Kimberlee Michals

Canavan disease: From spongy degeneration to molecular analysis☆☆☆★★★♢

Establishing the basic defect in Canavan disease has led to reliable biochemical methods for the diagnosis of this disease. The isolation of the gene and identification of mutations causing Canavan disease have led to the possibility of using DNA methods for the diagnosis of Canavan disease and for carrier detection. A surprising finding is the high carrier frequency of this gene defect among Ashkenazi Jewish people. Analysis for two mutations leads to the identification of 97% of Jewish patients with Canavan disease, and screening of Ashkenazi Jews is possible. N-Acetylaspartic acid has been considered to be an inert compound. The pathophysiology of Canavan disease links lack of NAA hydrolysis to a severe, debilitating white matter disease. Currently, NAA is being studied in many other brain disorders, such as Alzheimer disease, Huntington disease, and stroke. However, the only disease with a specific defect in the metabolism of NAA is Canavan disease. An animal model for Canavan disease is needed to study some of the questions regarding the role of NAA in brain tissue, and for the study of therapeutic modalities, including gene therapy.

Lipoamide dehydrogenase deficiency with primary lactic acidosis: Favorable response to treatment with oral lipoic acid

An 8-month-old boy with severe lactic acidosis was found to have lipoamide dehydrogenase deficiency. Treatment with thiamine, biotin, bicarbonate, protein restriction, and ketogenic diet failed to alleviate the lactic acidosis. Oral administration of lipoic acid 25 to 50 mg/kg produced dramatic improvement in lactic and pyruvic acidemia, which has continued for 2 years and which has been accompanied by clinical improvement.

Effects of Ascorbic Acid in Alkaptonuria: Alterations in Benzoquinone Acetic Acid and an Ontogenic Effect in Infancy

ABSTRACT: The effects of ascorbic acid on the excretion of homogentisic acid and its derivative benzoquinone acetic acid were studied in two adults and three infants. The administration of relatively large amounts of ascorbic acid to the adults was followed by a disappearance of benzoquinone acetic acid from the urine, whereas the level of excretion of homogentisic acid did not change. This could have relevance to the pathogenesis of ochronotic arthritis. In the 4-mo-old infant and the 5-mo-old infant ascorbic acid in the urine may have doubled the amount of homogentisic acid, presumably through an effect on the immature p-hydroxyphenylpyruvic acid oxidase. Dietary reduction of the intake of tyrosine and phenylalanine substantially reduced the excretion of homogentisic acid.

A treatment program for adolescents with phenylketonuria

A treatment program for adolescents with phenylketonuria (PKU) , incorporating education, goal-setting, self-monitoring, contracts, and rewards, was evaluated by measuring knowledge of PKU, blood phenylalanine concentrations, and health locus of control (LOC) before and after participation in the program. Of the 16 subjects, seven subjects successfully completed the program by achieving behavioral goals. These subjects increased their knowledge of PKU and decreased their blood phenylalanine concentrations, but the nine nonsuccessful subjects did not. There was no significant change in LOC scores for either group. There was a significant relationship between baseline blood phenylalanine levels and success with the program. Therefore, this pilot study demonstrates that adolescents who have already achieved some measure of metabolic control can be expected to be most successful with this program and realize the greatest benefits from it in the form of increased knowledge of PKU and even better metabolic control.

Phenylketonuria: Current dietary treatment practices in the United States and Canada

OBJECTIVE A survey of treatment centers for phenylketonuria (PKU) in the United States and Canada was undertaken regarding current practices of dietary treatment of PKU. METHODS A total of 111 centers, who follow more than 6,950 patients with PKU responded to the survey. RESULTS The majority of the centers, 87%, favor life-long dietary control of phenylalanine intake. The survey found lack of uniformity regarding acceptable range of blood phenylalanine levels. The frequency of clinic visits varied and became less frequent as patients got older. Although most of the clinics recommend diet for life, only one-third of the clinics follow patients beyond the age of 18 years, therefore, it is unclear who manages these patients beyond that age. The survey also showed a high number of families with children who were reported for medical neglect (3.0% compared to < 0.06% in the general population). Because of dietary noncompliance, 1% of the children were removed from the home. DISCUSSION The survey points to the common treatment goal of diet for life for patients with PKU and underscores the need for uniform guidelines for achieving this goal.

Prenatal diagnosis of Canavan disease.

Spongy degeneration of the brain, Canavan disease (CD; McKusick 271900), is an autosomal recessive disorder prevalent among Ashkenazi Jews. The disease is a leukodystrophy manifested by macrocephaly, mental retardation and early death (Canavan 1931; van Bogaert and Bertrand 1967). Patients with Canavan disease excrete large amounts of β-acetylaspartic acid (NAA) in their urine and have a profound deficiency of aspartoacylase (EC 3.5.1.15) in their cultured skin fibroblasts and other tissues (Matalon et al 1988, 1989)

The use of deuterated phenylalanine for the in vivo assay of phenylalanine hydroxylase activity in children.

Fifteen children, five with phenylketonuria (PKU), five with hyperphenylalaninaemia, and five phenotypically normal but at risk of being carriers for PKU, were given [ring2H5]phenylalanine orally in amounts ranging from 75 mg/kg to 10 mg/kg. Plama was assayed for [2H5]phenylalanine and [2H4]tyrosine at hourly intervals, the amino acids being measured as theN-acetyl, n-propyl esters by gas chromatography-mass spectroscopy. The results obtained were calculated as the log of the ratio [2H5]phenylalanine: [2H4]tyrosine in the plasma. The five patients with PKU had ratios of infinity because no [2H4]tyrosine was measured in their plasma during the experimental period. The patients with hyperphenylalaninaemia had log ratios over 2.00 throughout the assay period. Among the five normal children three are considered to be carriers for PKU as the logarithms of the [2H5]phenylalanine: [2H4]tyrosine ratios were 1.77, 1.73, and 1.33 and remained over 1.00 during the assay period. The other children had log ratios of 1.16 and 1.00 at the first hour which dropped below 1.00 subsequently, suggesting normal activity of phenylalanine hydroxylase.

Carrier Detection for Sanfilippo A Syndrome

SummaryIn Sanfillipo A families, sulphamidase activities in leukocytes and cultured fibroblasts determined at 55°C distinguish between heterozygote-carriers, normal individuals and the homozygotes.

Maternal PKU collaborative study: the effect of nutrient intake on pregnancy outcome

R. MATALON 1, K. MICHALS 1, C. AZEN 2, E. G. FRIEDMAN 2, R. KOCH z, E. WZNZ 2, H. LEVY 3, F. ROHR 3, B. R o u s e 4, L. CASTIGLIONI 4, W. HANLEY 5, V. AUSTIN 5 and F. DE LA CRUZ 6 1Department of Nutrition and Medical Dietetics, University of Illinois at Chicago and the Research Institute, Miami Childrens Hospital, 6125 S.W. 31st St., Miami, Florida 33155, USA; 2Childrens Hospital of Los Angeles, USA; 3Boston Childrens Hospital, USA; 4University of Texas Medical Branch, Galveston, Texas, USA; 5Hospital for Sick Children, Toronto, Canada; 6NICHD, Canada

Phenylalanine metabolites as indicators of dietary compliance in children with phenylketonuria

The data from this study showed that the excretion of three major metabolites of phenylalanine in patients with PKU approach normal values at blood phenylalanine levels less than 5.0 mg/dl. The MANOVA showed statistically significant differences in phenyllactate excretion when blood phenylalanine was greater than 10.0 mg/dl. The PL and total metabolite excretion were significantly correlated to blood phenylalanine in multiple samples taken from two individual subjects. Using data obtained from single patient observations may serve as a means for individualizing the PKU diet to insure low levels of phenylalanine metabolites and thus insure optimal development for patients with PKU.