Report of a Case and Additional Evidence for the “Mild” Phenotype

Arnold, Georgianne L.; Griebel, May L.; Porterfield, Melanie; Brewster, Marge A.

doi:10.1177/000992280104000909

Cited by 16 publications

(17 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We reported a further Canadian patient with this mutation and type A phenotype. p.A R631Q mutation has twice been described in patients with type A disease (Monnot et al, 2009;Wang et al, 2009) As stated above, only six patients with the milder late-onset type C PCD were reported before our study and the PCD causing variants were described in only two of them (Arnold et al, 2001;Hamilton et al, 1997;Schiff et al, 2006;Van Coster et al, 1991;Wang et al, 2008). Thus, our three type C patients significantly increase our ability to examine mutations in these mild patients.…”

Section: Variants In Type C Patientssupporting

confidence: 49%

Pyruvate carboxylase deficiency type A and type C: Characterization of five novel pathogenic variants inPCand analysis of the genotype–phenotype correlation

Coci

Gapsys²,

Shur

et al. 2019

Human Mutation

View full text Add to dashboard Cite

Pyruvate carboxylase deficiency (PCD) is caused by biallelic mutations of the PC gene. The reported clinical spectrum includes a neonatal form with early death (type B), an infantile fatal form (type A), and a late‐onset form with isolated mild intellectual delay (type C). Apart from homozygous stop‐codon mutations leading to type B PCD, a genotype–phenotype correlation has not otherwise been discernible. Indeed, patients harboring biallelic heterozygous variants leading to PC activity near zero can present either with a fatal infantile type A or with a benign late onset type C form. In this study, we analyzed six novel patients with type A (three) and type C (three) PCD, and compared them with previously reported cases. First, we observed that type C PCD is not associated to homozygous variants in PC. In silico modeling was used to map former and novel variants associated to type A and C PCD, and to predict their potential effects on the enzyme structure and function. We found that variants lead to type A or type C phenotype based on the destabilization between the two major enzyme conformers. In general, our study on novel and previously reported patients improves the overall understanding on type A and C PCD.

show abstract

Section: Variants In Type C Patientssupporting

confidence: 49%

Pyruvate carboxylase deficiency type A and type C: Characterization of five novel pathogenic variants inPCand analysis of the genotype–phenotype correlation

Coci

Gapsys²,

Shur

et al. 2019

Human Mutation

View full text Add to dashboard Cite

show abstract

“…The benign form (Type C, Benign Form) is represented by four cases, (11–14). The clinical phenotype is characterized by normal or mildly delayed neurological development and episodic metabolic acidosis.…”

Section: Introductionmentioning

confidence: 99%

The molecular basis of pyruvate carboxylase deficiency: Mosaicism correlates with prolonged survival

Wang

Yang

Braganca

et al. 2008

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

Pyruvate carboxylase (PC) deficiency (OMIM, 266150) is a rare autosomal recessive disease. The revised PC gene structure described in this report consists of 20 coding exons and four non-coding exons at the 5'-untranslated region (5'-UTR). The gene codes for three transcripts due to alternative splicing: variant 1 (NM_000920.3), variant 2 (NM_022172.2) and variant 3 (BC011617.2). PC deficiency is manifested by three clinical phenotypes -an infantile form (Type A), a neonatal form (Type B), and a benign form (Type C). We report the molecular basis for eight cases (one Type A, five Type B and two Type C) of PC deficiency. Eight novel complex mutations were identified representing different combinations of missense mutations, deletions, a splice site substitution and a nonsense mutation. The classical phenotypes (A, B and C) correlated poorly with clinical outcomes. Mosaicism was found in five cases (one Type A, three Type B and one Type C) and four of these cases had prolonged survival. Death in the fifth case resulted from unrelated medical complications. The discrepancy between the current findings and the existing classification system should be addressed to accommodate these new observations.

show abstract

“…To date, PC deficiency has commonly been described as occurring in three distinct forms, ranging in severity from a benign phenotype (Type C) [Arnold et al, 2001;Hamilton et al, 1997;Van Coster et al, 1991], to a simple phenotype (Type A), to a severe phenotype (Type B) [Robinson et al, 1987;Robinson et al, 1983;Robinson et al, 1984]. However, this description now seems rather limited since intermediary cases of moderate-severe PC deficiency have also been described [Wexler et al, 1998].…”

Section: Introductionmentioning

confidence: 99%

Intron retention and frameshift mutations result in severe pyruvate carboxylase deficiency in two male siblings

2002

View full text Add to dashboard Cite

This paper describes the molecular characterization of two male siblings displaying the complex (Type B) form of pyruvate carboxylase (PC) deficiency in which severe neonatal lactic acidosis and redox abnormalities results in death within the first few weeks of life. The two male siblings were found to be compound heterozygous for a TAGG deletion at the exon15/intron15 splice site (IVS15+2-5delTAGG) and a dinucleotide deletion in exon 16 (2491-2492delGT) of the PC gene. We also demonstrate through RT-PCR and sequencing of aberrant transcripts that the IVS15+2-5delTAGG results in the retention of intron 15 during pre-mRNA splicing. In addition, both deletions are predicted to result in a frameshift to generate a premature termination codon such that the encoded mRNA could be subject to nonsense mediated decay.

show abstract

Report of a Case and Additional Evidence for the “Mild” Phenotype

Cited by 16 publications

References 9 publications

Pyruvate carboxylase deficiency type A and type C: Characterization of five novel pathogenic variants inPCand analysis of the genotype–phenotype correlation

Pyruvate carboxylase deficiency type A and type C: Characterization of five novel pathogenic variants inPCand analysis of the genotype–phenotype correlation

The molecular basis of pyruvate carboxylase deficiency: Mosaicism correlates with prolonged survival

Intron retention and frameshift mutations result in severe pyruvate carboxylase deficiency in two male siblings

Contact Info

Product

Resources

About