Familial Occurrence of Formiminotransferase Deficiency Syndrome

Arakawa, Tsuneo; Tamura, Tsunenobu; Ohara, Kazuo; Narisawa, Kuniaki; Tanno, Kaneo; Honda, Yoshiyuki; Higashi, Ototaka

doi:10.1620/tjem.96.211

Cited by 17 publications

(11 citation statements)

References 4 publications

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“…They differ from four of the Japanese infants with glutamate formiminotransferase deficiency described previously (2)(3)(4)(5) in that their serum folate levels were normal rather than elevated. They differ from three of the six cases of this disorder reported previously (3,4,9) in that they had no evidence of hematologic disturbance.…”

Section: Discussioncontrasting

confidence: 81%

Metabolic Studies of a Family with Massive Formiminoglutamic Aciduria

et al. 1975

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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...

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Section: Discussioncontrasting

confidence: 81%

Metabolic Studies of a Family with Massive Formiminoglutamic Aciduria

et al. 1975

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“…Severe mental retardation was apparent and electroencephalograms showed low voltage in the frontal regions at 1 Yz years of age. Enzyme assays performed on a liver biopsy showed 55% activity compared to a control (Arakawa et al, 1968). His brother was diagnosed at 6 months of age after a histidine loading test, but presented with a considerably different phenotype.…”

Section: Glutamate Formiminotransferase Deficiencymentioning

confidence: 91%

“…No enzyme assay was performed. The parents were also examined, and they presented with elevated urinary FlGLU after histidine loading, slight macrocytosis, and abnormal electroencephalograms (Arakawa et al, 1968). With the parents also presenting abnormal clinical features, it is difficult to determine which features of the patients are actually associated with the deficiency.…”

Section: Glutamate Formiminotransferase Deficiencymentioning

confidence: 99%

“…A patient of Japanese descent also presented with defective glycine incorporation into urinary uric acid (Arakawa et al, 1972 CK (Arakawa et al, 1963) severe nr 40-200 HK (Arakawa et al, 1965) severe 768 nr YA (Arakawa et al, 1968) severe nr 258-6279 YN (Arakawa et al, 1968) severe In general, patients who present with the mild forrn of the disease excrete high levels of FIGLU in the absence of histidine loading, while severely affected individuals excrete low levels of FIGLU under the same circumstances. In addition, urinary FIGLU levels were much higher after histidine loading in patients with the mild forrn of the disease compared to severely affected individuals.…”

Section: Glutamate Formiminotransferase Deficiencymentioning

confidence: 99%

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The molecular basis of glutamate formiminotransferase deficiency

et al. 2003

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“…However, the severe form of this disorder was also reported to present with anemia (Arakawa et al. , ). It was proposed that the mild end of the spectrum is associated with reduced FT activity, while the severe form results from impeded CD activity, but this hypothesis is disputable (Hilton et al.…”

Section: Clinical Reportmentioning

confidence: 99%

Allelic spectrum of formiminotransferase‐cyclodeaminase gene variants in individuals with formiminoglutamic aciduria

Majumdar

Yori

Rush

et al. 2017

Molec Gen & Gen Med

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BackgroundElevated plasma and urine formiminoglutamic acid (FIGLU) levels are commonly indicative of formiminoglutamic aciduria (OMIM #229100), a poorly understood autosomal recessive disorder of histidine and folate metabolism, resulting from formiminotransferase‐cyclodeaminase (FTCD) deficiency, a bifunctional enzyme encoded by FTCD.MethodsIn order to further understanding about the molecular alterations that contribute to FIGLU‐uria, we sequenced FTCD in 20 individuals with putative FTCD deficiency and varying laboratory findings, including increased FIGLU excretion.ResultsIndividuals tested had biallelic loss‐of‐function variants in protein‐coding regions of FTCD. The FTCD allelic spectrum comprised of 12 distinct variants including 5 missense alterations that replace conserved amino acid residues (c.223A>C, c.266A>G, c.319T>C, c.430G>A, c.514G>T), an in‐frame deletion (c.1373_1375delTGG), with the remaining alterations predicted to affect mRNA processing/stability. These included two frameshift variants (c.990dup, c.1366dup) and four nonsense variants (c.337C>T, c.451A>T, c.763C>T, c.1607T>A).ConclusionWe observed additional FTCD alleles leading to urinary FIGLU elevations, and thus, providing molecular evidence of FTCD deficiency in cases identified by newborn screening or clinical biochemical genetic laboratory testing.

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Familial Occurrence of Formiminotransferase Deficiency Syndrome

Abstract: Clinical and biochemical findings of two siblings with formiminotransferase deficiency syndrome in a family were described and a hereditary background of this disorder was suggested.

Cited by 17 publications

References 4 publications

Metabolic Studies of a Family with Massive Formiminoglutamic Aciduria

Metabolic Studies of a Family with Massive Formiminoglutamic Aciduria

The molecular basis of glutamate formiminotransferase deficiency

Allelic spectrum of formiminotransferase‐cyclodeaminase gene variants in individuals with formiminoglutamic aciduria

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