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L-dopa and selegiline for tyrosine hydroxylase deficiency
THE JOURNAL OF PEDIATRICS
LETTERS
VOLUME 138, NUMBER 3
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tive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol 1997;19:417-28. Grandjean P. Mercury risks: controversy or just uncertainty? Public Health Rep 1999;114:512-5. Steuerwald U, Weibe P, Jørgensen PJ, Bjerve K, Brock J, Heinzow B, et al. Maternal seafood diet, methylmercury exposure, and neonatal neurologic function. J Pediatr 2000;136:599-605. Myers GJ, Davidson PW, Cox C, Shamlaye CF, Tanner MA, Choisy O, et al. Neurodevelopmental outcomes of Seychellois children sixty-six months after in utero exposure to methylmercury from a maternal fish diet: pilot study. Neurotoxicology 1995;16:639-52. Myers GJ, Davidson PW, Shamlaye CF, Axtell CD, Cemichiari E, Choisy O, et al. Effects of prenatal methylmercury exposure from a high fish diet on developmental milestones in the Seychelles Child Development Study. Neurotoxicology 1997;18:819-29. Davidson PW, Myers GJ, Cox C, Axtell C, Shamlaye C, Sloane-Reeves J, et al. Effects of prenatal and postnatal methylmercury exposure from fish consumption on neurodevelopment: outcomes at 66 months of age in the Seychelles Child Development Study. JAMA 1998;280:701-7.
Reply To the Editor: In commenting on the two reports in The Journal of Pediatrics examining the effects of mercury exposure of the fetus and newborn,1 we were unconvinced that these reports suggested the need for immediate action and were hopeful that new research and reassessments would continue to emerge. Dr Aschner’s letter highlights additional points important in clarifying the conflicting findings of the Seychelles and Faeroe Island studies while suggesting that regulatory agencies reassess these cohorts. In fact, this past summer additional guidance did emerge, though it is still not the final piece of the puzzle. The Environmental Protection Agency (EPA) had been directed by the United States Congress in 1999 to commission an independent study on the toxicologic effects of methylmercury, which would include recommendations for a scientifically appropriate exposure reference
dose (RfD). The report by the National Academy of Sciences (NAS),2 published in July of 2000, concluded that until new data are available, the Faeroe Islands study is the most appropriate one from which to derive the RfD. The committee also concluded that there is a need to harmonize efforts to establish a common scientific basis for exposure guidance and reduce differences among regulatory agencies. While the NAS report contributes to the available discussion in the area of mercury health risk assessment, it is only part of an ongoing process to collect and analyze human epidemiologic data. In addition, the report raised questions that need to be investigated before a reevaluation of “safe” levels of methylmercury can occur. As we pointed out in our editorial, the 96month data from the Seychelles Cohort exposed to only methylmercury through daily fish consumption should be published within the next year. These data are critical to any health assessment for methylmercury, as they include the results of the same neuropsychologic tests for which positive results were reported in the Faeroe Islands study. It should also serve to further assess any role of persistent organic pollutants (such as PCBs, DDT, and other neurotoxic organochlorines) in the findings in the Faeroe Islands. While a single health guidance value for methylmercury ingestion might initially seem to be ideal, several important points must be kept in mind. Health guidance values are, by definition of both the Agency for Toxic Substances and Disease Registry (ATSDR) and EPA and as acknowledged by NAS, surrounded by an area of uncertainty. Such health guidance values are not precise values or threshold levels above which toxicity will necessarily occur at any given level. The current difference between the EPA oral reference dose (RfD = 0.1 µg/kg/d) for methylmercury and the ATSDR chronic oral minimal risk level (MRL = 0.3 µg/kg/d), as well as the FDA and World Health Organization comparable health guidance values corresponding to a tolerable daily intake of approximately 0.4 µg/kg/d, is extremely small and well within the area of uncertainty of those values. To insist, as a matter of policy, that all government organizations have one,
and only one, health guidance value implies a level of precision that all agree does not exist. Scientific debate has resulted in the advanced state of knowledge in the biomedical field that exists today. Thus research on the potential health effects of exposure to thimerosal is continuing, as are investigations into methylmercury exposure. Results must be disseminated to the public and scientific communities as soon as they have been properly evaluated: in this we concur with the plea by Dr Aschner. Robert Pless, MD National Immunization Program Centers for Disease Control Atlanta, GA 30333 John F. Risher, PhD Division of Toxicology Agency for Toxic Substances and Disease Registry Atlanta, GA 30333 9/35/111811 doi:10.1067/mpd.2001.111811
REFERENCES 1. Pless R, Risher J. Mercury, infant neurodevelopment, and vaccination. J Pediatr 2000;136:571-3. 2. Committee on the Toxicological Effects of Methylmercury, Board on Environmental Studies and Toxicology, National Research Council. Toxicological effects of methylmercury. National Academy Press; 2000.
L-dopa and selegiline for tyrosine hydroxylase deficiency To the Editor: Dionisi-Vici et al1 reported a patient with severe tyrosine hydroxylase deficiency who responded well to a combined treatment with low-dose L-dopa and selegiline after poor response to Ldopa alone. We had a similar experience with a 10-year-old girl with severe tyrosine hydroxylase deficiency. Diagnosis was confirmed by biochemical and molecular genetic investigations. At 7 years of age, the girl had rigidity, no voluntary movements, mask face, and oculogyric crises. Treatment with L-dopa was started but could not be increased beyond 40 mg 451
LETTERS
THE JOURNAL OF PEDIATRICS MARCH 2001
(2.5 mg/kg daily) because intolerable dyskinesia developed. During 20 months of low-dose L-dopa treatment, the girl became more alert and developed more vocalization and facial motility and some voluntary movements (turning and lifting the head from supine). Afterwards, selegiline was added to the treatment (2.5 mg per day). During the following 17 months, voluntary movements improved (grasping, turning from supine to prone, rolling on the floor, speaking of first words). The oculogyric crises decreased in severity and frequency. L-dopa, however, could be increased to 70 mg (3.4 mg/kg daily) during the same time. Our experience seems to confirm that a combined treatment with low-dose L-dopa and selegiline is superior to treatment with L-dopa alone. L-dopa may not be well tolerated in patients with severe tyrosine hydroxylase deficiency when the treatment is started. It may still be a useful drug in
the long run when the dose is very slowly increased. Concerning treatment control, serial measurement of prolactin levels for 24 hours seems to be important.2 In our patient, during several single measurements, serum prolactin levels showed marked fluctuations that could not be attributed to changes in therapy. Serial measurements over 24 hours showed marked fluctuations during the day, which became less during the combined treatment with L-dopa and selegiline, but high nighttime prolactin levels persisted. Martin Häussler, MD Frühdiagnosezentrum Würzburg Center for Developmental Disorders and Disabilities D-97080 Würzburg Germany Georg F. Hoffmann, MD University Children’s Hospital Im Neuenheimer Feld 150
D-69120 Heidelberg Germany Ron A. Wevers, PhD UMC St Radboud Laboratory of Pediatrics and Neurology 6525 GC Nijmegen The Netherlands 9/35/110776 doi:10.1067/mpd.2001.110776
REFERENCES 1. Dionisi-Vici C, Hoffmann GF, Leuzzi V, Hoffken H, Bräutigam C, Rizzo C, et al. Tyrosine hydroxylase deficiency with severe clinical course: clinical and biochemical investigations and optimization of therapy. J Pediatr 2000; 136:560-2. 2. Birnbacher R, Scheibenreiter S, Blau N, Bieglmayer C, Frisch H, Waldhauser F. Hyperprolactinemia, a tool in treatment control of tetrahydrobiopterin deficiency: endocrine studies in an affected girl. Pediatr Res 1998; 43:427-77.
Access to The Journal of Pediatrics Online is reserved for print subscribers! Full-text access to The Journal of Pediatrics Online is available for all print subscribers. To activate your individual online subscription, please visit The Journal of Pediatrics Online, point your browser to http://www.mosby.com/jpeds, follow the prompts to activate online access here, and follow the instructions. To activate your account, you will need your subscriber account number, which you can find on your mailing label (note: the number of digits in your subscriber account number varies from 6 to 10). See the example below in which the subscriber account number has been circled: Sample mailing label
This is your subscription account number
**************************3-DIGIT 001 SJ P1 FEB00 J009 C: 1 1234567-89 U 05/00 Q: 1 J. H. DOE, MD 531 MAIN ST CENTER CITY, NY 10001-001
Personal subscriptions to The Journal of Pediatrics Online are for individual use only and may not be transferred. Use of The Journal of Pediatrics Online is subject to agreement to the terms and conditions as indicated online.
452
LETTERS
VOLUME 138, NUMBER 3
6.
7.
8.
9.
10.
tive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol 1997;19:417-28. Grandjean P. Mercury risks: controversy or just uncertainty? Public Health Rep 1999;114:512-5. Steuerwald U, Weibe P, Jørgensen PJ, Bjerve K, Brock J, Heinzow B, et al. Maternal seafood diet, methylmercury exposure, and neonatal neurologic function. J Pediatr 2000;136:599-605. Myers GJ, Davidson PW, Cox C, Shamlaye CF, Tanner MA, Choisy O, et al. Neurodevelopmental outcomes of Seychellois children sixty-six months after in utero exposure to methylmercury from a maternal fish diet: pilot study. Neurotoxicology 1995;16:639-52. Myers GJ, Davidson PW, Shamlaye CF, Axtell CD, Cemichiari E, Choisy O, et al. Effects of prenatal methylmercury exposure from a high fish diet on developmental milestones in the Seychelles Child Development Study. Neurotoxicology 1997;18:819-29. Davidson PW, Myers GJ, Cox C, Axtell C, Shamlaye C, Sloane-Reeves J, et al. Effects of prenatal and postnatal methylmercury exposure from fish consumption on neurodevelopment: outcomes at 66 months of age in the Seychelles Child Development Study. JAMA 1998;280:701-7.
Reply To the Editor: In commenting on the two reports in The Journal of Pediatrics examining the effects of mercury exposure of the fetus and newborn,1 we were unconvinced that these reports suggested the need for immediate action and were hopeful that new research and reassessments would continue to emerge. Dr Aschner’s letter highlights additional points important in clarifying the conflicting findings of the Seychelles and Faeroe Island studies while suggesting that regulatory agencies reassess these cohorts. In fact, this past summer additional guidance did emerge, though it is still not the final piece of the puzzle. The Environmental Protection Agency (EPA) had been directed by the United States Congress in 1999 to commission an independent study on the toxicologic effects of methylmercury, which would include recommendations for a scientifically appropriate exposure reference
dose (RfD). The report by the National Academy of Sciences (NAS),2 published in July of 2000, concluded that until new data are available, the Faeroe Islands study is the most appropriate one from which to derive the RfD. The committee also concluded that there is a need to harmonize efforts to establish a common scientific basis for exposure guidance and reduce differences among regulatory agencies. While the NAS report contributes to the available discussion in the area of mercury health risk assessment, it is only part of an ongoing process to collect and analyze human epidemiologic data. In addition, the report raised questions that need to be investigated before a reevaluation of “safe” levels of methylmercury can occur. As we pointed out in our editorial, the 96month data from the Seychelles Cohort exposed to only methylmercury through daily fish consumption should be published within the next year. These data are critical to any health assessment for methylmercury, as they include the results of the same neuropsychologic tests for which positive results were reported in the Faeroe Islands study. It should also serve to further assess any role of persistent organic pollutants (such as PCBs, DDT, and other neurotoxic organochlorines) in the findings in the Faeroe Islands. While a single health guidance value for methylmercury ingestion might initially seem to be ideal, several important points must be kept in mind. Health guidance values are, by definition of both the Agency for Toxic Substances and Disease Registry (ATSDR) and EPA and as acknowledged by NAS, surrounded by an area of uncertainty. Such health guidance values are not precise values or threshold levels above which toxicity will necessarily occur at any given level. The current difference between the EPA oral reference dose (RfD = 0.1 µg/kg/d) for methylmercury and the ATSDR chronic oral minimal risk level (MRL = 0.3 µg/kg/d), as well as the FDA and World Health Organization comparable health guidance values corresponding to a tolerable daily intake of approximately 0.4 µg/kg/d, is extremely small and well within the area of uncertainty of those values. To insist, as a matter of policy, that all government organizations have one,
and only one, health guidance value implies a level of precision that all agree does not exist. Scientific debate has resulted in the advanced state of knowledge in the biomedical field that exists today. Thus research on the potential health effects of exposure to thimerosal is continuing, as are investigations into methylmercury exposure. Results must be disseminated to the public and scientific communities as soon as they have been properly evaluated: in this we concur with the plea by Dr Aschner. Robert Pless, MD National Immunization Program Centers for Disease Control Atlanta, GA 30333 John F. Risher, PhD Division of Toxicology Agency for Toxic Substances and Disease Registry Atlanta, GA 30333 9/35/111811 doi:10.1067/mpd.2001.111811
REFERENCES 1. Pless R, Risher J. Mercury, infant neurodevelopment, and vaccination. J Pediatr 2000;136:571-3. 2. Committee on the Toxicological Effects of Methylmercury, Board on Environmental Studies and Toxicology, National Research Council. Toxicological effects of methylmercury. National Academy Press; 2000.
L-dopa and selegiline for tyrosine hydroxylase deficiency To the Editor: Dionisi-Vici et al1 reported a patient with severe tyrosine hydroxylase deficiency who responded well to a combined treatment with low-dose L-dopa and selegiline after poor response to Ldopa alone. We had a similar experience with a 10-year-old girl with severe tyrosine hydroxylase deficiency. Diagnosis was confirmed by biochemical and molecular genetic investigations. At 7 years of age, the girl had rigidity, no voluntary movements, mask face, and oculogyric crises. Treatment with L-dopa was started but could not be increased beyond 40 mg 451
LETTERS
THE JOURNAL OF PEDIATRICS MARCH 2001
(2.5 mg/kg daily) because intolerable dyskinesia developed. During 20 months of low-dose L-dopa treatment, the girl became more alert and developed more vocalization and facial motility and some voluntary movements (turning and lifting the head from supine). Afterwards, selegiline was added to the treatment (2.5 mg per day). During the following 17 months, voluntary movements improved (grasping, turning from supine to prone, rolling on the floor, speaking of first words). The oculogyric crises decreased in severity and frequency. L-dopa, however, could be increased to 70 mg (3.4 mg/kg daily) during the same time. Our experience seems to confirm that a combined treatment with low-dose L-dopa and selegiline is superior to treatment with L-dopa alone. L-dopa may not be well tolerated in patients with severe tyrosine hydroxylase deficiency when the treatment is started. It may still be a useful drug in
the long run when the dose is very slowly increased. Concerning treatment control, serial measurement of prolactin levels for 24 hours seems to be important.2 In our patient, during several single measurements, serum prolactin levels showed marked fluctuations that could not be attributed to changes in therapy. Serial measurements over 24 hours showed marked fluctuations during the day, which became less during the combined treatment with L-dopa and selegiline, but high nighttime prolactin levels persisted. Martin Häussler, MD Frühdiagnosezentrum Würzburg Center for Developmental Disorders and Disabilities D-97080 Würzburg Germany Georg F. Hoffmann, MD University Children’s Hospital Im Neuenheimer Feld 150
D-69120 Heidelberg Germany Ron A. Wevers, PhD UMC St Radboud Laboratory of Pediatrics and Neurology 6525 GC Nijmegen The Netherlands 9/35/110776 doi:10.1067/mpd.2001.110776
REFERENCES 1. Dionisi-Vici C, Hoffmann GF, Leuzzi V, Hoffken H, Bräutigam C, Rizzo C, et al. Tyrosine hydroxylase deficiency with severe clinical course: clinical and biochemical investigations and optimization of therapy. J Pediatr 2000; 136:560-2. 2. Birnbacher R, Scheibenreiter S, Blau N, Bieglmayer C, Frisch H, Waldhauser F. Hyperprolactinemia, a tool in treatment control of tetrahydrobiopterin deficiency: endocrine studies in an affected girl. Pediatr Res 1998; 43:427-77.
Access to The Journal of Pediatrics Online is reserved for print subscribers! Full-text access to The Journal of Pediatrics Online is available for all print subscribers. To activate your individual online subscription, please visit The Journal of Pediatrics Online, point your browser to http://www.mosby.com/jpeds, follow the prompts to activate online access here, and follow the instructions. To activate your account, you will need your subscriber account number, which you can find on your mailing label (note: the number of digits in your subscriber account number varies from 6 to 10). See the example below in which the subscriber account number has been circled: Sample mailing label
This is your subscription account number
**************************3-DIGIT 001 SJ P1 FEB00 J009 C: 1 1234567-89 U 05/00 Q: 1 J. H. DOE, MD 531 MAIN ST CENTER CITY, NY 10001-001
Personal subscriptions to The Journal of Pediatrics Online are for individual use only and may not be transferred. Use of The Journal of Pediatrics Online is subject to agreement to the terms and conditions as indicated online.
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