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PEDIATRICS Vol. 111 No. 5 May 2003, pp. 1123-1124

Partial Ornithine Transcarbamylase Deficiency

To the Editor.—

We have read the article by Scaglia et al¹ in which they describe the case report of a patient affected by ornithine transcarbamylase deficiency (OTCD) finally diagnosed after several approaches. Symptoms and routine metabolic analyses prompted genetic evaluation. After exhaustive research, no alteration could be found in the OTC gene. An allopurinol test was then performed and, according to the authors, was uninformative because of no increase in orotate excretion and lack of reference values to interpret the orotidine excretion.

We would like to point out that reference values to evaluate orotate and orotidine responses to allopurinol test do exist² in children and adults. In our experience, increased orotidine response yielded better diagnostic performance than orotate. According to these data, the allopurinol test described in the cited article¹ turns out to be clearly positive. We also found higher responses in infants than in children in normal populations. So, we usually normalize the orotate and orotidine responses in relation to the allopurinol dose and the body weight to obtain values independent of age.³

It is possible that a real false-negative result is related mainly to a favorable lyonization in a heterozygous female with mild phenotype⁴ or to excessive restriction of protein intake during testing.⁵ Another different discussion is the possibility of a false-positive result. It is known that other urea cycle disorders such as HHH syndrome, argininosuccinate aciduria, citrulinemia, argininemia, and lysinuric protein intolerance may result in a positive response to allopurinol load by the same mechanism as OTCD. However, these entities are relatively easily discarded by plasma and urine aminoacid analyses, as the authors found. Another cause of false-positive results is mitochondrial disorders,⁶ suggesting the possibility of secondary impairment of ureagenesis in these diseases.

Encarnació Riudor, MD
Jose Antonio Arranz, MD
Laboratori de Metabolopaties
Hospital Materno-Infantil Vall d’Hebron
08035 Barcelona, Spain

Margarida Rodés, MD
Institut de Bioquimica Clinica
Corporació Sanitària Clínic
08028 Barcelona, Spain

REFERENCES

1. Scaglia F, Zheng Q, O’Brien WE, et al. An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency. Pediatrics.2002; 109 :150 –152[Abstract/Free Full Text]
2. Arranz JA, Riudor E, Rodés M, et al. Optimization of allopurinol challenge: sample purification, protein intake control and the use of orotidine response as a discriminative variable improve performance of the test for diagnosing ornithine carbamoyltransferase deficiency. Clin Chem.1999; 45 :995 –1001[Abstract/Free Full Text]
3. Riudor E, Arranz JA, Rodés M, Rubio V, Sentis M, Burlina A. Influence of dose and age on the response of the allopurinol test for ornithine carbamoyltransferase deficiency in control infants. J Inherit Metab Dis.2000; 23 :662 –668[Medline]
4. Barshop BA, Nyhan WL, Climent C, Rubio V. Pitfalls in the detection of heterozygosity by allopurinol in a variant form of omithine carbamoyltransferase deficiency. J Inherit Metab Dis.2001; 24 :513 –514[Medline]
5. Spada M, Guardamagna O, Rabier D, et al. Recurrent episodes of bizarre behavior in a boy with ornithine transcarbamylase deficiency: diagnostic failure of protein loading and allopurinol challenge tests. J Pediatr.1994; 125 :249 –251[CrossRef][Medline]
6. Bonham JR, Guthrie P, Downing M, et al. The allopurinol load test lacks specificity for primary urea cycle defects but may indicate unrecognized mitochondrial disease. J Inherit Metab Dis.1999; 22 :174 –184[CrossRef][Web of Science][Medline]

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In Reply.—

We appreciate Dr Riudor and colleagues’ comments about reference values to evaluate orotate and orotidine responses to the allopurinol test. The article by Arranz et al¹ shows results for orotidine values in children and adults as peak values but not as true reference ranges with mean ± standard deviation. We did not include a citation of their most recent article² because at the time of manuscript submission it was not yet electronically available. Overall, the report that increased orotidine response yielded better diagnostic specificity than orotate will surely help to improve the interpretation of the results of the allopurinol challenge. However, a positive allopurinol response with increased orotidine excretion will not provide an in vivo estimate of phenotypic severity. In addition, because abnormal allopurinol challenge tests can be seen in mitochondrial defects with few other biochemical alterations, it is still necessary to pursue an integrated approach to the diagnosis and prospective management of partial OTC deficiency. Our article³ described the direct measurement of in vivo urea cycle activity in conjunction with (and not excluding) biochemical parameters to aid in the diagnosis and prospective management of our patient. In this particular case, the allopurinol testing was performed while the proband was 36 months old and on a 1.7 g/kg/day protein-restricted diet. This value, which is well above the 1985 WHO/FAO/UNU safe level of protein intake, does not represent an excessive dietary protein restriction that could have accounted for the lack of increase of orotate excretion. The severe phenotype of this patient including hyperammonemia, feeding intolerance, and developmental delay also would not have predicted a normal orotate excretion during the allopurinol challenge. Her initial degree of orotic aciduria prompted an evaluation for a possible mitochondrial disorder because, as it has been pointed out by Bonham et al,⁴ there is a possible secondary impairment of ureagenesis in these diseases. Our patient underwent a muscle biopsy and the diagnostic consideration of mitochondrial myopathy was considered unlikely given that the patient had normal histochemistry, electron microscopy, and respiratory chain enzyme activity. As we stated in our article,³ it is difficult a priori to distinguish those partial OTCD patients who are going to respond to medical therapy from those who are going to fail medical management using only in vitro biochemical data. Even increased orotidinuria may not provide by itself the most accurate assessment of altered urea cycle activity at steady state. Hence, both in vitro measures and in vivo measures are needed to support a rational, evidence-based approach for the diagnosis and prospective (surgical vs medical) management in partial OTCD patients.

Fernando Scaglia, MD^*
Qiping Zheng, PhD^*
William E. O’Brien, PhD^*
Joseph Henry, BS^*
Judy Rosenberger, BS^,
Brendan Lee, MD, PhD^*
* Department of Molecular and Human Genetics
Department of Pediatrics
Children’s Nutrition Research Center
Baylor College of Medicine
Houston, TX 77030

Peter Reeds, PhD
Department of Animal Sciences and Non-ruminant Nutrition
University of Illinois
Urbana, IL 61801

FOOTNOTES

Deceased.

REFERENCES

1. Arranz JA, Riudor E, Rodés M, et al. Optimization of allopurinol challenge: sample purification, protein intake control and the use of orotidine response as a discriminative variable improve performance of the test of diagnosing ornithine carbamoyltransferase deficiency. Clin Chem.1999; 45 :995 –1001
2. Riudor E, Arranz JA, Rodés M, Rubio V, Sentis M, Burlina A. Influence of dose and age on the response of the allopurinol test for ornithine carbamoyltransferase deficiency in control infants. J Inherit Metab Dis.2000; 23 :662 –668
3. Scaglia F, Zheng Q, O’Brien WE, et al. An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency. Pediatrics.2002; 109 :150 –152
4. Bonham JR, Guthrie P, Downing M, et al. The allopurinol load test lacks specificity for primary urea cycle defects but may indicate unrecognized mitochondrial disease. J Inherit Metab Dis.1999; 22 :174 –184

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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics

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