Liver transplantation for ornithine transcarbamylase deficiency in a girl

Hyperammonemia, abnormalities in plasma amino acids and abnormalities of standard liver functions were corrected by orthotopic liver transplantation in a 14-day-old boy with carbamyl phosphate synthetase-I deficiency and in a 35-yr-old man with argininosuccinic acid synthetase deficiency. The first patient had high plasma glutamine levels and no measureable citrulline, whereas citrulline values were markedly increased in Patient 2. Enzyme analysis of the original livers showed undetectable activity of carbamyl phosphate synthetase-I in Patient 1 and arginosuccinic acid synthetase in Patient 2. Both patients were comatose before surgery. Intellectual recovery of patient 1 has been slightly retarded because of a brain abscess caused by Aspergillus infection after surgery. Both patients are well at 34 and 40 mo, respectively, after surgery. Our experience has shown that orthotopic liver transplantation corrects the life-threatening metabolic abnormalities caused by deficiencies in the urea cycle enzymes carbamyl phosphate synthetase-I and arginosuccinic acid synthetase. Seven other patients-six with ornithine transcarbamylase deficiency and another with carbamyl phosphate synthetase-I deficiency-are known to have been treated elsewhere with liver transplantation 1½ yr or longer ago. Four of these seven recipients also are well, with follow-ups of 1½ to 5 yr. Thus liver transplantation corrects the metabolic abnormalities of three of the six urea cycle enzyme deficiencies, and presumably would correct all.

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“…Six of the seven had OTC deficiency (12,13). The seventh was a 20-mo-old boy with CPS-I deficiency (14).…”

Section: Discussionmentioning

confidence: 99%

Orthotopic liver transplantation for urea cycle enzyme deficiency

et al. 1992

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“…The hemizygous male patient typically is completely enzyme deficient and thus suffers from profound hyperammonemic encephalopathy, which presents as irritability, poor feeding, vomiting, and lethargy, usually within the first week of life. 1,8,11,12 A review of the literature documenting cases of ornithine transcarbamylase defi-ciency shows that the vast majority of afflicted boys who present during the neonatal period cannot be permanently maintained with dietary restrictions alone. 1,5,11,13,14 Furthermore, the majority of these infants develop profound mental retardation followed by early death.…”

Section: Discussionmentioning

confidence: 99%

The role of orthotopic liver transplantation in the treatment of ornithine transcarbamylase deficiency

et al. 1998

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The purpose of this study was to combine our clinical experience with a review of the literature to determine the value of orthotopic liver transplantation in the treatment of both boys and girls with ornithine transcarbamylase deficiency. Three boys younger than 1 year of age with symptomatic ornithine transcarbamylase deficiency (median age, 116 days; range, 40 to 223 days) underwent orthotopic liver transplantation. The patients' growth, developmental progress, ammonia levels, and amino acid levels were analyzed pre-and post-liver transplantation. The clinical courses of the respective patients and the treatment modalities used were compared with published reports from 1978 through 1997. The median follow-up period in these 3 patients was 3.2 years (range, 9 months to 5.2 years). Orthotopic liver transplantation restored normal urea production and stabilized ammonia levels within 24 hours of surgery (median serum ammonia level 24 hours post-liver replacement, 43 mol/L; range, 30 to 66 mol/L). After liver replacement, arginine synthesis was normalized; however, plasma citrulline levels remained less than normal in all patients. Linear growth was evaluated in all 3 patients at the time of the most recent follow-up; median z scores for patient height and weight were ؊2.16 and ؊1.16, respectively. Standardized intelligence tests showed that 2 of the 3 patients continue to perform at age-appropriate levels. The third child was developmentally delayed pretransplantation at 4 months of age on presentation and continues to perform in a below-average fashion. Orthotopic liver transplantation results in the restoration of normal urea production and serum ammonia levels in the boy suffering from symptomatic ornithine transcarbamylase deficiency. Serum arginine, but not citrulline, levels are normalized, probably because of the persistent intestinal mucosa defect. Patient growth is similar to that in infants undergoing liver transplantation for other causes. When liver transplantation is performed before cognitive impairment occurs, intellectual development is normal, because the risk of additional episodes of hyperammonemia is elevated.

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“…Despite dietary and pharmacological intervention, the therapeutic outcome is inadequate and frequently associated with recurrent acute episodes resulting in mental retardation or, in the majority of cases, death (1)(2)(3)(4)(5)(6)(7). Liver transplantation is an option for qualified patients but can be associated with high morbidity and mortality (8,9). Because of the severity of OTCD, the high frequency of new mutations, the limited organ target needed for enzymatic correction, and the currently inadequate therapy, we elected to develop a gene transfer method for treatment.…”

Section: Introductionmentioning

confidence: 99%

Patient selection may affect gene therapy success. Dominant negative effects observed for ornithine transcarbamylase in mouse and human hepatocytes.

Morsy¹,

Zhao²,

Ngo³

et al. 1996

J. Clin. Invest.

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We have achieved significant improvement of ornithine transcarbamylase deficiency (OTCD) in a mouse model through adenoviral-mediated gene transfer of the human ornithine transcarbamylase cDNA. Substantial reduction in orotic aciduria was observed within 24 h of treatment. Metabolic correction was later associated with phenotypic correction and moderate increase in enzymatic activity. In an effort to identify the level of gene expression required to achieve wild-type levels of enzyme activity we uncovered a dominant negative effect of the endogenous mutant protein on the activity of the delivered recombinant wild-type protein. This phenomenon is relevant to homomultimeric protein defects such as OTCD, which represent a challenging category of disorders for gene therapy. Thus, although our findings indicate that adenoviral-mediated gene transfer may have potential as a short-term treatment for OTCD in humans and may be effective especially during catabolic crisis, the observations in this study suggest that careful patient selection based on mutation class may be essential for initial OTCD gene therapy trials and, perhaps, for other homomultimeric enzyme deficiencies being considered as gene therapy targets. IntroductionOrnithine transcarbamylase (OTC) 1 deficiency (OTCD) is the most common and severe of the urea cycle disorders and is inherited as an X-linked recessive, with frequent new mutation occurrences (1, 2). Mutations range from deletions of the gene to point mutations that affect the activity and/or stability of the protein (1). The OTC protein is predominantly expressed in the liver and intestine with trace amounts found in kidney and brain (1). OTC is targeted to the mitochondria and assumes a homotrimer configuration in its active form (1). The deficiency is associated with citrulline and arginine depletion, orotic aciduria, hyperammonemia, and coma (3-6). Patients deteriorate rapidly if the hyperammonemia is not corrected within 24-48 h (2). Despite dietary and pharmacological intervention, the therapeutic outcome is inadequate and frequently associated with recurrent acute episodes resulting in mental retardation or, in the majority of cases, death (1-7). Liver transplantation is an option for qualified patients but can be associated with high morbidity and mortality (8, 9). Because of the severity of OTCD, the high frequency of new mutations, the limited organ target needed for enzymatic correction, and the currently inadequate therapy, we elected to develop a gene transfer method for treatment.There are two mouse models for OTC deficiency: the sparse fur ( spf ) and the sparse fur-abnormal skin and hair ( spf ash ) mutants. The molecular defect in the spf model is a missense point mutation in exon 4 which alters the pH optimum for the enzyme activity, resulting in only 20% wild-type activity at physiological pH despite high levels of expressed protein (10, 11). The spf ash OTC gene has a splice junction mutation, leading to expression of 5-15% wild-type levels of active enzyme (12). The ...

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Liver transplantation for ornithine transcarbamylase deficiency in a girl

Cited by 68 publications

References 8 publications

Orthotopic liver transplantation for urea cycle enzyme deficiency

Orthotopic liver transplantation for urea cycle enzyme deficiency

The role of orthotopic liver transplantation in the treatment of ornithine transcarbamylase deficiency

Patient selection may affect gene therapy success. Dominant negative effects observed for ornithine transcarbamylase in mouse and human hepatocytes.

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