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Vicente Rubio - One of the best experts on this subject based on the ideXlab platform.
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δ 1 pyrroline 5 carboxylate synthetase deficiency an emergent multifaceted urea cycle related disorder
Journal of Inherited Metabolic Disease, 2020Co-Authors: Clara Marcomarin, Juan Manuel Escamillahonrubia, Jose Luis Llacer, Marco Seri, Emanuele Panza, Vicente RubioAbstract:The bifunctional homooligomeric enzyme Δ1 -pyrroline-5-carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998. Two siblings who presented paradoxical hyperammonemia (alleviated by protein), mental disability, short stature, cataracts, cutis laxa, and joint laxity, were found to carry biallelic ALDH18A1 mutations. They showed biochemical indications of decreased ornithine/proline synthesis, agreeing with the role of P5CS in the biosynthesis of these amino acids. Of 32 patients reported with this Neurocutaneous Syndrome, 21 familial ones hosted homozygous or compound heterozygous ALDH18A1 mutations, while 11 sporadic ones carried de novo heterozygous ALDH18A1 mutations. In 2015 to 2016, an upper motor neuron Syndrome (spastic paraparesis/paraplegia SPG9) complicated with some traits of the Neurocutaneous Syndrome, although without report of cutis laxa, joint laxity, or herniae, was associated with monoallelic or biallelic ALDH18A1 mutations with, respectively, dominant and recessive inheritance. Of 50 SPG9 patients reported, 14 and 36 (34/2 familial/sporadic) carried, respectively, biallelic and monoallelic mutations. Thus, two Neurocutaneous Syndromes (recessive and dominant cutis laxa 3, abbreviated ARCL3A and ADCL3, respectively) and two SPG9 Syndromes (recessive SPG9B and dominant SPG9A) are caused by essentially different spectra of ALDH18A1 mutations. On the bases of the clinical data (including our own prior patients' reports), the ALDH18A1 mutations spectra, and our knowledge on the P5CS protein, we conclude that the four Syndromes share the same pathogenic mechanisms based on decreased P5CS function. Thus, these Syndromes represent a continuum of increasing severity (SPG9A < SPG9B < ADCL3 ≤ ARCL3A) of the same disease, P5CS deficiency, in which the dominant mutations cause loss-of-function by dominant-negative mechanisms.
Clara Marcomarin - One of the best experts on this subject based on the ideXlab platform.
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δ 1 pyrroline 5 carboxylate synthetase deficiency an emergent multifaceted urea cycle related disorder
Journal of Inherited Metabolic Disease, 2020Co-Authors: Clara Marcomarin, Juan Manuel Escamillahonrubia, Jose Luis Llacer, Marco Seri, Emanuele Panza, Vicente RubioAbstract:The bifunctional homooligomeric enzyme Δ1 -pyrroline-5-carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998. Two siblings who presented paradoxical hyperammonemia (alleviated by protein), mental disability, short stature, cataracts, cutis laxa, and joint laxity, were found to carry biallelic ALDH18A1 mutations. They showed biochemical indications of decreased ornithine/proline synthesis, agreeing with the role of P5CS in the biosynthesis of these amino acids. Of 32 patients reported with this Neurocutaneous Syndrome, 21 familial ones hosted homozygous or compound heterozygous ALDH18A1 mutations, while 11 sporadic ones carried de novo heterozygous ALDH18A1 mutations. In 2015 to 2016, an upper motor neuron Syndrome (spastic paraparesis/paraplegia SPG9) complicated with some traits of the Neurocutaneous Syndrome, although without report of cutis laxa, joint laxity, or herniae, was associated with monoallelic or biallelic ALDH18A1 mutations with, respectively, dominant and recessive inheritance. Of 50 SPG9 patients reported, 14 and 36 (34/2 familial/sporadic) carried, respectively, biallelic and monoallelic mutations. Thus, two Neurocutaneous Syndromes (recessive and dominant cutis laxa 3, abbreviated ARCL3A and ADCL3, respectively) and two SPG9 Syndromes (recessive SPG9B and dominant SPG9A) are caused by essentially different spectra of ALDH18A1 mutations. On the bases of the clinical data (including our own prior patients' reports), the ALDH18A1 mutations spectra, and our knowledge on the P5CS protein, we conclude that the four Syndromes share the same pathogenic mechanisms based on decreased P5CS function. Thus, these Syndromes represent a continuum of increasing severity (SPG9A < SPG9B < ADCL3 ≤ ARCL3A) of the same disease, P5CS deficiency, in which the dominant mutations cause loss-of-function by dominant-negative mechanisms.
Rubio Vicente - One of the best experts on this subject based on the ideXlab platform.
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Δ1 -Pyrroline-5-carboxylate synthetase (P5CS) deficiency: An emergent multifaceted urea cycle-related disorder
'Wiley', 2020Co-Authors: Escamilla-honrubia, Juan M, Seri Marco, Panza Emanuele, Rubio VicenteAbstract:The bifunctional homooligomeric enzyme \u3941 -pyrroline-5-carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998. Two siblings who presented paradoxical hyperammonemia (alleviated by protein), mental disability, short stature, cataracts, cutis laxa and joint laxity, were found to carry biallelic ALDH18A1 mutations. They showed biochemical indications of decreased ornithine/proline synthesis, agreeing with the role of P5CS in the biosynthesis of these amino acids. Of 32 patients reported with this Neurocutaneous Syndrome, 21 familial ones hosted homozygous or compound heterozygous ALDH18A1 mutations, while 11 sporadic ones carried de novo heterozygous ALDH18A1 mutations. In 2015-2016 an upper motor neuron Syndrome (spastic paraparesis/paraplegia SPG9) complicated with some traits of the Neurocutaneous Syndrome, although without report of cutis laxa, joint laxity or herniae, was associated with monoallelic or biallelic ALDH18A1 mutations with, respectively, dominant and recessive inheritance. Of fifty SPG9 patients reported, 14 and 36 (34/2 familial/sporadic) carried, respectively, biallelic and monoallelic mutations. Thus, two Neurocutaneous Syndromes (recessive and dominant cutis laxa 3, abbreviated ARCL3A and ADCL3, respectively) and two SPG9 Syndromes (recessive SPG9B and dominant SPG9A) are caused by essentially different spectra of ALDH18A1 mutations. On the bases of the clinical data (including our own prior patients' reports), the ALDH18A1 mutations spectra, and our knowledge on the P5CS protein, we conclude that the four Syndromes share the same pathogenic mechanisms based on decreased P5CS function. Thus, these Syndromes represent a continuum of increasing severity (SPG9A\u2009<\u2009SPG9B\u2009<\u2009ADCL3\u2009 64\u2009ARCL3A) of the same disease, P5CS deficiency, in which the dominant mutations cause loss-of-function by dominant-negative mechanisms. This article is protected by copyright. All rights reserved
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\u3941 -Pyrroline-5-carboxylate synthetase (P5CS) deficiency: An emergent multifaceted urea cycle-related disorder
'Wiley', 2020Co-Authors: Marco-mar\uedn Clara, Escamilla-honrubia, Juan M, Seri Marco, Panza Emanuele, Ll\ue1cer, Jos\ue9 L, Rubio VicenteAbstract:The bifunctional homooligomeric enzyme \u3941 -pyrroline-5-carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998. Two siblings who presented paradoxical hyperammonemia (alleviated by protein), mental disability, short stature, cataracts, cutis laxa and joint laxity, were found to carry biallelic ALDH18A1 mutations. They showed biochemical indications of decreased ornithine/proline synthesis, agreeing with the role of P5CS in the biosynthesis of these amino acids. Of 32 patients reported with this Neurocutaneous Syndrome, 21 familial ones hosted homozygous or compound heterozygous ALDH18A1 mutations, while 11 sporadic ones carried de novo heterozygous ALDH18A1 mutations. In 2015-2016 an upper motor neuron Syndrome (spastic paraparesis/paraplegia SPG9) complicated with some traits of the Neurocutaneous Syndrome, although without report of cutis laxa, joint laxity or herniae, was associated with monoallelic or biallelic ALDH18A1 mutations with, respectively, dominant and recessive inheritance. Of fifty SPG9 patients reported, 14 and 36 (34/2 familial/sporadic) carried, respectively, biallelic and monoallelic mutations. Thus, two Neurocutaneous Syndromes (recessive and dominant cutis laxa 3, abbreviated ARCL3A and ADCL3, respectively) and two SPG9 Syndromes (recessive SPG9B and dominant SPG9A) are caused by essentially different spectra of ALDH18A1 mutations. On the bases of the clinical data (including our own prior patients' reports), the ALDH18A1 mutations spectra, and our knowledge on the P5CS protein, we conclude that the four Syndromes share the same pathogenic mechanisms based on decreased P5CS function. Thus, these Syndromes represent a continuum of increasing severity (SPG9A\u2009<\u2009SPG9B\u2009<\u2009ADCL3\u2009 64\u2009ARCL3A) of the same disease, P5CS deficiency, in which the dominant mutations cause loss-of-function by dominant-negative mechanisms. This article is protected by copyright. All rights reserved
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Δ 1 -Pyrroline-5-carboxylate synthetase deficiency: An emergent multifaceted urea cycle-related disorder
'Wiley', 2020Co-Authors: Marco-marín Clara, Escamilla-honrubia, Juan M, Seri Marco, Panza Emanuele, Llácer, José Luis, Rubio VicenteAbstract:14 páginas, 4 figurasThe bifunctional homooligomeric enzyme Δ1 -pyrroline-5-carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998. Two siblings who presented paradoxical hyperammonemia (alleviated by protein), mental disability, short stature, cataracts, cutis laxa, and joint laxity, were found to carry biallelic ALDH18A1 mutations. They showed biochemical indications of decreased ornithine/proline synthesis, agreeing with the role of P5CS in the biosynthesis of these amino acids. Of 32 patients reported with this Neurocutaneous Syndrome, 21 familial ones hosted homozygous or compound heterozygous ALDH18A1 mutations, while 11 sporadic ones carried de novo heterozygous ALDH18A1 mutations. In 2015 to 2016, an upper motor neuron Syndrome (spastic paraparesis/paraplegia SPG9) complicated with some traits of the Neurocutaneous Syndrome, although without report of cutis laxa, joint laxity, or herniae, was associated with monoallelic or biallelic ALDH18A1 mutations with, respectively, dominant and recessive inheritance. Of 50 SPG9 patients reported, 14 and 36 (34/2 familial/sporadic) carried, respectively, biallelic and monoallelic mutations. Thus, two Neurocutaneous Syndromes (recessive and dominant cutis laxa 3, abbreviated ARCL3A and ADCL3, respectively) and two SPG9 Syndromes (recessive SPG9B and dominant SPG9A) are caused by essentially different spectra of ALDH18A1 mutations. On the bases of the clinical data (including our own prior patients' reports), the ALDH18A1 mutations spectra, and our knowledge on the P5CS protein, we conclude that the four Syndromes share the same pathogenic mechanisms based on decreased P5CS function. Thus, these Syndromes represent a continuum of increasing severity (SPG9A < SPG9B < ADCL3 ≤ ARCL3A) of the same disease, P5CS deficiency, in which the dominant mutations cause loss-of-function by dominant-negative mechanisms.The authors thank the American Spastic Paraplegia Foundation for the EP grant “Understanding Hereditary Spastic Paraplegia: in vivo models to identify pathogenetic mechanism and therapeutic targets for SPG9”. V.R. and C.M.-M. were supported by grants of the Fundación Inocente Inocente and of the Spanish Government (MINECO BFU2017-84264-P).Peer reviewe
Jose Luis Llacer - One of the best experts on this subject based on the ideXlab platform.
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δ 1 pyrroline 5 carboxylate synthetase deficiency an emergent multifaceted urea cycle related disorder
Journal of Inherited Metabolic Disease, 2020Co-Authors: Clara Marcomarin, Juan Manuel Escamillahonrubia, Jose Luis Llacer, Marco Seri, Emanuele Panza, Vicente RubioAbstract:The bifunctional homooligomeric enzyme Δ1 -pyrroline-5-carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998. Two siblings who presented paradoxical hyperammonemia (alleviated by protein), mental disability, short stature, cataracts, cutis laxa, and joint laxity, were found to carry biallelic ALDH18A1 mutations. They showed biochemical indications of decreased ornithine/proline synthesis, agreeing with the role of P5CS in the biosynthesis of these amino acids. Of 32 patients reported with this Neurocutaneous Syndrome, 21 familial ones hosted homozygous or compound heterozygous ALDH18A1 mutations, while 11 sporadic ones carried de novo heterozygous ALDH18A1 mutations. In 2015 to 2016, an upper motor neuron Syndrome (spastic paraparesis/paraplegia SPG9) complicated with some traits of the Neurocutaneous Syndrome, although without report of cutis laxa, joint laxity, or herniae, was associated with monoallelic or biallelic ALDH18A1 mutations with, respectively, dominant and recessive inheritance. Of 50 SPG9 patients reported, 14 and 36 (34/2 familial/sporadic) carried, respectively, biallelic and monoallelic mutations. Thus, two Neurocutaneous Syndromes (recessive and dominant cutis laxa 3, abbreviated ARCL3A and ADCL3, respectively) and two SPG9 Syndromes (recessive SPG9B and dominant SPG9A) are caused by essentially different spectra of ALDH18A1 mutations. On the bases of the clinical data (including our own prior patients' reports), the ALDH18A1 mutations spectra, and our knowledge on the P5CS protein, we conclude that the four Syndromes share the same pathogenic mechanisms based on decreased P5CS function. Thus, these Syndromes represent a continuum of increasing severity (SPG9A < SPG9B < ADCL3 ≤ ARCL3A) of the same disease, P5CS deficiency, in which the dominant mutations cause loss-of-function by dominant-negative mechanisms.
Emanuele Panza - One of the best experts on this subject based on the ideXlab platform.
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δ 1 pyrroline 5 carboxylate synthetase deficiency an emergent multifaceted urea cycle related disorder
Journal of Inherited Metabolic Disease, 2020Co-Authors: Clara Marcomarin, Juan Manuel Escamillahonrubia, Jose Luis Llacer, Marco Seri, Emanuele Panza, Vicente RubioAbstract:The bifunctional homooligomeric enzyme Δ1 -pyrroline-5-carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998. Two siblings who presented paradoxical hyperammonemia (alleviated by protein), mental disability, short stature, cataracts, cutis laxa, and joint laxity, were found to carry biallelic ALDH18A1 mutations. They showed biochemical indications of decreased ornithine/proline synthesis, agreeing with the role of P5CS in the biosynthesis of these amino acids. Of 32 patients reported with this Neurocutaneous Syndrome, 21 familial ones hosted homozygous or compound heterozygous ALDH18A1 mutations, while 11 sporadic ones carried de novo heterozygous ALDH18A1 mutations. In 2015 to 2016, an upper motor neuron Syndrome (spastic paraparesis/paraplegia SPG9) complicated with some traits of the Neurocutaneous Syndrome, although without report of cutis laxa, joint laxity, or herniae, was associated with monoallelic or biallelic ALDH18A1 mutations with, respectively, dominant and recessive inheritance. Of 50 SPG9 patients reported, 14 and 36 (34/2 familial/sporadic) carried, respectively, biallelic and monoallelic mutations. Thus, two Neurocutaneous Syndromes (recessive and dominant cutis laxa 3, abbreviated ARCL3A and ADCL3, respectively) and two SPG9 Syndromes (recessive SPG9B and dominant SPG9A) are caused by essentially different spectra of ALDH18A1 mutations. On the bases of the clinical data (including our own prior patients' reports), the ALDH18A1 mutations spectra, and our knowledge on the P5CS protein, we conclude that the four Syndromes share the same pathogenic mechanisms based on decreased P5CS function. Thus, these Syndromes represent a continuum of increasing severity (SPG9A < SPG9B < ADCL3 ≤ ARCL3A) of the same disease, P5CS deficiency, in which the dominant mutations cause loss-of-function by dominant-negative mechanisms.