A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts

Alberto B. Burlina, Carlo Dionisi-Vici, Michael J. Bennett, Kenneth M. Gibson, Serenella Servidei, Enrico Bertini, Daniel Hale, Eberhard Schmidt-Sommerfeld, Gaetano Sabetta, Franco Zacchello, Piero Rinaldo

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Abstract

We describe four Italian male infants with a novel clinical phenotype characterized by orthostatic acrocyanosis, relapsing petechiae, chronic diarrhea, progressive pyramidal signs, mental retardation, and brain magnetic resonance imaging abnormalities. The first symptoms appeared after the termination of breast-feeding and introduction of formula feeding. Marked persistent 2-ethylmalonic aciduria was associated with abnormal excretion of C 4 -C 5 (n-butyryl-, isobutyryl-, isovaleryl-, and 2-methylbutyryl-) acylglycines and acylcarnitines and with intermittent lactic acidosis. Short- and branched-chain plasma acylcarnitine levels were also elevated. 2-Ethylmalonic aciduria is generally regarded as being indicative of a defect in fatty acid oxidation. Extensive studies of cultured fibroblasts failed to reveal such a defect. The observation of intermittent urinary excretion of 2-ethylhydracrylic acid pointed to involvement of the isoleucine R pathway in ethylmalonate biosynthesis. This hypothesis was tentatively corroborated by the biochemical responses to an oral isoleucine challenge in two patients. However, fibroblast studies showed normal oxidation rates of [ 14 C]isoleucine (ul), indicating that this is not a defect of isoleucine oxidation expressed in skin fibroblasts. In one of two patients tested, cytochrome c oxidase activity was partially reduced (45%) in cultured fibroblasts. This unique clinical and biochemical phenotype identifies a new metabolic encephalopathy of yet undetermined cause. (J PEDIATR 1994;124:79-86)

Original languageEnglish (US)
Pages (from-to)79-86
Number of pages8
JournalJournal of Pediatrics
Volume124
Issue number1
DOIs
StatePublished - Jan 1 1994

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Isoleucine
Fatty Acids
Fibroblasts
Metabolic Brain Diseases
Phenotype
Lactic Acidosis
Purpura
Electron Transport Complex IV
Breast Feeding
Intellectual Disability
Diarrhea
Magnetic Resonance Imaging
Observation
Skin
Brain
acylcarnitine

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health

Cite this

Burlina, A. B., Dionisi-Vici, C., Bennett, M. J., Gibson, K. M., Servidei, S., Bertini, E., ... Rinaldo, P. (1994). A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts. Journal of Pediatrics, 124(1), 79-86. https://doi.org/10.1016/S0022-3476(94)70257-8
Burlina, Alberto B. ; Dionisi-Vici, Carlo ; Bennett, Michael J. ; Gibson, Kenneth M. ; Servidei, Serenella ; Bertini, Enrico ; Hale, Daniel ; Schmidt-Sommerfeld, Eberhard ; Sabetta, Gaetano ; Zacchello, Franco ; Rinaldo, Piero. / A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts. In: Journal of Pediatrics. 1994 ; Vol. 124, No. 1. pp. 79-86.
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abstract = "We describe four Italian male infants with a novel clinical phenotype characterized by orthostatic acrocyanosis, relapsing petechiae, chronic diarrhea, progressive pyramidal signs, mental retardation, and brain magnetic resonance imaging abnormalities. The first symptoms appeared after the termination of breast-feeding and introduction of formula feeding. Marked persistent 2-ethylmalonic aciduria was associated with abnormal excretion of C 4 -C 5 (n-butyryl-, isobutyryl-, isovaleryl-, and 2-methylbutyryl-) acylglycines and acylcarnitines and with intermittent lactic acidosis. Short- and branched-chain plasma acylcarnitine levels were also elevated. 2-Ethylmalonic aciduria is generally regarded as being indicative of a defect in fatty acid oxidation. Extensive studies of cultured fibroblasts failed to reveal such a defect. The observation of intermittent urinary excretion of 2-ethylhydracrylic acid pointed to involvement of the isoleucine R pathway in ethylmalonate biosynthesis. This hypothesis was tentatively corroborated by the biochemical responses to an oral isoleucine challenge in two patients. However, fibroblast studies showed normal oxidation rates of [ 14 C]isoleucine (ul), indicating that this is not a defect of isoleucine oxidation expressed in skin fibroblasts. In one of two patients tested, cytochrome c oxidase activity was partially reduced (45{\%}) in cultured fibroblasts. This unique clinical and biochemical phenotype identifies a new metabolic encephalopathy of yet undetermined cause. (J PEDIATR 1994;124:79-86)",
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Burlina, AB, Dionisi-Vici, C, Bennett, MJ, Gibson, KM, Servidei, S, Bertini, E, Hale, D, Schmidt-Sommerfeld, E, Sabetta, G, Zacchello, F & Rinaldo, P 1994, 'A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts', Journal of Pediatrics, vol. 124, no. 1, pp. 79-86. https://doi.org/10.1016/S0022-3476(94)70257-8

A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts. / Burlina, Alberto B.; Dionisi-Vici, Carlo; Bennett, Michael J.; Gibson, Kenneth M.; Servidei, Serenella; Bertini, Enrico; Hale, Daniel; Schmidt-Sommerfeld, Eberhard; Sabetta, Gaetano; Zacchello, Franco; Rinaldo, Piero.

In: Journal of Pediatrics, Vol. 124, No. 1, 01.01.1994, p. 79-86.

Research output: Contribution to journalArticle

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T1 - A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts

AU - Burlina, Alberto B.

AU - Dionisi-Vici, Carlo

AU - Bennett, Michael J.

AU - Gibson, Kenneth M.

AU - Servidei, Serenella

AU - Bertini, Enrico

AU - Hale, Daniel

AU - Schmidt-Sommerfeld, Eberhard

AU - Sabetta, Gaetano

AU - Zacchello, Franco

AU - Rinaldo, Piero

PY - 1994/1/1

Y1 - 1994/1/1

N2 - We describe four Italian male infants with a novel clinical phenotype characterized by orthostatic acrocyanosis, relapsing petechiae, chronic diarrhea, progressive pyramidal signs, mental retardation, and brain magnetic resonance imaging abnormalities. The first symptoms appeared after the termination of breast-feeding and introduction of formula feeding. Marked persistent 2-ethylmalonic aciduria was associated with abnormal excretion of C 4 -C 5 (n-butyryl-, isobutyryl-, isovaleryl-, and 2-methylbutyryl-) acylglycines and acylcarnitines and with intermittent lactic acidosis. Short- and branched-chain plasma acylcarnitine levels were also elevated. 2-Ethylmalonic aciduria is generally regarded as being indicative of a defect in fatty acid oxidation. Extensive studies of cultured fibroblasts failed to reveal such a defect. The observation of intermittent urinary excretion of 2-ethylhydracrylic acid pointed to involvement of the isoleucine R pathway in ethylmalonate biosynthesis. This hypothesis was tentatively corroborated by the biochemical responses to an oral isoleucine challenge in two patients. However, fibroblast studies showed normal oxidation rates of [ 14 C]isoleucine (ul), indicating that this is not a defect of isoleucine oxidation expressed in skin fibroblasts. In one of two patients tested, cytochrome c oxidase activity was partially reduced (45%) in cultured fibroblasts. This unique clinical and biochemical phenotype identifies a new metabolic encephalopathy of yet undetermined cause. (J PEDIATR 1994;124:79-86)

AB - We describe four Italian male infants with a novel clinical phenotype characterized by orthostatic acrocyanosis, relapsing petechiae, chronic diarrhea, progressive pyramidal signs, mental retardation, and brain magnetic resonance imaging abnormalities. The first symptoms appeared after the termination of breast-feeding and introduction of formula feeding. Marked persistent 2-ethylmalonic aciduria was associated with abnormal excretion of C 4 -C 5 (n-butyryl-, isobutyryl-, isovaleryl-, and 2-methylbutyryl-) acylglycines and acylcarnitines and with intermittent lactic acidosis. Short- and branched-chain plasma acylcarnitine levels were also elevated. 2-Ethylmalonic aciduria is generally regarded as being indicative of a defect in fatty acid oxidation. Extensive studies of cultured fibroblasts failed to reveal such a defect. The observation of intermittent urinary excretion of 2-ethylhydracrylic acid pointed to involvement of the isoleucine R pathway in ethylmalonate biosynthesis. This hypothesis was tentatively corroborated by the biochemical responses to an oral isoleucine challenge in two patients. However, fibroblast studies showed normal oxidation rates of [ 14 C]isoleucine (ul), indicating that this is not a defect of isoleucine oxidation expressed in skin fibroblasts. In one of two patients tested, cytochrome c oxidase activity was partially reduced (45%) in cultured fibroblasts. This unique clinical and biochemical phenotype identifies a new metabolic encephalopathy of yet undetermined cause. (J PEDIATR 1994;124:79-86)

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Burlina AB, Dionisi-Vici C, Bennett MJ, Gibson KM, Servidei S, Bertini E et al. A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts. Journal of Pediatrics. 1994 Jan 1;124(1):79-86. https://doi.org/10.1016/S0022-3476(94)70257-8