This study has shown that newborn screening for OAT deficiency may be feasible by determination of the proline/citrulline ratio. Although only two cases are reported, there is a clear disease marker ratio (Fig. ), and data have been compared with >450,000 control subjects. Ornithine concentration at birth (case 1) was within normal limits. This is in accordance with our previous study (Cleary et al. 2005
) and with the study of Wang et al. who showed that ornithine rises to abnormally high levels at 3–4 months after birth (Wang et al. 1996
), well past the time that the newborn screening blood spot is collected. The increased proline/citrulline ratio also supports the hypothesis that the net flux in the OAT reaction in neonates is in the direction of ornithine synthesis rather than ornithine degradation.
OAT deficiency is a genetic condition that involves the choroid and retina. Since it has been hypothesized that direct ornithine toxicity to retinal cells, particularly to the RPE (retinal pigment epithelium), is involved in the earliest stages of the pathophysiology of OAT deficiency and since ornithine is not increased in the neonatal period, this unique feature of nature (reversibility of the enzyme) gives us a broad time window for effective therapeutical intervention. It is plausible that screening for OAT deficiency and early treatment may not only prevent irreversible damage of the eyes but may also prevent neurological impairment as hyperammonemia can be avoided. Insight in the natural history of this disease may help to further develop therapeutical trials.
Because there is effective treatment for patients with an OAT deficiency (Kaiser-Kupfer et al. 2004
; Weleber and Kennaway 1981
), screening for this disease fully meets the recommendations by the American College of Medical Genetics (Watson et al. 2006
). In addition, OAT deficiency has been found in several ethnic groups around the world with a particularly high incidence in Finland with an estimated frequency of about 1 in 50,000 (Heinanen et al. 1998
). This makes OAT deficiency, at least in Finland, a more common disorder than many of the diseases currently screened for. The implementation of newborn screening for OAT deficiency would not require new technologies and/or markers since proline and citrulline are already included in several newborn screening programs in the United States.
The differential diagnosis of neonatal hyperammonemia should include OAT deficiency. Biochemical diagnosis may be challenging since hyperornithinemia may be absent (case 1). However, the proline/citrulline ratio in plasma of our patient was strongly increased. In addition, retrospective plasma analyses of the sibling with proven OAT deficiency (at the age of 71 days) also revealed an increased proline/citrulline ratio. Currently, there are ten patients with OAT deficiency known in the Netherlands [data provided by the Dutch Diagnosis Registration Metabolic Diseases (DDRMD)]. The vast majority of these cases were diagnosed after childhood (>16 years of age). The rarity of the neonatal OAT presentation and/or the failure to correctly diagnose young patients limits the number of patients available to study. Reports with proven neonatal OAT deficiency (Champion et al. 2002
; Webster et al. 1999
) are scarce and do not report on proline concentrations in plasma. From this study, we suggest that calculating proline/citrulline ratio in plasma may help to adequately diagnose OAT deficiency in the neonatal period especially since enzyme analysis is cumbersome and over 50 different mutations (most point mutations) have been reported (Brody et al. 1992
It is unknown at this time how reliably the minority of patients (<5%) which are responsive to therapy with vitamin B6 could be detected when screening for OAT deficiency.
The present finding shows that gyrate atrophy due to OAT deficiency may be one of the few hereditary degenerative retinopathies, which may be prevented if this disorder is included in newborn screening and that such screening is likely to be feasible, practical, and ethically acceptable.