Hypocitrullinemia in patients with MELAS: an insight into the “MELAS paradox”

Naini, Ali; Kaufmann, Petra; Shanske, Sara; Engelstad, Kristin; Vivo, Darryl C. De; Schon, Eric A.

doi:10.1016/j.jns.2004.11.026

Cited by 93 publications

(101 citation statements)

References 35 publications

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“…Post-mortem genetic testing identified the m.8993T>G variant in the liver, muscle and blood with variant loads of 82-87% (Henriques et al 2012). Persistent hypocitrullinemia has been described in other mitochondrial disorders including Pearson syndrome (Ribes et al 1993), Leigh syndrome caused by isolated complex I deficiency (Debray et al 2010), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS syndrome) (Naini et al 2005), mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease (Bindoff 2006), and with secondary mitochondrial respiratory chain dysfunction caused by organic acidemias (Atkuri et al 2009) and deficiency of mitochondrial pyrroline-5-carboxylate synthetase (P5CS) (Baumgartner et al 2000). In a small series of 16 Leigh syndrome patients, sensitivity and specificity of hypocitrullinemia as a marker for the m.8993T>G variant were reported to be 66% and 85%, respectively (Debray et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)

et al. 2016

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Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, is a genetically heterogeneous, relentlessly progressive, devastating neurodegenerative disorder that usually presents in infancy or early childhood. A diagnosis of Leigh-like syndrome may be considered in individuals who do not fulfil the stringent diagnostic criteria but have features resembling Leigh syndrome.We describe a unique presentation of Leigh-like syndrome in a 3-year-old boy with elevated 3-hydroxyisovalerylcarnitine (C5-OH) on newborn screening (NBS).Subsequent persistent plasma elevations of C5-OH and propionylcarnitine (C3) as well as fluctuating urinary markers were suggestive of multiple carboxylase deficiency (MCD). Normal enzymology and mutational analysis of genes encoding holocarboxylase synthetase (HLCS) and biotinidase (BTD) excluded MCD. Biotin uptake studies were normal excluding biotin transporter deficiency. His clinical features at 13 months of age comprised psychomotor delay, central hypotonia, myopathy, failure to thrive, hypocitrullinemia, recurrent episodes of decompensation with metabolic keto-lactic acidosis and an episode of hyperammonemia. Biotin treatment from 13 months of age was associated with increased patient activity, alertness,

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Section: Discussionmentioning

confidence: 99%

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)

et al. 2016

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“…We detected hypocitrullenimia in plasma from mitochondrial and organic acidemia subjects. Hypocitrullinemia has also been reported in some individuals with Reye syndrome, MELAS, and NARP (21)(22)(23). Low levels of plasma citrulline are a classic biochemical hallmark of proximal urea cycle disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Low levels of plasma citrulline are a classic biochemical hallmark of proximal urea cycle disorders. In addressing the relationship between citrulline levels and mitochondrial function, it has been postulated that primary deficiencies in OXPHOS result in decreased citrulline synthesis via secondary impairment of carbamyl phosphate synthetase I, an early urea cycle enzyme that plays a key role in citrulline synthesis (23), or by inhibiting production of the citrulline precursor ⌬-1-pyrroline carboxylate through inhibition of proline oxidase (22).…”

Section: Discussionmentioning

confidence: 99%

Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia

Atkuri

Cowan

Kwan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Disorders affecting mitochondria, including those that directly affect the respiratory chain function or result from abnormalities in branched amino acid metabolism (organic acidemias), have been shown to be associated with impaired redox balance. Almost all of the evidence underlying this conclusion has been obtained from studies on patient biopsies or animal models. Since the glutathione (iGSH) system provides the main protection against oxidative damage, we hypothesized that untreated oxidative stress in individuals with mitochondrial dysfunction would result in chronic iGSH deficiency. We confirm this hypothesis here in studies using high-dimensional flow cytometry (Hi-D FACS) and biochemical analysis of freshly obtained blood samples from patients with mitochondrial disorders or organic acidemias. T lymphocyte subsets, monocytes and neutrophils from organic acidemia and mitochondrial patients who were not on antioxidant supplements showed low iGSH levels, whereas similar subjects on antioxidant supplements showed normal iGSH. Measures of iROS levels in blood were insufficient to reveal the chronic oxidative stress in untreated patients. Patients with organic acidemias showed elevated plasma protein carbonyls, while plasma samples from all patients tested showed hypocitrullinemia. These findings indicate that measurements of iGSH in leukocytes may be a particularly useful biomarker to detect redox imbalance in mitochondrial disorders and organic acidemias, thus providing a relatively noninvasive means to monitor disease status and response to therapies. Furthermore, studies here suggest that antioxidant therapy may be useful for relieving the chronic oxidative stress that otherwise occurs in patients with mitochondrial dysfunction. organic acidemia ͉ mitochondrial disorders

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“…This may cause an imbalance in the NAD ϩ /NADH ratio inside mitochondria and be the reason for the block in fatty acid ␤-oxidation. Studies in patients suffering from OXPHOS disorders have shown the presence of increased serum alanine levels and/or decreases in citrulline levels (67)(68)(69)(70). This was not found in the blood of Ndufs4 fky/fky mice, which only had levels of glycine, phenylalanine, and homocitrulline significantly elevated (Fig.…”

Section: Dnmt3lmentioning

confidence: 91%

Proteomic and Metabolomic Analyses of Mitochondrial Complex I-deficient Mouse Model Generated by Spontaneous B2 Short Interspersed Nuclear Element (SINE) Insertion into NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (Ndufs4) Gene

Leong

Komen

Hewitt

et al. 2012

Journal of Biological Chemistry

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Background: Mitochondrial complex I deficiency is a common inherited metabolic disease. Results: B2 transposable element insertion into Ndufs4 in mice causes loss of the "N assembly module" of complex I, alterations in cellular metabolites, and neurological symptoms. Conclusion: NDUFS4 subunit is required for complex I stability. Significance: Understanding the effects of oxidative phosphorylation defects is essential for the development of treatments.

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Hypocitrullinemia in patients with MELAS: an insight into the “MELAS paradox”

Cited by 93 publications

References 35 publications

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)

Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia

Proteomic and Metabolomic Analyses of Mitochondrial Complex I-deficient Mouse Model Generated by Spontaneous B2 Short Interspersed Nuclear Element (SINE) Insertion into NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (Ndufs4) Gene

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