Hereditary urea cycle diseases in Finland

Keskinen, Päivi; Siitonen, Anna; Salo, Matti K.

doi:10.1111/j.1651-2227.2008.00923.x

Cited by 55 publications

(47 citation statements)

References 19 publications

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“…At the end of the first year, the frequency of developmental impairment is similar to other UCD (64%) attributable to sequelae of neonatal hyperammonaemia in early-onset patients (Burgard et al 2016). This frequency increases to 65–100% with time (this study; Keskinen et al 2008; Tuchman et al 2008; Ah Mew et al 2013; Ruegger et al 2014). …”

Section: Discussionsupporting

confidence: 54%

“…(Arg385Cys)p. (Arg385Cys)Early onsetPrenatal diagnosis ( n = 3, Keskinen et al 2008; Balmer et al 2014), early onset ( n = 4, this study, Kleijer et al 2002; Keskinen et al 2008), late onset ( n = 7, Kleijer et al 2002; Keskinen et al 2008), unknown ( n = 3, Balmer et al 2014)19c.1284G>Ac.1366C>Tp. (Trp428 * )p.…”

Section: Resultsmentioning

confidence: 59%

“…The homozygous mutation c.1153C>T p.(Arg385Cys) has been associated previously with both early-onset ( n = 4) (Kleijer et al 2002; Keskinen et al 2008) or late-onset phenotypes ( n = 7) (Kleijer et al 2002; Keskinen et al 2008). However, all patients with late-onset phenotype were diagnosed before 20 months of life.…”

Section: Discussionmentioning

confidence: 95%

“…However, all patients with late-onset phenotype were diagnosed before 20 months of life. p.(Arg385Cys) has been reported as a founder mutation in the Finnish population (Keskinen et al 2008) and is associated with very low ASL activity affecting an amino acid near the catalytic site (Hu et al 2015). …”

Section: Discussionmentioning

confidence: 99%

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Expanding the phenotype in argininosuccinic aciduria: need for new therapies

Baruteau

Jameson

Morris

et al. 2017

J of Inher Metab Disea

115

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ObjectivesThis UK-wide study defines the natural history of argininosuccinic aciduria and compares long-term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia-lowering drugs.MethodsRetrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs. ASL genotyping.ResultsFifty-six patients were defined as early-onset (n = 23) if symptomatic < 28 days of age, late-onset (n = 23) if symptomatic later, or selectively screened perinatally due to a familial proband (n = 10). The median follow-up was 12.4 years (range 0–53). Long-term outcomes in all groups showed a similar neurological phenotype including developmental delay (48/52), epilepsy (24/52), ataxia (9/52), myopathy-like symptoms (6/52) and abnormal neuroimaging (12/21). Neuroimaging findings included parenchymal infarcts (4/21), focal white matter hyperintensity (4/21), cortical or cerebral atrophy (4/21), nodular heterotopia (2/21) and reduced creatine levels in white matter (4/4). 4/21 adult patients went to mainstream school without the need of additional educational support and 1/21 lives independently. Early-onset patients had more severe involvement of visceral organs including liver, kidney and gut. All early-onset and half of late-onset patients presented with hyperammonaemia. Screened patients had normal ammonia at birth and received treatment preventing severe hyperammonaemia. ASL was sequenced (n = 19) and 20 mutations were found. Plasma argininosuccinate was higher in early-onset compared to late-onset patients.ConclusionsOur study further defines the natural history of argininosuccinic aciduria and genotype–phenotype correlations. The neurological phenotype does not correlate with the severity of hyperammonaemia and plasma argininosuccinic acid levels. The disturbance in nitric oxide synthesis may be a contributor to the neurological disease. Clinical trials providing nitric oxide to the brain merit consideration.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-017-0022-x) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 54%

Section: Resultsmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Expanding the phenotype in argininosuccinic aciduria: need for new therapies

Baruteau

Jameson

Morris

et al. 2017

J of Inher Metab Disea

115

View full text Add to dashboard Cite

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“…OTCD accounts for about half of all urea cycle defects (Brusilow and Horwich, 2001; Seminara et al, 2010). The estimated prevalence of OTCD is one in 14,000 (Brusilow and Maestri, 1996), but more recent estimates based on a review of national medical records and comparisons of newborn screening data with the number of patients with urea cycle disorders indicate a prevalence of one in 62,000–77,000 (Dionisi-Vici et al, 2002; Keskinen et al, 2008; Balasubramaniam et al, 2010; Summar et al, 2013). Most of the patients with OTCD are hemizygous males; approximately 20% of female carriers of OTC mutations also present symptoms of OTCD (Maestri et al, 1996; Maestri et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Genotype–Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update

Caldovic

Abdikarim

Narain

et al. 2015

Journal of Genetics and Genomics

120

128

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Ornithine transcarbamylase (OTC) deficiency is an X-linked trait that accounts for nearly half of all inherited disorders of the urea cycle. OTC is one of the enzymes common to both the urea cycle and the bacterial arginine biosynthesis pathway; however, the role of OTC has changed over evolution. For animals with a urea cycle, defects in OTC can trigger hyperammonemic episodes that can lead to brain damage and death. This is the fifth mutation update for human OTC with previous updates reported in 1993, 1995, 2002, and 2006. In the 2006 update, 341 mutations were reported. This current update contains 417 disease-causing mutations, and also is the first report of this series to incorporate information about natural variation of the OTC gene in the general population through examination of publically available genomic data and examination of phenotype/genotype correlations from patients participating in the Urea Cycle Disorders Consortium Longitudinal Study and the first to evaluate the suitability of systematic computational approaches to predict severity of disease associated with different types of OTC mutations.

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Molecular Genetics of Argininosuccinic Aciduria

Trevisson

Doimo

Salviati

2014

Encyclopedia of Life Sciences

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Argininosuccinic aciduria is an autosomal recessive disorder of the urea cycle caused by mutations in argininosuccinate lyase ( ASL ). Two main clinical phenotypes are reported: an acute neonatal form characterised by severe hyperammonaemia and coma, and a subacute, late‐onset form which may present with relatively milder neurological symptoms. More than 120 ASL mutations have been reported so far: the majority are missense, but virtually all types of point mutations are found. Large rearrangements are rare and standard genomic deoxyribonucleic acid (DNA) analysis has a high diagnostic yield. Genotype–phenotype correlations have been difficult to establish as standard biochemical techniques are not sufficiently sensitive to measure residual activity, and other factors such as intragenic complementation, overexpression of nonfunctional ASL transcripts and environmental factors may modulate the phenotype. Clinical manifestations result from the block in the urea cycle and also from impairment of nitric oxide biosynthesis, and the therapy is aimed at restoring these two functions. Key Concepts: Argininosuccinic aciduria is caused by deficiency of argininosuccinate lyase (ASL). ASL is a component of the urea cycle and is essential for detoxification of ammonia, and for the synthesis of arginine and nitric oxide (NO). Two clinical forms of argininosuccinic aciduria exist: an acute, potentially lethal, neonatal onset disease and a milder, late‐onset form. More than 120 ASL mutations have been described but the exact genotype/phenotype correlations are still not completely clear. Other factors (genetic and environmental) may influence the clinical phenotype. Treatment is based on protein restriction, arginine, nitrogen scavengers and NO donors.

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Hereditary urea cycle diseases in Finland

Cited by 55 publications

References 19 publications

Expanding the phenotype in argininosuccinic aciduria: need for new therapies

Expanding the phenotype in argininosuccinic aciduria: need for new therapies

Genotype–Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update

Molecular Genetics of Argininosuccinic Aciduria

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