Chronic kidney disease in propionic acidemia

Shchelochkov, Oleg A.; Manoli, Irini; Sloan, Jennifer L.; Ferry, Susan; Pass, Alexandra; Ryzin, Carol Van; Myles, Jennifer; Schoenfeld, Megan; McGuire, Peter J.; Rosing, Douglas R.; Levin, Mark; Kopp, Jeffrey B.; Venditti, Charles P.

doi:10.1038/s41436-019-0593-z

Cited by 52 publications

(79 citation statements)

References 20 publications

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“…Esta presentación clínica puede ser catalogada equivocadamente como sepsis. 4,5 Además, se estima que hasta el 85 % del debut de la AP se asocia a una infección bacteriana o a un cuadro de sepsis, que favorece la descompensación. Por ello, es importante descartar la enfermedad metabólica al igual que la sepsis en los neonatos con esta clínica de presentación.…”

Section: Discussionunclassified

“…Durante la descompensación aguda, es característica la acidosis metabólica con anión gap elevado, acidosis láctica, cetonuria, hipoglucemia, hiperamoniemia y citopenias. 5,6 Los factores pronósticos más relevantes desde el punto de vista neurológico son la elevación de niveles de amonio y el tiempo transcurrido hasta su normalización. Por ello, el diagnóstico y el tratamiento deben realizarse simultáneamente.…”

Section: Discussionunclassified

“…Estas descompensaciones suelen asociar acidosis metabólica con anión gap elevado, lactacidemia, cetonuria, hipoglucemia, hiperamoniemia y citopenias. 5,6 Las formas leves pueden demorar su debut y manifestarse como retraso en el crecimiento y en el desarrollo.…”

Section: Introductionunclassified

“…A pesar de la posibilidad de detección bioquímica mediante el CN y el estudio de ácidos orgánicos en orina, el diagnóstico definitivo se confirma con el estudio genético. 5…”

Section: Introductionunclassified

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Acidemia propiónica: diagnóstico clínico vs. cribado neonatal

et al. 2020

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Presentación de casos clínicos RESUMEN La acidemia propiónica es una rara enfermedad metabólica (prevalencia: 1/100 000), cuya detección puede hacerse de forma precoz mediante el cribado neonatal en las primeras 72 horas de vida. Puede tener una presentación neonatal grave, tardía intermitente o crónica progresiva. El tratamiento de las crisis consiste en la inversión del catabolismo que detiene la ingesta proteica con aporte intravenoso de calorías no proteicas. La mortalidad depende, fundamentalmente, de los episodios de descompensación aguda, mientras que la evolución asocia una alta tasa de secuelas neurológicas y déficits cognitivos. Se presenta el caso de una recién nacida de 11 días de vida con clínica de estancamiento ponderal, letargia, acidosis metabólica e hiperamonemia, que, debido a una falla en el proceso de cribado, no se benefició del diagnóstico precoz. A pesar de la ya existente detección por cribado, es vital mantener un alto índice de sospecha en casos sugestivos de metabolopatías.

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Section: Discussionunclassified

Section: Introductionunclassified

“…A pesar de la posibilidad de detección bioquímica mediante el CN y el estudio de ácidos orgánicos en orina, el diagnóstico definitivo se confirma con el estudio genético. 5…”

Section: Introductionunclassified

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Acidemia propiónica: diagnóstico clínico vs. cribado neonatal

et al. 2020

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“…Defects in many proteins 253 that are up-regulated in mice fed HP cause inborn errors of metabolism. Absence or 254 reduction in activity of PCCA and PCCB cause propionic academia [42]; maple syrup 255 urine disease is caused by defects in BCKDHA and BCKDHB genes and proteins [43], 256 metymalonyl academia is caused by defects in the MUT gene and protein [44].…”

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AMPK signaling regulates expression of urea cycle enzymes in response to changes in dietary protein intake

Heibel

McGuire

Haskins

et al. 2018

Preprint

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Abundance of urea cycle enzymes in the liver is regulated by the dietary protein intake. Although urea cycle enzyme levels rise in response to a high protein diet, signaling networks that sense dietary protein intake and trigger changes in expression of urea cycle genes have not been identified. The aim of this study was to identify signaling pathway(s) that respond to changes in protein intake and regulate expression of urea cycle genes in mice and human hepatocytes. Mice were adapted to either control or high (HP) protein diets followed by isolation of liver protein and mRNA and integrated analysis of the proteomic and transcriptome profiles. HP diet led to increased expression of mRNA and enzymes in amino acid degradation pathways, and decreased expression of mRNA and enzymes in carbohydrate and fat metabolism, which implicated AMPK as a possible regulator. Primary human hepatocytes, treated with AICAR an activator of AMPK, were used to test whether AMPK regulates expression of urea cycle genes. The abundance of CPS1 and OTC mRNA increased in hepatocytes treated with AICAR, which supports a role for AMPK signaling in regulation of the urea cycle. Because AMPK is either a target of drugs used to treat type-2 diabetes, these drugs might increase the expression of urea cycle enzymes in patients with urea cycle disorders, which could be the basis of a new therapeutic approach.

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Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise

Dimitrov

Molema

Williams

et al. 2020

J of Inher Metab Disea

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Organic acidurias (OADs) comprise a biochemically defined group of inherited metabolic diseases. Increasing awareness, reliable diagnostic work‐up, newborn screening programs for some OADs, optimized neonatal and intensive care, and the development of evidence‐based recommendations have improved neonatal survival and short‐term outcome of affected individuals. However, chronic progression of organ dysfunction in an aging patient population cannot be reliably prevented with traditional therapeutic measures. Evidence is increasing that disease progression might be best explained by mitochondrial dysfunction. Previous studies have demonstrated that some toxic metabolites target mitochondrial proteins inducing synergistic bioenergetic impairment. Although these potentially reversible mechanisms help to understand the development of acute metabolic decompensations during catabolic state, they currently cannot completely explain disease progression with age. Recent studies identified unbalanced autophagy as a novel mechanism in the renal pathology of methylmalonic aciduria, resulting in impaired quality control of organelles, mitochondrial aging and, subsequently, progressive organ dysfunction. In addition, the discovery of post‐translational short‐chain lysine acylation of histones and mitochondrial enzymes helps to understand how intracellular key metabolites modulate gene expression and enzyme function. While acylation is considered an important mechanism for metabolic adaptation, the chronic accumulation of potential substrates of short‐chain lysine acylation in inherited metabolic diseases might exert the opposite effect, in the long run. Recently, changed glutarylation patterns of mitochondrial proteins have been demonstrated in glutaric aciduria type 1. These new insights might bridge the gap between natural history and pathophysiology in OADs, and their exploitation for the development of targeted therapies seems promising.

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Chronic kidney disease in propionic acidemia

Cited by 52 publications

References 20 publications

Acidemia propiónica: diagnóstico clínico vs. cribado neonatal

Acidemia propiónica: diagnóstico clínico vs. cribado neonatal

AMPK signaling regulates expression of urea cycle enzymes in response to changes in dietary protein intake

Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise

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