The neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome mtDNA mutation (T8993G) triggers muscle ATPase deficiency and hypocitrullinaemia

Parfait, Béatrice; Lonlay, Pascale de; Kleist-Retzow, J. C. von; Cormier‐Daire, Valérie; Chrétien, Dominique; Rötig, Agnès; Rabier, Daniel; Saudubray, J. M.; Rustin, Pierre; Münnich, Arnold

doi:10.1007/s004310051009

Cited by 50 publications

(39 citation statements)

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“…The blot was probed with anti-SMVT antibody and expression was normalized relative to b-actin istic unique to patients with the m.8993T>G mutation, seen in 90% of patients, as opposed to less than 20% for other respiratory chain deficiencies (Rabier et al 1998). These findings are sufficiently convincing to consider hypocitrullinemia as a useful biochemical marker for the m.8993T>G mutation and, more generally, as a marker of impaired oxidative phosphorylation in the enterocyte (Rabier et al 1998;Parfait et al 1999;Debray et al 2010;Henriques et al 2012;Mori et al 2014).…”

Section: Discussionmentioning

confidence: 93%

“…Persistent hypocitrullinemia has previously been reported in 13 patients with the m.8993T>G variant (Rabier et al 1998;Parfait et al 1999;Enns et al 2006;Debray et al 2010;Henriques et al 2012;Mori et al 2014). In an additional report, a female patient who was prenatally diagnosed with apparently mild ornithine transcarbamylase (OTC) deficiency succumbed during an acute febrile encephalopathic illness at 6 months of age, with neuroimaging suggestive of Leigh syndrome.…”

Section: Discussionmentioning

confidence: 96%

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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: 93%

Section: Discussionmentioning

confidence: 96%

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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“…Persistent hypocitrullinemia has been seen in patients with mitochondrial disorders (Atkuri et al 2009) including patients with Pearson syndrome (OMIM 557000) (Ribes et al 1993), m.8993T>G-associated Leigh syndrome/ NARP (OMIM 516060) (Rabier et al 1998;Parfait et al 1999;Enns et al 2006;Debray et al 2010;Henriques et al 2012), and mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes syndrome (MELAS, OMIM 540000) (Perry et al 1989;Koga et al 2005;Naini et al 2005). Hypocitrullinemia is also associated with secondary mitochondrial respiratory chain dysfunction caused by organic acidemias (Atkuri et al 2009), deficiency of mitochondrial pyrroline-5-carboxylate synthase (P5C) (Rabier and Kamoun 1995;Baumgartner et al 2000), or intestinal malrotation in newborns (Cavicchi et al 2009).…”

Section: Discussionmentioning

confidence: 98%

m.8993T>G-Associated Leigh Syndrome with Hypocitrullinemia on Newborn Screening

et al. 2014

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Citrulline is among the metabolites measured by expanded newborn screening (NBS). While hypocitrullinemia can be a marker for deficiency of proximal urea cycle enzymes such as ornithine transcarbamylase (OTC), only a handful of state newborn screening programs in the United States officially report a low citrulline value for further work-up due to low positive predictive value. We report a case of a male infant who was found to have hypocitrullinemia on NBS. After excluding proximal urea cycle disorders by DNA sequencing, his NBS result was felt to be a false positive. At 4 months of age, he developed poor feeding, failure to thrive, apnea and infantile spasms with a progression to intractable seizures, as well as persistent hypocitrullinemia. He was diagnosed with Leigh syndrome due to a maternally inherited homoplasmic m.8993T>G mutation in the ATPase 6 gene. His mother, who had previously been diagnosed with cerebral palsy, was concurrently diagnosed with neuropathy, ataxia, and retinitis pigmentosa (NARP) due to heteroplasmy of the same mutation. She had progressive muscle weakness, ataxia, and speech dyspraxia. The m.8993T>G mutation causes mitochondrial ATP synthase deficiency and it is hypothesized to undermine the synthesis of citrulline by CPS1. In addition to proximal urea cycle disorders, the evaluation of an infant with persistent hypocitrullinemia should include testing for the m.8993T>G mutation and other disorders that cause mitochondrial dysfunction.

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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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The neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome mtDNA mutation (T8993G) triggers muscle ATPase deficiency and hypocitrullinaemia

Abstract: We suggest giving consideration to hypocitrullinaemia as a hallmark of the neurogenic weakness, ataxia and retinitis pigmentosa syndrome mutation and more generally of impaired oxidative phosphorylation in the small intestine in vivo.

Cited by 50 publications

References 10 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)

m.8993T>G-Associated Leigh Syndrome with Hypocitrullinemia on Newborn Screening

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

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