Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia

Kleijer, Wim J.; Garritsen, Victor H.; Sterre, Marianne L. T. van der; Berning, Christoph; Häberle, Johannes; Huijmans, J. G. M.

doi:10.1002/pd.1390

Cited by 19 publications

(12 citation statements)

References 23 publications

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“…Elevated levels of argininosuccinic acid in the amniotic fluid can also reliably detect affected fetuses 40, 41, 42 . Analysis of enzyme activity by either direct methods from chorionic villus tissue or amniocytes or indirect methods such as 14 C-citrulline incorporation in uncultured chorionic villus samples, have been successfully performed 24, 43 .…”

Section: Diagnosismentioning

confidence: 99%

Argininosuccinate lyase deficiency

Nagamani

Erez

Lee

2012

Genetics in Medicine

103

105

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SUMMARY The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCD), a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia. Argininosuccinate Lyase (ASL) catalyzes the fourth reaction in this cycle resulting in the breakdown of argininosuccinic acid to arginine and fumarate. Argininosuccinate Lyase deficiency (ASLD) is the second most common UCD with a prevalence of ~1 in 70,000 live births. ASLD can manifest as either a severe neonatal onset form with hyperammonemia within the first few days after birth or as a late onset form with episodic hyperammonemia and/or long term complications that include liver dysfunction, neuro-cognitive deficits and hypertension. These long term complications can occur in the absence of hyperammonemic episodes implying that ASL has functions outside of its role in ureagenesis and the tissue specific lack of ASL may be responsible for these manifestations. The biochemical diagnosis of ASLD is typically established with elevation of plasma citrulline together with elevated argininosuccinic acid in the plasma or urine. Molecular genetic testing of ASL and assay of ASL enzyme activity are helpful when the biochemical findings are equivocal. However, there is no correlation between the genotype, or enzyme activity and clinical outcome. Treatment of acute metabolic decompensations with hyperammonemia involves discontinuing oral protein intake; supplementing oral intake with intravenous lipids and/or glucose, and use of intravenous arginine and nitrogen scavenging therapy. Dietary restriction of protein and dietary supplementation with arginine are the mainstays in long-term management. Orthotopic liver transplantation is best considered only in patients with recurrent hyperammonemia or metabolic decompensations resistant to conventional medical therapy.

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Section: Diagnosismentioning

confidence: 99%

Argininosuccinate lyase deficiency

Nagamani

Erez

Lee

2012

Genetics in Medicine

103

105

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“…However, compound heterozygous carriers of some of these mutations (Ivs15-1G4C, R157C, V263M, E283K, G324S, R363W, and G390R) have been identified who, owing to the function of the second allele, present only mild clinical symptoms [Gao et al, 2003;Häberle et al, 2002;Hong et al, 2000;Sander et al, 2003]. A total of 30 mutations occur in compound heterozygotes with neonatal onset of citrullinemia [Gao et al, 2003;Häberle et al, 2002;Kakinoki et al, 1997;Kleijer et al, 2006;Kobayashi et al, 1990Kobayashi et al, , 1991Kobayashi et al, , 1994Li et al, 2001;Vilaseca et al, 2001]. Again, some of these aberrations-such as G14S, G117D, and E191Q-were also revealed to account for mild or late onset forms of the disease.…”

Section: Mutations and Polymorphismsmentioning

confidence: 99%

“…A total of 17 mutations have been shown to cause neonatal onset of the disorder when found in a homozygous state (see Table 1) [Gao et al, 2003;Kakinoki et al, 1997;Kleijer et al, 2006;Kobayashi et al, 1990Kobayashi et al, , 1991Kobayashi et al, , 1994Kobayashi et al, , 1995Sander et al, 2003;Vilaseca et al, 2001]: among them are two nonsense mutations in addition to four splice-site defects, two deletions, and seven missense mutations. However, compound heterozygous carriers of some of these mutations (Ivs15-1G4C, R157C, V263M, E283K, G324S, R363W, and G390R) have been identified who, owing to the function of the second allele, present only mild clinical symptoms [Gao et al, 2003;Häberle et al, 2002;Hong et al, 2000;Sander et al, 2003].…”

Section: Mutations and Polymorphismsmentioning

confidence: 99%

“…Since the ASS gene was cloned by Bock et al [1983] and studies on the human ASS mRNA showed that due to mRNA stability mutations in this gene could easily be detected by PCR methods [Kobayashi et al, 1990], mutations in the ASS gene have been described in an increasing number of families [Ban et al, 2001;Gao et al, 2003;Häberle et al, 2002Häberle et al, , 2003Hong et al, 2000;Kakinoki et al, 1997;Kleijer et al, 2006;Kobayashi et al, 1990Kobayashi et al, , 1991Kobayashi et al, , 1994Li et al, 2001;Ruitenbeek et al, 2003;Sander et al, 2003;Vilaseca et al, 2001]. As outlined above, the clinical presentation is very heterogeneous, ranging from neonatal metabolic decompensation due to fatal hyperammonemia in cases of mild disease with mainly a biochemical phenotype to adult onset of symptoms related to hyperammonemia and citrullinemia.…”

Section: Clinical Diagnostic and Biological Relevancementioning

confidence: 99%

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Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene

2008

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Citrullinemia type I is an autosomal recessive disorder that is caused by a deficiency of the urea cycle enzyme argininosuccinate synthetase (ASS1). Deficiency of ASS1 shows various clinical manifestations encompassing severely affected patients with fatal neonatal hyperammonemia as well as asymptomatic individuals with only a biochemical phenotype. This is a comprehensive report of all 87 mutations found to date in the ASS1 gene on chromosome 9q34.1. A large proportion of the mutations (n 5 27) are described here for the first time. Mutations are distributed throughout exons 3 to 15, most of them being identified in exons 5, 12, 13, and 14. The mutation G390R in exon 15 is the single most common mutation in patients with the classical phenotype. Certain mutations clearly link to specific clinical courses but the clinical phenotype cannot be anticipated in all patients. This update presents a survey of the correlation between mutations in the ASS1 gene and the respective clinical courses as described so far. It also sheds light on the geographic incidence of the mutations. Enzymatic studies have been done in bacterial and human cell systems. However, the prognostic value of genetic aberrations with respect to their effect on protein function and clinical manifestation remains uncertain.

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“…These results suggest the occurrence of preferential transmission of the mutant allele compared to the normal allele. Kleijer et al (2006) suggested that this phenomenon could be explained by a protective role of ASS deficiency in mutant sperm cells against the possible detrimental or apoptotic effect of nitric oxide produced normally from arginine by nitric oxide synthase.…”

Section: Resultsmentioning

confidence: 99%

Molecular Epidemiology of Citrullinemia Type I in a Risk Region of Argentina: A First Step to Preconception Heterozygote Detection

et al. 2012

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Classical citrullinemia type I (CTLN1) is an autosomal recessive disorder encoded by the ASS1 gene, which codes for argininosuccinate synthetase (ASS), the rate-limiting enzyme in the urea cycle. Previously, we identified the mutation p.G390R in patients with CTLN1 in the San Luis Province of Argentina. Here, we report the results of p.G390R analysis in a larger number of probands, relatives of involved families and additionally, a population study to identify carriers. Altogether, we analyzed 420 alleles, belonging to 12 probands, 26 relatives, and 172 healthy volunteers. All the probands were homozygous for the mutation, and 21 of 26 relatives were carriers. The occurrence of the disease in descendants of couples at risk was 57% showing a preferential transmission of the mutant allele compared to the normal allele. The carrier frequency in the general San Luis Province population was 4.1%, suggesting the incidence of CTLN1 to be 1:2,427, which is approximately 20 times higher than for the general population. This work suggests that there should be an increased awareness of preconceptual screening of CTNL1 among individuals/couples who are at risk in the San Luis Province in order to better inform them of their reproductive options.Cascade/family and population molecular screening for carrier identification were performed in an Argentinean province with high incidence of CTLN1, a first step to preconceptional screening.

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Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia

Cited by 19 publications

References 23 publications

Argininosuccinate lyase deficiency

Argininosuccinate lyase deficiency

Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene

Molecular Epidemiology of Citrullinemia Type I in a Risk Region of Argentina: A First Step to Preconception Heterozygote Detection

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