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Docosahexaenoic acid (DHA) deficiency has recently been documented in several children with long-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHADD). We studied a 13-year-old boy with LCHADD who had limb girdle myopathy, recurrent myoglobinuria, and progressive sensorimotor axonopathy with demyelination. At 11 years of age, he was started on cod liver oil extract, high in DHA content. Over 12 months, he demonstrated a marked clinical recovery. Nerve conduction studies (NCS) demonstrated reappearance of previously absent posterior tibial and peroneal nerve responses and the amplitudes on motor ulnar and median NCS markedly increased from 7- to 14-fold, respectively.

Fifth-eight people receiving residential or other services for idiopathic mental retardation were evaluated for evidence of metabolic disease. Five (8%) demonstrated persistent urinary organic acid abnormalities on at least three occasions, which pointed towards specific genetic metabolic defects. Instigation of specific treatment programs may have improved the quality of life for one of these participants. Appropriate genetic counseling was provided but could have been instigated much earlier had these investigations been performed as part of a routine workup for idiopathic mental retardation. This pilot study suggests a need for evaluation of other similar populations with idiopathic mental retardation.

Study Objective: The discovery of pancreatitis in two children with methylmalonic acidemia led us to review the experience with pancreatitis in a large number of patients with organic acidemias to determine whether pancreatitis is an important complication of these disorders., Design: Case series., Setting: Pediatric metabolism services at five tertiary care centers., Patients: Records of all patients with organic acidemias followed at the five institutions during the past 10 years were reviewed. Pancreatitis was recognized by symptoms and laboratory findings and confirmed by imaging studies, surgery, or autopsy. At three institutions all cases of pancreatitis in children younger than 10 years were reviewed., Measurements and Results: Nine children with pancreatitis (seven with acute and two with chronic cases) were identified among 108 children with branched-chain organic acidemias. They ranged in age from 13 months to 9 years. Five had methylmalonic acidemia, three had isovaleric acidemia, and one had maple syrup urine disease. There were three deaths; acute hemorrhagic pancreatitis occurred in two children, and chronic pancreatitis was found at autopsy in a third. All three patients with isovaleric acidemia and pancreatitis were identified after the occurrence of pancreatitis. The survey of pancreatitis at three institutions found 57 other patients (none with an inborn error) in addition to three patients with inborn errors included in this study., Conclusions: Acute or chronic pancreatitis may complicate branched-chain organic acidemias and must be considered in the assessment of patients with these disorders who have acute clinical deterioration and vomiting, abdominal pain, encephalopathy or shock, or milder symptoms. Conversely, an inborn error of organic acid metabolism should be considered in children with pancreatitis of unknown origin.

Three patients presented with evidence of a fatty acid oxidation disorder. Analysis of urinary organic acids by gas chromatography/mass spectrometry demonstrated the presence of medium-chain (C6-C12) dicarboxylic, 3-hydroxydicarboxylic, and 3-ketodicarboxylic acids in all three urines. 3-Ketodicarboxylic aciduria is reported for the first time here, as are the mass spectra for 3-ketosuberic, 3-ketosebacic, and 3-ketododecanedioic acids and the oximated spectrum for 3-ketoadipic acid. The presence of 3-ketodicarboxylic acids suggests a defect at the level of a long-chain 3-ketoacyl-CoA thiolase, an enzyme for which a deficiency state has not previously been described. Our patients may represent the first cases of a long-chain thiolase defect.

Prenatal diagnosis has been undertaken in 17 pregnancies in 15 families at risk for aspartoacylase deficiency. Amniocentesis was at 14-18 weeks gestation followed by measurement of amniotic fluid N-acetyl-L-aspartate (NAA) levels in all pregnancies and amniocyte aspartoacylase activity in most pregnancies. In one case amniocentesis was performed at 11 weeks gestation in conjunction with chorionic villus sampling. At 14-18 weeks of gestation, control levels of NAA were 0.30-2.55 mumol/L. The fetus was predicted to be affected in 8 of the pregnancies, 4 of which were confirmed by enzyme analysis on fetal tissue and 2 by the clinical and metabolic expression of Canavan disease in a newborn. In two cases there was no fetal tissue available for enzyme confirmation. One of these had the highest amniotic fluid NAA level (8.68 mumol/L) and in the other pregnancy there were two amniocenteses, both with markedly elevated levels. Of 9 fetuses predicted to be normal, 8 newborns were clinically and biochemically normal. A single case with amniotic fluid NAA in the normal range (1.56 mumol/L, measured in one laboratory only) resulted in an aborted fetus in whom aspartoacylase was deficient in cultured skin fibroblasts. We propose that amniotic fluid NAA levels remain the best predictor of an affected fetus and recommend that the assay be performed in multiple laboratories.

Ibuprofen [(+/-)-2-(p-isobutylphenyl)propionic acid] has recently been introduced as a pediatric anti-inflammatory agent. To determine how this agent interferes with urine organic acid analysis, an important pediatric investigation, we have analyzed urine from two subjects pre- and post-Ibuprofen dosage and two subjects on chronic Ibuprofen therapy. A distinctive pattern of drug interference on the organic acid profile was detected. There were three major components, corresponding to unmetabolized Ibuprofen and to the oxidation products hydroxy Ibuprofen and carboxy Ibuprofen. Therefore, the major mechanism of Ibuprofen metabolism appears to be microsomal, although mitochondrial and peroxisomal routes cannot be excluded. Laboratories carrying out routine organic acid analysis should be aware of the nature and magnitude of the organic aciduria caused by Ibuprofen.

Combined 3-methylglutaconic and 3-methylglutaric aciduria, one of the more common urinary organic acid abnormalities, has been observed in at least three clinical syndromes. We studied an additional seven patients with 3-methylglutaconic aciduria, four of whom were best categorized as having the type II syndrome, two as having an "unspecified" syndrome, and one who may have had a primary urea cycle defect. In cultured cells and autopsy tissues derived from patients with the type II and unspecified syndromes, we were unsuccessful in identifying a defect in the leucine degradative pathway distal to 3-methylcrotonyl-coenzyme A carboxylase and in the cholesterol biosynthetic pathway between 3-hydroxy-3-methylglutaryl-coenzyme A reductase and diphosphomevalonate decarboxylase. Further assessment of the cholesterol biosynthetic pathway in several patients with one of the two types of disease also provided no defined abnormality. The primary metabolic defects in the type II and unspecified syndromes remain undefined.

Cultured fibroblasts from 13 patients with organic aciduria suggesting 3-oxothiolase deficiency were studied by measuring first the capacity of the isoleucine degradative pathways in whole cells, as the incorporation of 1-[14C]-2-methylbutanoic acid into macromolecules, and, second, the activity of 3-oxothiolase in cell homogenates using specific 3-oxoacyl-CoA substrates to identify the different enzymes. Nine patients showed low incorporation by the macromolecular labeling assay, as well as deficiency of 2-methylacetoacetyl-CoA thiolase. In this group of patients, low activity by the macromolecular labeling assay was associated with clinically severe symptoms, and vice versa. Two patients showed reduced macromolecular labeling, but apparently normal 3-oxothiolase. Finally, two patients showed normal activities by either test, the reason for their particular organic aciduria being unknown. In conclusion, occurrence of urinary 2-methyl-3-hydroxybutyric acid and/or tiglyglycine is not an unequivocal indicator of the absence of the thiolase that metabolizes 2-methylacetoacetyl-CoA. Measurement of 1-[14C]-2-methylbutanoic acid incorporation in cultured fibroblasts adds important information in studying possible defects of the isoleucine catabolic pathway.

Coffin-Siris syndrome is an infrequent condition characterised by mental retardation, nail hypoplasia or absence with fifth digit involvement and feeding problems. In addition, sparse scalp hair and chronic intractable eczema has been described in this syndrome. We report a 26-month-old girl with the disease and partial biotinidase deficiency.

A 2-year-old boy had acute fever, malaise, and somnolence with hepatomegaly, increased blood ammonia content (338 microM), high SGOT, low blood glucose content, and mild acidosis. A liver biopsy showed diffuse accumulation of lipid droplets in swollen hepatocytes, and abnormal urinary metabolites included beta-hydroxy-beta-methyl glutarate (HMG), beta-methylglutaconate, beta-hydroxyisovalerate, and beta-methylglutaric and glutaric acids. In cultured skin fibroblasts and liver, beta-hydroxy-beta-methyl glutaryl CoA lyase activity was about 10% of normal. Therefore, a genetic deficiency of HMGCoA lyase activity can cause a clinical syndrome similar to that of Reye syndrome when the patient is stressed by an acute viral infection.

Two patients with biotin-responsive multiple carboxylase deficiency, both presenting with predominant lactic acidosis, are reported. One with disease of early neonatal onset had considerable acute neurologic and persistent dermatologic abnormalities. The other, with late juvenile-onset disease, had chronic neurologic abnormalities without dermatologic findings. Early-onset cases generally have been associated with holocarboxylase synthetase deficiency, whereas those of juvenile onset have been characterized as representing defects in intestinal biotin absorption. However, enzyme analyses of fibroblasts from both patients, grown in biotin-deficient medium, revealed markedly diminished activities of pyruvate, propionyl-CoA, and beta-methylcrotonyl-CoA carboxylases, and all three enzymes showed normal activities after growth in biotin-rich medium. Furthermore, lymphoblast enzyme analysis in the patient with disease of early onset had previously revealed a defect in holocarboxylase synthetase, and fibroblast complementation studies showed that both patients belong to the bio complementation group. These findings indicate that considerable clinical heterogeneity exists among patients with holocarboxylase synthetase deficiency, an observation which does not permit differentiation of the biochemical forms of multiple carboxylase deficiency on the basis of age at onset and clinical presentation.

Low protein diets are used to treat infants and children with hyperammonemia due to urea cycle and other metabolic disorders as well as a number of amino and organic acidopathies. The incidence of these disorders is small and many are life-threatening. As a result, there is little in the literature on the dietary management of these patients. This paper draws on 10 years of clinical experience at the Hospital for Sick Children in Toronto, Ontario and presents a guide to the preparation of infant formulas providing levels of protein intake from 0.5 to 2.0 g per kg. Also described is a low protein equivalency system that is a useful guide for measuring both baby foods and table foods for affected children up to about six years of age. This dietary information is accompanied by a description of the disorders amenable to low protein diets, some of the adjunctive therapies employed and the nutritional concerns associated with severe restriction of protein.

We report here the expression of biotin-responsive multiple carboxylase deficiency in cultured lymphoblasts of a patient whose fibroblasts belong to the bio genetic complementation group. Cultured lymphoblasts from the patient lost propionyl-CoA carboxylase (PCC) and beta-methylcrotonyl-CoA carboxylase (MCC) activities at a faster rate than normal cells when grown in biotin-deficient medium. Recovery of normal PCC and MCC activities, which was independent of protein synthesis, required a 2,500-fold higher biotin concentration than that required by normal lymphoblasts. Holocarboxylase synthetase activity was detected in cell-free extracts through the biotinylation of endogenous apo-PCC in the presence of ATP to form active holo-PCC. While the apo-PCC in extracts of normal biotin-starved lymphoblasts could be activated to 28% of maximal activity, extracts of patient lymphoblasts did not exhibit any ATP and biotin-dependent increase in PCC activity. A normal cell extract, cleared of apocarboxylases by immunoprecipitation, stimulated the PCC activity of a patient cell extract 20-fold. These results indicate that the apoenzyme in bio cells is normal and that the defect lies in the holocarboxylase synthetase.

A male child presented on the first day of life with metabolic acidosis with elevated blood lactate (15 mM), pyruvate (0.4 mM), and free fatty acid (1.3 mM) levels and a blood pH of 7.16. The severity of the acidosis was diminished by intravenous administration of glucose in large doses and by bicarbonate. On two occasions, when the acidosis was particularly severe, peritoneal dialysis using an acetate buffer was required. Restriction of the dietary intake of saturated fatty acids or treatment with nicotinic acid also appeared to diminish the severity of acidosis. No improvement was achieved by the administration of thiamine or biotin. Tissues taken at postmortem showed normal activity of gluconeogenic enzymes and pyruvate dehydrogenase. The activity of pyruvate dehydrogenase in tissue homogenates preincubated with ATP was reduced by 60-75% both in liver of the patient and of the controls because of the inactivation of the enzyme by pyruvate dehydrogenase kinase. Addition of Ca++ and Mg++ to the inactivated enzyme caused a prompt return of the activity to normal in controls but not in the patient. This defect, which was apparent in muscle and liver but not in brain, we attribute to a markedly reduced activity of pyruvate dehydrogenase phosphatase in the patient.

The prognosis of patients with cardiomyopathy associated with hypocarnitinemia is uncertain. Cardiac hemodynamics, histologic findings and response to oral L-carnitine therapy were retrospectively evaluated in 11 children with cardiomyopathy associated with abnormal carnitine metabolism. Three had systemic carnitine deficiency, two familial hypocarnitinemia with neutropenia, three transient neonatal hypocarnitinemia and three a carnitine insufficiency syndrome. Six had a hypertrophic and five a dilated cardiomyopathy. Hypotonia was present in seven (64%). The cardiothoracic ratio was greater than 0.60 in eight (73%). The most frequent abnormality on the electrocardiogram was ST-T wave inversion in the left precordial leads with various degrees of left ventricular hypertrophy. Echocardiographically, two patients with hypertrophic cardiomyopathy had decreased left ventricular function and two patients with dilated cardiomyopathy had increased thickness of the left ventricular wall. Histologic evaluation (two autopsies and one endomyocardial biopsy) revealed striking lipid accumulation within hypertrophied myocytes. Six of eight patients on carnitine replacement therapy had improvement echocardiographically during a 3 month to 2 year follow-up period. In summary, both hypertrophic and dilated cardiomyopathy can result from abnormal carnitine metabolism. The determination of plasma carnitine concentrations and fatty acid metabolism by-products should be performed in all patients with either form of cardiomyopathy of unknown etiology because carnitine supplementation may lead to improvement.

Pyruvate dehydrogenase deficiency is among the most common causes of congenital lactic acidosis. We describe siblings with congenital lactic acidosis due to a deficiency of pyruvate dehydrogenase complex. The findings of computed tomography and pathologic studies suggest that central nervous system damage had occurred in utero. These observations have implications for treatment and outcome in patients with enzymatic defects causing congenital lactic acidosis.

Biotinidase deficiency satisfies all the criteria for incorporation into neonatal mass screening programmes for inborn errors of metabolism. We report our preliminary experiences with screening of 24,300 newborns during a 6 month-period when 1 infant with biotinidase deficiency was detected. On the basis of these results, this disorder appears to be as common as other well known metabolic disorders for which mass screening is available.

The rate of glucose turnover (RT) has been studied in 33 subhuman primate newborn (Macaca mulatta). There appears to be a linear relationship between RT and plasma glucose (G) such that RT = 1.053 G + 0.242. Liver enzymes show a change in specificity such that hexokinase is predominant in the preterm animals and glucokinase has little activity, while in the term animal these enzymes of of equal activity. In the 1-year-old animal glucokinase predominates. Hexokinase activity in the brain remains constant throughout development. These results imply that low blood glucose in the neonate is not associated with increased glucose utilization.

Eight cases of isolated human pyruvate carboxylase deficiency were examined from seven families. Although all patients presented with a chronic lacticacidemia, two particular patients presented with the added features of hyperammonemia, citrullinemia, and hyperlysinemia. When cultured skin fibroblasts from these patients were examined for their ability to synthesize [3H]biotin-containing proteins, it was found that the two patients who presented with hyperammonemia, citrullinemia, and hyperlysinemia did not synthesise a protein of the correct subunit molecular weight (Mr = 125 K daltons) corresponding to pyruvate carboxylase. In addition, when skin fibroblast proteins were labeled with [35S]methionine, cross-reacting material (CRM) corresponding to pyruvate carboxylase was immunoprecipitated by antipyruvate carboxylase antiserum in most patients, but again the two patients with the atypical presentation showed no CRM. We propose that the different clinical presentation of human pyruvate carboxylase deficiency is a manifestation of two different mutations in the pyruvate carboxylase gene, one that results in the synthesis of a relatively inactive pyruvate carboxylase protein CRM(+ve) and one that results in the lack of expression of the gene in the form of a recognizable protein CRM(-ve).

A total of 40 skin fibroblast cultures from pediatric cases of lactic acidosis were subjected to a series of tests designed to elucidate the nature of an underlying defect in metabolism. Of these 40 cases, in 14 we were able to define the following problems. Pyruvate carboxylase deficiency was evident in five cases showing < 10% normal activity. Phosphoenolpyruvate carboxykinase deficiency was evident in one case where the whole cells showed 17% of normal activity whereas the mitochondrial activity of this enzyme was 6% of normal. Pyruvate dehydrogenase deficiency was present in six cases showing 8 to 39% of normal activity, five of them being due to deficient pyruvate decarboxylase activity and one of them being due to deficient dihydrolipoyl dehydrogenase activity. Two cases were found with normal enzymes of pyruvate metabolism in which the production of 14CO2 from [3-14C]pyruvate was deficient at 13 and 28% of normal activity, respectively, which we consider to be indicative of reduced activity of the Krebs' cycle. The grounds for the diagnosis of these 14 affected cases are documented, and the clinical presentation of these enzyme deficiencies is assessed in the light of present knowledge about lactic acidosis.

Neonatal lung morphology was evaluated in 12 rhesus monkeys delivered by caesarean section 1 month before term and cared for as human premature neonates. In 6 monkeys, 0.20 to 0.27 ml of natural rabbit surfactant (SA) was instilled intratracheally before the first breath; the other 6 served as controls. Histology and morphometry of the controls' lungs revealed changes typical of hyaline membrane disease (HMD) in human premature infants, whereas the SA-treated lungs showed improved alveolar expansion and only minor lesions typical of HMD. Transmission and scanning electron microscopy of the controls' lungs showed extensive necrosis and desquamation of bronchiolar epithelium, with formation of hyaline membranes; Type I alveolar epithelial cells showed lesions similar to those in bronchioles, but immature Type II cells appeared relatively well preserved. In the lungs of SA-treated animals, the epithelial lining of most airways and alveoli was intact. This first demonstration of the beneficial effect of exogenous SA on lung adaptation in premature primates indicates that prophylaxis with SA might prevent HMD in premature human infants.

Congenital childhood lactic acidaemia is a poorly understood group of genetic diseases. The most common underlying inherited defect encountered in this group is deficiency of the pyruvate dehydrogenase complex. Of 23 cases we have diagnosed, 18 have a deficiency in the first component of the complex, the E1 decarboxylase, while the other five have multiple alpha-keto acid dehydrogenase deficiency due to a defect in lipoamide dehydrogenase. In addition to the lactic acidosis associated with pyruvate decarboxylase deficiency, ten of the cases showed evidence of facial dysmorphism consisting of a narrow head, wide nasal bridge and flared nostrils or gross microcephaly. Two further patients had agenesis of the corpus callosum. Isolated pyruvate carboxylase deficiency was found to present in two different forms, one with lactic acidaemia and mental retardation, the other with lactic acidaemia, hyperammonaemia citrullinaemia and hyperlysinaemia. The former presentation we have shown to be associated with the presence of a biotinylated pyruvate carboxylase protein of the correct subunit molecular weight (125 kd) which has no catalytic activity (CRM + ve). The latter we have shown to be associated with the absence of any recognizable pyruvate carboxylase protein (CRM - ve).

The development of total pyruvate dehydrogenase activity in the subhuman primate, Macaca mulatta, was investigated in brain, liver, kidney cortex, and skeletal and cardiac muscle. Newborn primates delivered prematurely at 135 days of gestation had only 32% of this enzyme activity present in the brain compared to the full-term animal. Full-term animals were similar to adults. All tissues showed high activities of enzyme at 1 year of age compared either with neonates or adults. Kidney cortex showed an increase in activity from 807 +/- 74 mumol/g/min in prematurely delivered neonates to a maximum of 3,769 +/- 275 mumol/g/min in 1-year-old animals. The results are discussed in relation to the developing energy requirements of the tissues concerned.

We report the case of a patient who at age 39 first developed an episode of muscle weakness and transient ketoacidosis with biopsy proven fatty infiltration of the liver. Over the next several years, myopathy ensued; biopsy revealed extensive deposition of lipid globules in type 1 muscle fibres. Further investigations established the diagnosis of systemic carnitine deficiency (SCD) with skeletal muscle, hepatic, and cardiac involvement. The patient has benefited from L-carnitine supplementation. Our case represents an unusually late onset of SCD and highlights the necessity, when appropriate, of a high index of suspicion of this rare but treatable disorder.

A study of treatment practices of pediatric centers managing hereditary fructose intolerance and a review of recent literature on this subject were undertaken in an attempt to establish the degree of dietary liberalization allowable with age and the acceptability of foods containing trace amounts of fructose. The information was needed to plan optimal therapy and thus avoid the consequences of the disorder, namely intestinal dysfunction, metabolic imbalance, and hepatic and renal damage. Fifty responses to 113 letters to centers in Canada and the United States, as well as data from The Hospital for Sick Children, Toronto, Ontario, identified only 29 affected children and provided information on their care, including food lists and literature references. Major principles of treatment were similar, but the approach to allowing and quantifying dietary fructose differed. In response to the apparent need for standardization of treatment, the authors formulated improved recommendations for the control of dietary fructose (less than 1.5 gm/day). Only a few foods of vegetable origin are allowed, including a limited selection of vegetables and cereal products from grain endosperm. Repeated dietary counseling is advocated with regard to allowed foods, sweeteners, and medications to ensure long-term dietary compliance.

Clinical findings are presented for 30 patients with lactic acidemia in whom activity of the pyruvate dehydrogenase complex in fibroblasts was significantly (P = less than 0.01) below that of control cell lines. Residual activity of the activated complex ranged from 1.6% to 68.5% of control activity. Seven patients died before 6 months of age, and another five before reaching 2 years of age. Sixteen of the surviving patients and the five who died between 6 months and 2 years all had psychomotor retardation. Seventeen children had structural central nervous system damage, as determined either by computed tomography or at autopsy. The extent and location of damage varied from cerebral atrophy to the development of cystic lesions in the cerebral cortex, basal ganglia, and brain stem. Two patients had ataxic episodes only and were not developmentally delayed. This cohort of patients strongly resembles a comparable group assembled from various other reports.

A female child presented at one year of age with a febrile illness and loose stools, then developed severe ketoacidosis with vomiting; an apparent salicylate level of 11 mg/dl was measured. A sibling had died in similar circumstances nine years earlier. Investigation revealed that the child did not have salicylate intoxication, and that high levels of acetoacetate in blood and urine were giving readings indicative of the presence of salicylate on routine testing. Gas-liquid chromatographic analysis combined with mass spectrometry on urine samples revealed the presence of 2-methyl-acetoacetate, 2-methyl-3-hydroxybutyrate, and tiglyl glycine in appreciable amounts, indicating a defect in isoleucine catabolism located at the beta-ketothiolase step. The oxidation of 14C-isoleucine to CO2 in cultured fibroblasts confirmed that this pathway was defective. We present evidence that beta-ketothiolase deficiency is not simply a defect of isoleucine degradation; the deficient enzyme is the K+ dependent short-chain mitochondrial thiolase, which also plays a major catalytic role in ketone body and fatty acid oxidation.

In a case of dihydrolipoyl dehydrogenase deficiency, there was not only an elevation of lactate and alpha-ketoglutarate but also of branched chain amino acids. The levels of branched-chain amino acids varied from the normal range to three times the upper limit of normal during the patient's lifetime, and alloisoleucine was detectable at all times. Examination of postmortem tissues revealed that the activity of branched-chain keto acid dehydrogenases was between zero and 10% of that in control tissues. It is suggested that the multiple defects seen in oxidative decarboxylation in this patient is the consequence of a single genetic deletion of an enzyme common to pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched chain keto acid dehydrogenases.

A male child died at 7 months of age with progressive neurologic deterioration and persistent metabolic acidosis. Investigations during life showed this child to have elevated blood pyruvate, lactate, and alpha-ketoglutarate as well as elevation of branched chain amino acids and occasional hypoglycemia. Cofactor therapy using either thiamine-HCl (2 g/kg/24 hr) or thiamine tetrahydrofurfuryl disulfide had no measurable effect on the clinical or biochemical status of the patient. Tissue taken postmortem showed normal levels of key gluconeogenic enzymes but a deficiency in the activity of pyruvate dehydrogenase in all tissues tested (liver, brain, kidney, skeletal muscle, and heart). Examination of the individual activities of pyruvate dehydrogenase complex showed pyruvate decarboxylase (E1) to be normal in liver and other tissues. Dihydrolipoyl dehydrogenase (E3), on the other hand, was deficient in all tissues tested. alpha-Ketoglutarate dehydrogenase complex, which depends of E3 for its total activity, was also deficient in all tissues tested. The absence of this enzyme id discussed in relation to the clinical and biochemical status of the patient.

The capacity for gluconeogenesis has been studied in 33 subhuman primate newborn (Macaca mulatta) in the basal steady state. Basal blood glucose levels were seen to rise with increasing postnatal age. Availability of the major gluconeogenic substrates, alanine and lactate, was adequate at times when blood glucose and the rate of gluconeogenesis were low. Hepatic and renal cortical content of the four key gluconeogenic enzymes was low during the 1st week of life compared to adult levels. Diminished induction of the gluconeogenic enzymes did not appear to be the cause of low blood glucose levels. The serum-free fatty levels were directly correlated to both the basal glucose levels and to the rate of gluconeogenesis.