Metabolic Studies of a Family with Massive Formiminoglutamic Aciduria

Abstract

Extractand pneumoencephalographic evidence of cortical atrophy and ventricular dilatation. serum folate values were normal or We have described two siblings excrete massive elevated in all five patients, but two of the patients had amounts (up to 3.89 mmo1/24 hr) of N-formiminoglutamic changes in peripheral blood or bone marrow suggestive of a acid in their urine. This was functional folate deficiency. The diagnosis was proven in each isolated from urine, purified, and firmly identified as FIGLU of the five J~~~~~~~ patients by the finding of markedly by gas The deficient enzyme activity for glutamate formiminotransferase ~& i e n t s re sum ably have a deficiency in activity of the in specimens of liver obtained at biopsy or autopsy. A sixth hepatic enzyme, glutamate formiminotransferase, which case of glutamate formiminotransferase deficiency has been carries out the fourth sequential step in the main pathway of described by Herman and coworkers (9) in a Caucasian woman histidine degradation. Unlike children reported previously with of normal intelligence, whose symptoms included weight loss this disorder, our patients had normal serum folate levels, had and intolerance of dietary carbohydrate, and whose bone no hematologic abnormalities, and were not mentally retarded. marrow showed megaloblastic changes despite a normal serum Very small amounts of FIGLU were present in the plasma of folate level. one of the patients, but FIGLU was not detectable in the We describe here two further cases of probable glutamate cerebrospinal fluid of either patient. Administration of formiminotransferase deficiency occurring in a Caucasian ~harmacologic doses of folic or folinic acid produced a sibship. These children excrete massive amounts of FIGLU in decrease in excretion of FIGLU. in urine. Histidine loading their urine, but they have normal serum and erythrocyte folate caused a small and comparable urlnarY excretion of FIGLU levels, and no hematologic abnormalities. Although they have the children's parents and in control adult subjects.mild cerebral dysfunction, they show no evidence of mental or physical retardation that can be attributed to their enzymatic Speculation defect.Glutamate formiminotransferase deficiency may represent a further example of a genetically determined metabolic error PATIENTS which does not result either in accumulation of a toxic metabolite or in failure to synthesize a crucial metabolite, andThe proband of this study, patient KS, was first investigated which therefore produces no clinical disease syndrome.at the age of 2% years because of delayed speech development. Two-dimensional paper chromatography of his urine for amino acids revealed a grossly excessive amount of glutamic acid (Fig. Human urine normally contains only very small amounts of 1). However, when the urine was analyzed by automated FIGLU, a metabolite in the major degradative pathway of column chromatography, it did not contain abnormal amounts histidine. Healthy adults excrete about 8 pmo1/24 hr (22). of glutamic acid, but inst...

The molecular basis of glutamate formiminotransferase deficiency

“…Bath were in good physical and mental health and were not found ta excrete any FIGLU (Perry et al, 1975). This suggests that one functional copy of the gene is more than sufficient ta meet the histidine degradation demands of the human body.…”

“…Both presented with normal serum folate levels, no hematological findings and no mental retardation. No enzyme assays were performed on either liver or erythrocyte lysates (Perry et al, 1975). There has also been one reported case of a deficient FTCD being diagnosed in adulthood.…”

“…She also exereted very high levels of FIGLU in the urine. No liver biospy was performed (Perry et al, 1975).…”

Formiminoglutamic aciduria in a slightly retarded boy with chronic obstructive lung disease

“…Excretion of formiminoglutamic acid (FIGLU) in urine has been described in ten patients, among whom were three pairs of sibs (Arakawa et al, 1963(Arakawa et al, , 1965(Arakawa et al, , 1968a(Arakawa et al, , 1968b(Arakawa et al, , 1972Niederwieser et al, 1974;Perry et al, 1975).…”

Falsely elevated C4‐carnitine as expression of glutamate formiminotransferase deficiency in tandem mass spectrometry newborn screening

“…Folate plasma level was normal (13 ng/ml; n.v. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. At the age of 5 months, the child showed a mild persistent axial hypotonia and a mild hypertonia of legs.…”