Retinal Degeneration

Morini, Chiara; Capozzi, P.; Boenzi, Sara; Rizzo, Cristiano; Santorelli, Filippo M.; Dionisi‐Vici, Carlo

doi:10.1016/j.ophtha.2009.03.039

Cited by 13 publications

(18 citation statements)

References 5 publications

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“…Retinal involvement, with photophobia, hemeralopia, tapetoretinal degeneration, cataract and abnormal electroretinogram has also been reported [37,38,44]. …”

Section: Resultsmentioning

confidence: 99%

“…As the liver extracts only a small quantity of citrulline, this aminoacid is mainly transported to the kidney and metabolized to arginine in the tubules of the cortical zone and used for guanidino acetate synthesis by arginine-glycine amidotransferase (AGAT), the first step of creatine synthesis, with ornithine as by-product [73]. In ORC1 deficiency, the high cytosolic ornithine concentrations inhibit AGAT leading to secondary creatine deficiency [21,44,74]. Secondary creatine deficiency may be also due to low cellular arginine availability due to the block in UC flow.…”

Section: Resultsmentioning

confidence: 99%

“…Protein restriction may be combined with sodium benzoate or sodium phenylbutyrate. If plasma creatine levels are low, creatine supplementation should be instituted [1,44,74]. Citrulline supplementation has been shown to allow better metabolic control and to avoid secondary creatine deficiency [21].…”

Section: Resultsmentioning

confidence: 99%

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The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

Martinelli

Diodato

Ponzi

et al. 2015

Orphanet J Rare Dis

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BackgroundHyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a major prevalence in Canada, Italy and Japan. Acute clinical signs include intermittent episodes of vomiting, confusion or coma and hepatitis-like attacks. Alternatively, patients show a chronic course with aversion for protein rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction. HHH syndrome is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15 gene, which encodes for the mitochondrial ornithine carrier ORC1. The diagnosis relies on clinical signs and the peculiar metabolic triad of hyperammonemia, hyperornithinemia, and urinary excretion of homocitrulline. HHH syndrome enters in the differential diagnosis with other inherited or acquired conditions presenting with hyperammonemia.MethodsA systematic review of publications reporting patients with HHH syndrome was performed.ResultsWe retrospectively evaluated the clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases. Lethargy and coma are frequent at disease onset, whereas pyramidal dysfunction and cognitive/behavioural abnormalities represent the most common clinical features in late-onset cases or during the disease course. Two common mutations, F188del and R179* account respectively for about 30% and 15% of patients with the HHH syndrome. Interestingly, the majority of mutations are located in residues that have side chains protruding into the internal pore of ORC1, suggesting their possible interference with substrate translocation. Acute and chronic management consists in the control of hyperammonemia with protein-restricted diet supplemented with citrulline/arginine and ammonia scavengers. Prognosis of HHH syndrome is variable, ranging from a severe course with disabling manifestations to milder variants compatible with an almost normal life.ConclusionsThis paper provides detailed information on the clinical, metabolic and genetic profiles of all HHH syndrome patients published to date. The clinical phenotype is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels. Early intervention allows almost normal life span but the prognosis is variable, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0242-9) contains supplementary material, which is available to authorized users.

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“…Retinal involvement, with photophobia, hemeralopia, tapetoretinal degeneration, cataract and abnormal electroretinogram has also been reported [37,38,44]. …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

Martinelli

Diodato

Ponzi

et al. 2015

Orphanet J Rare Dis

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“…Secondary Cr deficiency has also been observed in HHH (Hyperammonemia, Hyperornithinemia, Homocitrullinuria) syndrome (MIM 238970), the other inherited condition causing massive cellular ornithine accumulation (Dionisi Vici et al 1987;Morini et al 2009). Martinelli et al (2011), have recently reported brain Cr deficiency in a child with pyrroline-5-carboxylate synthetase deficiency, which normalized upon arginine supplementation improving neurodevelopmental and metabolic parameters, suggesting a pathogenic role of brain creatine decrease and the value of arginine therapy.…”

Section: Introductionmentioning

confidence: 99%

Creatine metabolism in urea cycle defects

Boenzi

Pastore

Martinelli

et al. 2012

J of Inher Metab Disea

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Creatine (Cr) and phosphocreatine play an essential role in energy storage and transmission. Maintenance of creatine pool is provided by the diet and by de novo synthesis, which utilizes arginine, glycine and s-adenosylmethionine as substrates. Three primary Cr deficiencies exists: arginine:glycine amidinotransferase deficiency, guanidinoacetate methyltransferase deficiency and the defect of Cr transporter SLC6A8. Secondary Cr deficiency is characteristic of ornithine-aminotransferase deficiency, whereas non-uniform Cr abnormalities have anecdotally been reported in patients with urea cycle defects (UCDs), a disease category related to arginine metabolism in which Cr must be acquired by de novo synthesis because of low dietary intake. To evaluate the relationships between ureagenesis and Cr synthesis, we systematically measured plasma Cr in a large series of UCD patients (i.e., OTC, ASS, ASL deficiencies, HHH syndrome and lysinuric protein intolerance). Plasma Cr concentrations in UCDs followed two different trends: patients with OTC and ASS deficiencies and HHH syndrome presented a significant Cr decrease, whereas in ASL deficiency and lysinuric protein intolerance Cr levels were significantly increased (23.5 vs. 82.6 μmol/L; p < 0.0001). This trend distribution appears to be regulated upon cellular arginine availability, highlighting its crucial role for both ureagenesis and Cr synthesis. Although decreased Cr contributes to the neurological symptoms in primary Cr deficiencies, still remains to be explored if an altered Cr metabolism may participate to CNS dysfunction also in patients with UCDs. Since arginine in most UCDs becomes a semi-essential aminoacid, measuring plasma Cr concentrations might be of help to optimize the dose of arginine substitution.

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“…There are also a few secondary creatine defects, in particular, two inherited conditions causing hyperornithinemia have been associated to secondary creatine deficiency: deficiency of ornithine delta-aminotransferase activity (OAT) [9], and hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH) [10,11]. In these cases, treatment with creatine can improve some clinical aspects of the disease.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous determination of creatine and guanidinoacetate in plasma by liquid chromatography–tandem mass spectrometry (LC–MS/MS)

Boenzi

Rizzo

Ciommo

et al. 2011

Journal of Pharmaceutical and Biomedical Analysis

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a b s t r a c tBackground: Guanidinoacetate (GAA) and creatine are reliable biochemical markers for primary and secondary creatine defects. We describe a method by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) for simultaneous determination of plasma GAA and creatine. We analyzed 283 healthy subjects from 0 to 63 years old to obtain age-related control values. Methods: Plasma samples were extracted with acetonitrile containing 13C2-GAA and d3-creatine. Samples were analyzed by LC-MS/MS in positive ionisation mode, after derivatization to butyl-esters. Optimal chromatographic separation was achieved using a column Supelcosil TM LC-4.6 mm with isocratic elution in 5 min. Results: Run time was 5 min. Standard curves were linear from 0.05 to 200 mol/L for creatine and from 0.02 to 40 mol/L for GAA. Limit of detection (LOD) and limit of quantitation (LOQ) were respectively 0.005 and 0.05 mol/L for creatine; LOD and LOQ were 0.002 and 0.02 mol/L respectively for GAA. Intra and inter-assay CVs for creatine and GAA were <8%. Recovery experiments adding 50 and 100 mol/L creatine and 10 and 20 mol/L GAA were 102.1% and 101.2%, for creatine; 102.95% and 96.45% for GAA. The method was applied to 283 plasma controls from healthy subjects to obtain control values in three specific age ranges: 0-12, 13-20, >20 years old. Conclusion: A rapid and high sensitive LC-MS/MS method was developed and validated for determination of creatine and GAA in plasma and it could also be applied to other biological materials, such as CFS and urines. This method is useful for diagnoses of primary and also for secondary creatine defects that may occur in inherited metabolic diseases in which precursors of creatine biosynthesis are involved.

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Retinal Degeneration

Cited by 13 publications

References 5 publications

The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

Creatine metabolism in urea cycle defects

Simultaneous determination of creatine and guanidinoacetate in plasma by liquid chromatography–tandem mass spectrometry (LC–MS/MS)

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