalonic acid itself on the in vitro growth of bone marrow-committed stem cells. The patients plasma obtained before B12 treatment completely inhibited the marrow cell growth, whereas the posttreatment plasma showed no inhibition. Methylmalonic acid when added to the culture dishes in concentrations comparable to those reported in plasma of methylmalonic acidemia patients, inhibited growth of marrow stem cells in a concentration-dependent fashion. On the other hand, 16 to 18 hr incubation of cells in the same concentration of methylmalonic acid did not affect the recovery or viability of the cells. The observations suggest that methylmalonic acid is inhibitory to the proliferation of marrow stem cells. The mechanism of inhibition is yet to be elucidated.Speculation: MMA at a concentration comparable to that reported in patients with methylmalonic acidemia inhibited in vitro growth of marrow hemopoietic cells, but overnight incubation of the cells in MMA at the same concentration did not reduce the number of viable cells determined by the trypan blue dye exclusion test. It appears, therefore, that MMA within the range of concentration tested is not immediately cytotoxic. Its inhibitory action thus seems to require longer cell contact hours than the 16 to 18 hr we used, and it may be directed against rapidly proliferating cell population. The potential mechanisms of inhibition are unknown and more work is needed to understand the interaction of MMA with hemopoietic cells.

Gyrate atrophy of the choroid and retina

Ornithine-delta-aminotransferase deficiency is the primary biochemical defect in gyrate atrophy of the choroid and retina and results in the characteristic accumulation of ornithine. An additional consequence of this inborn error is that arginine, the precursor of ornithine, becomes an essential amino acid. Therefore, to reduce the accumulated ornithine, we placed nine gyrate atrophy patients on an arginine-restricted diet. Plasma ornithine decreased by 50 to 85% within one month. Orally administered, alpha-aminoisobutyric acid facilitated the reduction in ornithine by augmenting renal losses. Over the long term, three patients have maintained near normal plasma ornithine concentrations from 4 to 32 months. Two patients have maintained less striking reductions in ornithine, and four have either been poorly controlled or have terminated the diet. Urinary losses of arginine and ornithine in gyrate atrophy patients with high or low plasma ornithine concentrations are less than 50% of the estimated arginine intake. This observation suggests that the bulk of ingested arginine is somehow metabolized despite the severe reduction in ornithine-delta-aminotransferase activity.Gyrate atrophy of the choroid and retina, which is often shortened to gyrate atrophy, is an inherited disorder characterized by progressive vision loss. People with this disorder have an ongoing loss of cells (atrophy) in the retina, which is the specialized lightsensitive tissue that lines the back of the eye, and in a nearby tissue layer called the choroid. During childhood, they begin experiencing nearsightedness (myopia), difficulty seeing in low light (night blindness), and loss of side (peripheral) vision. Over time, their field of vision continues to narrow, resulting in tunnel vision. Many people with gyrate atrophy also develop clouding of the lens of the eyes (cataracts). These progressive vision changes lead to blindness by about the age of 50.

RELATION OF SPECIFIC DYNAMIC ACTION |[lpar]|SDA|[rpar]| TO WEIGHT GAIN IN NORMAL AND MALNOURISHED RATS

In two independent studies of infants recovering from malnutrition Krieger et al. (J.Ped.1969) showed a positive linear correlation between SDA and weight gain and lack of a correlation with nitrogen (N) intake, while Ashworth (Nature 1969), noting also a correlation with weight gain, called for a “new concept of SDA.” It is not known whether during growth normal individuals show the same relationships. In this study malnourished rats had metabolic rate measurements 4 and 17 hours after food removal. The difference was 3.9% during growth arrest at 5 weeks, but 20.0 and 28.7% during growth recovery at 7 and 14 weeks, suggesting that the mechanism is the same as in human infants with malnutrition. Measurements were therefore conducted in 39 normal 4 to 36 week rats. The metabolic rate, 4 hours after food removal, rose from 15.6 to 45.1 kcal/day at 10-13 weeks, and then declined to 38.5 kcal/day at 32-36 weeks. The difference between the 4 and 17 hour values, which can be attributed to SDA, was determined in 21 rats. It was 28.8% in 5-15 week old rats who gained 5.2 g/day and 1.1% at 24-36 weeks when weight gain had ceased.CONCLUSION: SDA reflects energy requiring anabolic processes in normal and malnourished rats. Similar observations in malnourished human infants thus do not represent an abnormal phenomenon of catch-up growth. These findings are not incompatible with the correlation between SDA and N-intake known to exist in adults who are in N-balance. A new concept of SDA is indeed necessary.