PubMed · 7823796
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A Mitchell, N Steffenson, H Hogan. A case study: organic acidemia.. https://pubmed.ncbi.nlm.nih.gov/7823796/
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Glutaric acidemia type I (GA-I) is an autosomal recessive disorder of amino acid metabolism resulting from a deficiency of glutaryl-CoA dehydrogenase (GCDH). Patients accumulate glutaric acid (GA) and 3-OH glutaric acid (3-OHGA) in their blood, urine and CSF. Clinically, GA-I is characterized by macrocephaly, progressive dystonia and dyskinesia. Degeneration of the caudate and putamen of the basal ganglia, widening of the Sylvian fissures, fronto-temporal atrophy and severe spongiform change in the white matter are also commonly observed. In this report we describe the phenotype of a mouse model of GA-I generated via targeted deletion of the Gcdh gene in embryonic stem cells. The Gcdh-/- mice have a biochemical phenotype very similar to human GA-I patients, including elevations of GA and 3-OHGA at levels similar to those seen in GA-I patients. The affected mice have a mild motor deficit but do not develop the progressive dystonia seen in human patients. Pathologically, the Gcdh-/- mice have a diffuse spongiform myelinopathy similar to that seen in GA-I patients. However, unlike in human patients, there is no evidence of neuron loss or astrogliosis in the striatum. Subjecting the Gcdh-/- mice to a metabolic stress, which often precipitates an encephalopathic crisis and the development of dystonia in GA-I patients, failed to have any neurologic effect on the mice. We hypothesize that the lack of similarity in regards to the neurologic phenotype and striatal pathology of GA-I patients, as compared with the Gcdh-/- mice, is due to intrinsic differences between the striata of mice and men.
BACKGROUND: Most reports on phenylketonuria (PKU) screening focused solely on the result of the initial investigation of the neonatal screening sample. The aim of this study was to evaluate an enzymatic phenylalanine (Phe) determination in the whole context spanning from the initial investigation over the recall period, up to the confirmation or exclusion of the disease. METHODS: Phe of dried blood spot specimens was analysed colorimetrically in a microtitre-plate assay based on the L-phenylalanine dehydrogenase reaction coupled with an intermediate electron acceptor system. This assay was evaluated for analytical variables and for neonatal PKU screening in a total number of 423,773 neonates during a 6-year period. RESULTS: Method validation with respect to linearity, precision (within-run CVs 3.4-4.2%, between-run CVs 6.2-10.4%), and accuracy fulfilled all requirements for a screening method. Mean Phe (+/-SD) of 130,000 healthy neonates was 84 (+/-22) micromol/l with a cut-off point (mean+3 SD) of 150 micromol/l. From 423,773 neonates, hyperphenylalaninemia was confirmed in 155 cases and further differentiated into PKU (41 cases, 27%), BH(4) deficiency (3, 2%), non-PKU HPA (67, 43%), transient neonatal HPA (28, 18%), and secondary HPA (16, 10%). The number of false-positives (recall-rate) was 0.23%, and no false-negatives were noted. CONCLUSIONS: Detailed studies over a period of 6 years including more than 400,000 neonates clearly show that the enzymatic assay is a reliable and sensitive method for neonatal screening of PKU. The proven prevalence of non-PKU HPA in the German population disclosed by the assay was twice as high as compared to the "Guthrie test" used previously. The growing use and application of tandem mass spectrometry in neonatal screening will not derogate the usefulness of the enzymatic assay in PKU screening in the foreseeable future. Careful analysis of our screening results and monitoring of all pathological samples resulted in an evidence-based flow chart for a rational PKU screening.
Isolated sulfite oxidase deficiency is a rare autosomal inherited disorder of the normal degradation of sulfur-containing amino acids. Premature death in infancy secondary to severe neurologic deterioration is the usual outcome. This article provides an analysis, in temporal form, of brain imaging findings in this disorder.