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Biomedical subjects

F K Trefz

Publications and source records attributed to F K Trefz.

At least 55 records · Page 3Linked to original sources
PubMed1991

[Macrocephaly as the initial manifestation of glutaryl-CoA-dehydrogenase deficiency (glutaric aciduria type I)].

Glutaric aciduria type I is due to an impaired glutaryl-CoA-dehydrogenase with an increased urinary excretion of glutaric and 3-OH glutaric acid. Typically, the clinical course until the sixth month or even 3rd year of life is symptom free, and only later an encephalopathic crisis develops. The only symptom of our 4 patients was macrocephaly (head circumference greater than 97. percentile) in early infancy. 3 of them suffered from an encephalopathic crisis at 8 months to 3 years of age; during that time they lost already established abilities as sitting, walking and speaking, and developed choereoathetotic movements. One child aged 15 months was normal beside it's macrocephalus. All children were treated with a diet low in lysine (80 mg/kg BW/day), tryptophane (21 mg/kg BW/day), and by supplementation of L-carnitine (200 mg/kg BW/day) and riboflavine (200 mg/day) and the motorically disturbed children received Lioresal 1 mg/kg BW/day. The effect of this treatment cannot be evaluated so far, but there is evidence that the dietetic therapy together with carnitine supplementation may prevent further deterioration in affected, or an encephalopathic crisis in unaffected patients. Therefore we suggest to investigate organic acids in urine in every child or infant with macrocephalus to exclude glutaric aciduria type I.

Amino Acid Metabolism, Inborn Errors↗
PubMed1991

Glutaryl-coenzyme A dehydrogenase deficiency: a distinct encephalopathy.

Clinical course, diagnostic and therapeutic management, and neurodevelopmental outcome were evaluated in 11 patients with glutaryl-coenzyme A dehydrogenase deficiency. In 9 patients macrocephalus was present at or shortly after birth and preceded the neurological disease. In 7 children an acute illness resembling encephalitis appeared after a period of normal development; 2 had developmental delay and progressive "dystonic cerebral palsy." Later, all 9 displayed typical signs of a disorder of the basal ganglia. In 1 patient with macrocephalus the disorder was diagnosed before the onset of neurological disease; in another it was diagnosed prenatally. Computed tomography and magnetic resonance imaging scans revealed severe generalized cerebral atrophy, most striking in the frontal and temporal lobes in 10 patients. Further deterioration was halted after initiation of treatment consisting of low-protein diets, special formulas low in lysine and tryptophan, and supplements of riboflavin and L-carnitine. Only 1 patient showed a slight clinical improvement. Later, dietary therapy was discontinued in 2 older patients and relaxed in a third without observed adverse effects. Two patients in whom treatment could be initiated before the onset of neurological symptoms have developed normally. However, duration of follow-up (6 and 29 months) does not yet allow classification of glutaryl-coenzyme A dehydrogenase deficiency as a treatable disorder. Total body production of glutaric acid, reflected in the daily urinary output, was efficiently reduced by therapeutic measures. Levels of glutaric acid in plasma and cerebrospinal fluid remained unchanged, which may in part explain the overall unsatisfactory outcome. All patients presented with a severe secondary deficiency of carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)

Child, Preschool↗
PubMed1990

Significance of the in vivo deuterated phenylalanine load for long-term phenylalanine tolerance and psycho-intellectual outcome in patients with PKU.

In 20 patients with PAH deficiency, in vivo RA was determined by an intravenous deuterated Phe load. Sixteen patients had RAs of less than 0.4% of normal, 3 a clearly detectable activity between 0.8 and 1.4% of normal. Long-term Phe tolerance as measured by the distribution of plasma Phe levels in categories (0-3.9, 4.0-9.9, 10-15.9 and over 16 mg/dl) was much improved in patients with RAs greater than 0.8%. There was a negative correlation between RA and number of plasma Phe levels greater than 16 mg/dl. Relationship between full scale IQ at the age of 9 years and dietary control showed a positive correlation between IQ and the number of Phe levels between 0-10 mg/dl (k = .50 p less than 0.05). Highest (negative) correlation (k = -0.67 p less than 0.007) was found between full scale IQ and the number of Phe values greater than 16 mg/dl as measured over 9 years. On the one hand detectable RA of PAH reduces the risk of high Phe levels and thus may also reduce the risk of brain damage in untreated or suboptimally treated patients with PAH. On the other hand enzyme measurement of PAH is no predictive parameter for Phe tolerance in an individual patient since RA may be very similar in phenylketonuric/hyperphenylalaninaemic patients. For practical purposes the oral protein loading test at the age of 6 months will give the most reliable results for differential diagnosis of PAH deficiency.

Aging↗
PubMed1990

[Pre- and postnatal diagnosis of organoacidopathies].

Organoacidopathies are the most common life-threatening inborn errors of metabolism presenting acutely in the neonatal period. Early diagnosis rests on a high degree of suspicion. Clinical and laboratory findings are often nonspecific and can be misinterpreted. We present an algorithm for a quick and comprehensive diagnosis of these disorders using commonly available parameters. Different methods for the prenatal diagnosis of organoacidopathies are discussed and our experience with over 150 cases presented. The method of choice is the precise quantification of elevated levels of metabolites in amniotic fluid obtained by amniocentesis at 12-18 weeks of pregnancy. Quantification is best done by stable isotope dilution analysis with the addition of the labelled metabolite to the amniotic fluid. A positive prenatal diagnosis allows a decision of the family for a termination of pregnancy or the immediate institution of therapy after birth. The conduction of a prenatal diagnosis requires the knowledge of the exact diagnosis of a previously affected child.

Acidosis↗
PubMed1989

DNA haplotype analysis at the phenylalanine hydroxylase locus in the Turkish population.

Thirty-nine Turkish phenylketonuria (PKU) families were investigated for their DNA haplotypes at the phenylalanine hydroxylase (PAH) locus. There was a threefold higher incidence of consanguinity in the population studied compared with the general Turkish population. The PAH DNA haplotype 6 was found to be almost exclusively associated not only with the mutant PAH genes but also with the classic phenotype in 39% of the Turkish patients. This haplotype was of not importance in northern European populations. The two DNA haplotypes (1 and 4) that were almost equally frequent among the normal and the mutant PAH genes in northern European populations show virtually the same distribution in Turkish individuals. In all populations studied, these haplotypes are associated with different phenotypes.

Blotting, Southern↗
PubMed1989

Direct detection of a major mutation responsible for phenylketonuria in the population of the Federal Republic of Germany.

Forty-six individuals having phenylketonuria (PKU) alleles at the phenylalanine hydroxylase (PAH) locus were tested for the haplotype 2 PKU mutation by allele-specific hybridization following in vitro DNA amplification. Patients and carriers previously shown to have a mutant haplotype 2 PAH allele demonstrated conservation of this mutation. In vitro DNA amplification greatly facilitated this analysis and provides the possibility of population screening for 37% of the mutant German PAH alleles.

Alleles↗
PubMed1989

[DNA diagnosis of monogene hereditary diseases exemplified by phenylketonuria and mucoviscidosis].

In 170 inherited diseases there exists the possibility for diagnosis at the DNA level. Using phenylketonuria (PKU) and cystic fibrosis (CF) as examples we demonstrate the capability of direct and indirect DNA-diagnosis through the use of DNA markers and allelespecific oligonucleotide hybridization respectively. In 88% of our PKU-patients and in 98% of the CF-patients DNA linkage analysis and therefore prenatal diagnosis on the DNA level can be carried out in affected families. The reliability of DNA-diagnosis is 99.0% for PKU and between 96.0-99.99% for CF depending on where the DNA-markers are localized. In contrast to CF, the PKU gene has been isolated and distinct mutations within the phenylalanine hydroxylase gene have been characterized. There is evidence for a correlation between genotype and clinical and biochemical phenotype. Also in CF it is indicated that certain DNA haplotypes correlate with the severity of the disease: less frequent haplotypes seem to be more often associated with a milder course than haplotype "B/B" which represents 85% of the CF chromosomes. Therefore DNA diagnostic methods not only make a major contribution to improved genetic counseling but also offer the possibility for a better future understanding of the heterogeneity of genetic diseases.

Cystic Fibrosis↗
PubMed1988

Phenylalanine hydroxylase deficiency caused by a single base substitution in an exon of the human phenylalanine hydroxylase gene.

A novel restriction fragment length polymorphism in the phenylalanine hydroxylase (PAH) locus generated by the restriction endonuclease MspI was observed in a German phenylketonuria (PKU) patient. Molecular cloning and DNA sequence analyses revealed that the MspI polymorphism was created by a T to C transition in exon 9 of the human PAH gene, which also resulted in the conversion of a leucine codon to a proline codon. The effect of the amino acid substitution was investigated by creating a corresponding mutation in a full-length human PAH cDNA by site-directed mutagenesis followed by expression analysis in cultured mammalian cells. Results demonstrate that the mutation in the gene causes the synthesis of an unstable protein in the cell corresponding to a CRM- phenotype. Together with the other mutations recently reported in the PAH gene, the data support previous biochemical and clinical observations that PKU is a heterogeneous disorder at the gene level.

Base Sequence↗
PubMed1988

Linkage disequilibrium between mutation and RFLP haplotype at the phenylalanine hydroxylase locus in the German population.

Restriction fragment length polymorphism (RFLP) haplotypes at the phenylalanine hydroxylase (PAH) locus have been determined in 60 German families with PAH deficiency. Similar to the Danish population, about 90% of the mutant alleles are confined to four distinct haplotypes. There are however, differences in the frequency distribution of these haplotypes among the mutant alleles between the two populations. Using an oligonucleotide probe for the splicing mutation associated with mutant haplotype 3 in the Danish population, a tight association between the mutation and the RFLP haplotype has also been observed in Germany. The results provide strong evidence that the splicing mutation occurred on a haplotype 3 chromosome and that the mutant allele has spread into different populations among Caucasians.

Adult↗