Louise A. Dilling

Phenotypic variability in glutaric aciduria type I: Report of fourteen cases in five Canadian Indian kindreds

We describe 14 patients with glutaric aciduria type 1 in five Canadian Indian kindreds living in Manitoba and northwest Ontario. The patients had marked clinical variability of the disease, even within families. Eight followed the typical clinical course of normal early growth and development until the onset of neurologic abnormalities, often precipitated by infection, between 6 weeks and 7 1/2 months of age. Five patients had early developmental delay; one was thought to be normal until 8 years of age. Three patients died, seven are severely mentally and physically handicapped, and four have only mild mental retardation or incoordination. Six patients had macrocephaly in the neonatal period. Computed tomography was done for 12 patients, and findings were abnormal in 11. Glutaric acid and 3-hydroxyglutaric acid were detected in increased amounts in the urine of all patients, but the concentrations were much lower than those in most other reported patients. Glutaryl coenzyme A dehydrogenase activity in skin fibroblasts, interleukin-2-dependent lymphocytes, or both, ranged from 0% to 13% of control values. There was no correlation between clinical severity and urine glutaric acid concentration or level of residual enzyme activity. We recommend that organic acid analysis of the urine be done in patients with unexplained cerebral palsy-like disorders, especially if the computed tomographic scan is abnormal. If there is suspicion of glutaric aciduria, glutaryl-coenzyme A dehydrogenase should be measured in fibroblasts or lymphocytes even if glutaric acid is not increased in the urine.

Fetal growth retardation in cigarette-smoking mothers is not due to decreased maternal food intake

To determine whether the fetal growth-retarding effect of maternal cigarette smoking could be due to a lower dietary intake in smokers than in nonsmokers, the energy and nutrient intake of 302 smoking and 234 nonsmoking women were assessed toward the end of the last trimester of pregnancy. The women were from two socioeconomic groups which differed greatly in age, height, education, family income, racial origin, and pregnancy weight gain. Within each group, smokers had significantly smaller infants, but pregnancy weight gain was not different. Daily dietary intake of the smokers was not less than that of the nonsmokers; in fact, for some nutrients it was significantly greater. Therefore, fetal growth retardation due to smoking is not caused by the mothers diminished intake of food.

The paradox of the carnitine palmitoyltransferase type Ia P479L variant in Canadian Aboriginal populations

Investigation of seven patients from three families suspected of a fatty acid oxidation defect showed mean CPT-I enzyme activity of 5.9+/-4.9 percent of normal controls. The families, two Inuit, one First Nation, live in areas of Canada geographically very distant from each other. The CPT1 and CPT2 genes were fully sequenced in 5 of the patients. All were homozygous for the same P479L mutation in a highly conserved region of the CPT1 gene. Two patients from the first family were also homozygous for the CPT2 F352C polymorphism in the CPT2 gene. Genotyping the patients and their family members confirmed that all seven patients were homozygous for the P479L variant allele in the CPT1 gene, as were 27 of 32 family members. Three of the seven patients and two cousins had hypoketotic hypoglycemia attributable to CPT-Ia deficiency, but adults homozygous for the variant denied hypoglycemia. We screened 422 consecutive newborns from the region of one of the Inuit families for this variant; 294 were homozygous, 103 heterozygous, and only 25 homozygous normal; thus the frequency of this variant allele is 0.81. There was an infant death in one family and at least 10 more deaths in those infants (7 homozygous, 3 heterozygous) consecutively tested for the mutation at birth. Thus there is an astonishingly high frequency of CPT1 P479L variant and, judging from the enzyme analysis in the seven patients, also CPT-I deficiency in the areas of Canada inhabited by these families. Despite the deficiency of CPT-Ia which is the major rate-limiting enzyme for long chain fatty acid oxidation, clinical effects, with few exceptions, were slight or absent. One clue to explaining this paradox is that, judging from the fatty acid oxidation studies in whole blood and fibroblasts, the low residual activity of CPT-Ia is sufficient to allow a reasonable flux through the mitochondrial oxidation system. It is likely that the P479L variant is of ancient origin and presumably its preservation must have conveyed some advantage.

Prognosis of Infants of Diabetic Mothers in Relation to Neonatal Hypoglycaemia

A prospective follow‐up study was conducted to determine whether neonatal hypoglycaemia in infants of diabetic mothers affects subsequent neurological and intellectual performance. 37 such infants (25 hypoglycaemic and 12 non‐hypoglycaemic) were examined for physical, neurological and developmental performance at an average age of 41/2 years. 11 children were abnormal, with generalised retardation and neurological abnormalities, or delays in particular areas of development; three children were possibly abnormal; and 23 children were normal. Abnormality at follow‐up could not be related to neonatal blood glucose level, to the duration of hypoglycaemia or to any other measurement made in the neonatal period, nor to any factor relating to the maternal diabetes. Compared with the normal children, the abnormal group had slightly smaller head‐circumferences at birth relative to their gestational age, but at follow‐up there was no difference in head size. At follow‐up the children of diabetic mothers tended to be shorter than average. The poor prognosis of the infants in this study was not due to brain damage caused by neonatal hypoglycaemia.

Relation of maternal cigarette smoking, obesity, and energy consumption to infant size

The dietary energy intakes of 153 public patients (94 smokers and 59 nonsmokers) and 383 Private patients (208 smokers and 175 nonsmokers) were assessed in the last month of pregnancy. Birth weight and crown-heel length of offspring were related to maternal size (weight for height) and smoking habits. Birth weight and length increased significantly with increasing maternal weight for height in the Private group but not in the Public group. In both groups, and in all weight categories, infants of smokers were lighter and shorter than those of nonsmokers. Neither the fetal growth retardation in the smokers nor the fetal growth enhancement in the overweight mothers was explainable on the basis of maternal dietary energy intake. Maternal obesity and cigarette smoking act independently of each other and maternal overweight does not protect the fetus against the growth-retarding of smoking.

Atypical features of the hepatic form of carnitine palmitoyltransferase deficiency in a Hutterite family

We describe hepatic carnitine palmitoyltransferase (CPT I) deficiency in three children (a brother and sister and their second cousin) from an extended inbred Hutterite kindred. The patients were first seen between 8 and 18 months of age with recurrent episodes of hypoketotic hypoglycemia accompanied by a decreased level of consciousness and hepatomegaly. One patient had two Reye syndrome-like episodes. Abnormal organic acids were rarely detected in urine. Serum total and free carnitine levels were elevated in all three patients. Fibroblast acyl-coenzyme A dehydrogenase activities were normal in all, but palmitic acid oxidation, performed in fibroblasts from one patient, was less than 10% of control values. Activity of CPT I in cultured skin fibroblasts from the three patients was 10% to 15% of control levels; CPT II activity was normal. Activity of CPT I and CPT II in muscle from one patient was normal. Atypical features in two of these patients were greatly elevated levels of liver enzymes and creatine kinase during acute episodes. The patients have recently been successfully treated with medium-chain triglycerides and avoidance of fasting. Early identification and treatment of this disorder may avert potentially fatal episodes of hypoglycemia.

Relation of blood-glucose to haematocrit, birthweight, and other body measurements in normal and growth-retarded newborn infants.

Abstract Blood-glucose and haematocrits were determined from birth to 7 days of age in forty normal-sized term infants and in thirty-eight term infants with intrauterine growth retardation whose birthweights were below the 10th percentile on the Denver intrauterine growth chart. Mean values for blood-glucose and haematocrit in eighteen of the growth-retarded infants, whose birthweights were less than 2 standard deviations below the mean for their gestational ages, did not differ from the normals. The remaining twenty growth-retarded infants whose birthweights were greater than 2 standard deviations below the mean, had mean blood-glucose levels which were significantly lower and haematocrits which were significantly higher than normal-sized infants at most times during the first 7 days of life. Birth-weight, blood-glucose, and haematocrit were not significantly related in the normal infants. Blood-glucose and haematocrit were inversely related in the growth-retarded infants, but in the severely growth-retarded infants this relationship was not a real one since glucose and haematocrit were related to birthweight. When the effect of birthweight was removed by multiple regression analysis, the relation of blood-glucose and haematocrit became insignificant. Blood-glucose was inversely related to the ratio of head circumference to body-weight in the severely growth-retarded infants. It is concluded that it is the infant whose birth-weight is more than two standard deviations below the mean for his gestational age, with

A simple screening test for fatty acid oxidation defects using whole-blood palmitate oxidation

We report that measurement of whole-blood palmitate oxidation is a rapid and inexpensive screening test for fatty acid oxidation defects. The assay has been adapted from published assays using cultured fibroblasts or isolated white blood cells. Micro whole-blood samples are incubated with tritiated palmitic acid as substrate. The tritiated water produced is proportional to the mitochondrial β-oxidation of palmitic acid. Patients with confirmed β-oxidation defects show low whole-blood palmitate oxidation.

Relationships between maternal glucose intolerance and neonatal blood glucose.

Blood glucose changes in 63 infants during the first three hours of life were related to indices of glucose tolerance of their mothers. Of the mothers, 34 had insulin-dependent diabetes, 16 had gestational diabetes, and 11 had minor abnormalities of glucose tolerance. The fasting blood glucose level of the mother and the umbilical cord blood glucose level were both proportional to the rate of glucose decline in the infant after birth which, in turn, was inversely related to the lowest glucose level attained within three hours. Hypoglycemia occurred in 77% of the infants of diabetic mothers, 25% of the infants of mothers with gestational diabetes, and one of 12 (8%) of infants of mothers with minor degrees of glucose intolerance. The blood glucose level at two hours during an oral glucose tolerance test in the mother can be used to predict the probability of her infant having neonatal hypoglycemia.