Bluma Tischler

Glutamine depletion in phenylketonuria.A possible cause of the mental defect.

Abstract Two adult brothers with untreated phenylketonuria, one with a severe mental defect and the other with superior intelligence, were compared biochemically. No significant differences were found in their degree of hyperphenylalaninemia, nor in their urinary excretion of phenylalanine metabolites. A striking difference between the two, however, was a significant reduction in concentration of glutamine in the plasma of the defective brother, but not in the intelligent brother. A second adult with untreated phenylketonuria and normal intelligence, as well as a group of phenylketonuric children who were receiving a low-phenylalanine diet, also had plasma glutamine concentrations within the normal range. Twelve mentally defective untreated patients with phenylketonuria all showed a significant reduction in plasma glutamine. These findings cast doubt on some proposed mechanisms for the mental defect in phenylketonuria, and suggest that chronic insufficiency of glutamine may play a part in damaging the gro...

Unrecognized adult phenylketonuria. Implications for obstetrics and psychiatry.

Abstract Phenylketonuria is rarely suspected in adults of normal intelligence, and its complications can therefore be overlooked. Of four adult siblings with previously unrecognized and untreated phenylketonuria, three have normal intelligence, one being a university graduate. Three phenylketonuric women in the sibship have given birth to nine non-phenylketonuric children, all of whom have varying degrees of intellectual deficit. Two of the adults with phenylketonuria have suffered major psychotic illnesses resulting in their admission to a mental hospital, where they were inappropriately given electroconvulsive therapy and antipsychotic drugs. Our experience, together with that of others, suggests that routine testing of urine with the ferric chloride test early in every womans first pregnancy could prevent some cases of mental retardation. Similar routine screening of the urine of mentally ill patients might avoid illogical treatment for occasional psychotic adults. (N Engl J Med 289:395–398, 1973)

Inverted tandem duplication generates a duplication deficiency of chromosome 8p

An adult female with severe mental retardation and dysmorphic features is described. A de novo chromosomal aberration involving 8p was found. The karyotype was 46, XX, inv dup (8) (pl2→p23.1). Dosage studies with the DNA probe D8S7, which is located at 8p23→8pter, showed that the patient was monosomic for this marker. Thus the de novo rearrangement generated a duplication‐deficiency chromosome. The possible mechanisms of formation of this abnormal chromosome are discussed.

A simple test for heterozygosity for phenylketonuria

Abstract Thirty-six known heterozygotes for phenylketonuria, and 47 control subjects were tested for heterozygosity by determination of fasting serum phenylalanine and tyrosine concentrations. In addition, intravenous phenylalanine loading tests were performed on 23 subjects from each group. Intravenous administration of the phenylalanine load failed to improve the discriminating ability of oral phenylalanine loading tests reported by other investigators. Combined use of the fasting serum or plasma phenylalanine concentration and the fasting phenylalanine-tyrosine ratio allows accurate classification of approximately two-thirds of all subjects as to heterozygosity, and leaves approximately onethird unclassified. This test is much simpler than any loading test. It is suggested that it be employed as an aid to genetic counselling of close relatives of phenylketonurics, and as an additional diagnostic check for asymptomatic infants who are thought to have phenylketonuria and are under treatment with a low-phenylalanine diet.

TREATMENT OF HOMOCYSTINURIA WITH A LOW-METHIONINE DIET, SUPPLEMENTAL CYSTINE, AND A METHYL DONOR

Abstract Plasma-homocystine levels were reduced significantly in three children with homocystinuria through the use of a diet providing only 10 mg. of methionine per kg. body-weight per day, supplemented by L-cystine and large doses of the methyl donor, choline. Pyridoxine had no effect on the biochemical changes in their blood. Reduction of plasma-homocystine may be an important measure for preventing intravascular thromboses in patients who already exhibit the other clinical manifestations of homocystinuria. A 3-year-old child treated for homocystinuria since early infancy with a low-methionine diet and supplemental cystine remains mentally and physically normal, thus suggesting the possibility of preventing all of the ill-effects of the disease by early diagnosis and dietary therapy.

Determination of heterozygosity for phenylketonuria on the amino acid analyzer

Abstract Concentrations of phenylalanine and tyrosine in fasting blood plasma were determined with the amino acid analyzer on 43 known heterozygotes for phenylketonuria, and on 80 control subjects, and phenylalanine: tyrosine ratios were calculated. The results suggest that a phenylalanine: tyrosine ratio of less than unity indicates absence of the abnormal gene for phenylketonuria, while a ratio of 1.20 or higher indicates heterozygosity for the gene. 20% of subjects tested had ratios falling in the zone of overlap between 1.00 and 1.19, and their genotype could not be determined.

Krabbe's leukodystrophy without globoid cells

Krabbes infantile cerebral sclerosis with a prolonged course was present in a boy who became increasingly hypertonic during infancy and had an increased protein level in the spinal fluid. At 4 years he showed significant growth failure, profound mental retardation, spastic quadriplegia, bilateral optic atrophy, and depressed tendon reflexes. Conduction velocity in motor fibers of the median nerve had become progressively impaired. Autopsy at 5 years 10 months showed severe leukodystrophy with demyelination and gliosis. No stored breakdown products or globoid cells were seen in the brain. Galactosyl ceramide beta-galactosidase was virtually absent, and hardly any myelin was demonstrable on chemical and electron microscopic studies. The presence of globoid cells may not be essential for the pathologic diagnosis of Krabbes leukodystrophy in the presence of appropriate enzyme deficiency.

DEFECTIVE 5-HYDROXYLATION OF TRYPTOPHAN IN PHENYLKETONURIA.

Summary Untreated phenylketonuric patients excreted less serotonin and less 5-HIAA in their urine than did patients with mongolism. They also excreted less than a normal adult. The difference between phenylketonurics and the control subjects was accentuated after oral administration of tryptophan. When 5-HTP was given by mouth, the phenylketonuric subjects excreted relatively large amounts of serotonin. After their serum phenylalanine concentrations had been reduced to a normal level by the use of a low-phenylalanine diet, phenylketonurics spontaneously excreted normal amounts of serotonin and 5-HIAA. A reversible defect in the 5-hydroxylation of tryptophan thus seems primarily responsible for the decreased production of serotonin in phenylketonuria.

The incidence of mental illness in the relatives of individuals suffering from phenylketonuria or mongolism

Abstract A search for cases of mental illness and behavioural abnormalities was carried out among 1268 relatives of 34 unrelated phenylketonuric patients. A comparable number of the relatives of 34 unrelated patients with mongolism were similarly surveyed for evidence of mental illness. No significant differences were found in the incidence of psychoses, admissions to mental hospitals, personality disorders, chronic alcoholism, suicide, or the commission of crimes, between the relatives of phenylketonurics and the control group of relatives of patients with mongolism. Marital separations occurred somewhat more frequently among the parents and uncles and aunts of phenylketonurics than among the corresponding relatives of mongoloids, but may well not have been related to emotional instability in phenylketonuric heterozygotes. The results of this study do not support the hypothesis that heterozygosity for phenylketonuria predisposes the individual to mental illness in adult life.

Phenylketonuria in a Woman of Normal Intelligence and Her Child

THREE cases are on record in which a phenylketonuric parent has produced a phenylketonuric child.1 2 3 An additional family in which phenylketonuria occurred in 2 successive generations is describe...