Creatine metabolism in combined methylmalonic aciduria and homocystinuria disease revisited.код для вставкиСкачать
GlakoSmithKline, and TEVA, and speaking honorarium from Novartis. Dr Ahlskog receives no financial support from industry. Dr Factor has received research funding from TEVA Neuroscience and Schering Plough, legal fees from Boehringer Ingelheim, and speaking honoraria from TEVA. Dr Suchowersky has received research funding from Solvay Pharma. Dr Reich has received research funding from Cephalon and has served on a speaking bureau for Teva. 2. Pahwa R, Factor SA, Lyons KE, et al. Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:983–995. 3. National Institute of Clinical Excellence (NICE). Parkinson’s disease guidelines 2006. Available at: www.nice.org.uk DOI: 10.1002/ana.21690 Editor Note: We thank Dr. Weiner and colleagues for raising important questions related to editorial policies at the Annals of Neurology. The Annals does not accept any manuscript without peer review. Accordingly, each article published in the “Unresolved Issues in Parkinson’s Disease” supplement underwent the same submission, vetting, peer review, and conflict of interest standards applied to all content under consideration for publication in the Annals. References 1. Hauser SL, Johnson SC. Scripts for science: a new wrinkle on academic ties with industry. Ann Neurol 2008;64:A13–A15. 2. Schapira AH, Olanow CW. Drug selection and timing of initiation of treatment in early Parkinson’s disease. Ann Neurol 2008;64(suppl):547–555. 3. Miyasaki JM, Martin W, Suchowersky O, et al. Practice parameter: initiation of treatment for Parkinson’s disease: an evidence based review. Neurology 2002;58:11–17. DOI: 10.1002/ana.21667 Reply Anthony H. Schapira, MD, DSc, FRCP, FMedSci1 and C. Warren Olanow, MD, FRCPC2 We were disappointed to read the letter by Weiner and colleagues, which contains not only errors of fact but also of judgment. Our peer-reviewed article produced a clear and comprehensive survey of treatments available for early Parkinson disease, as was demanded by the title, and included a balanced account of the advantages and disadvantages of the drugs included. Emphasis was placed and repeated recurrently on the need to “individualize” treatment for patients. Far from relegating levodopa to a second-line therapy, we highlighted that this drug remains the most potent oral dopaminergic agent and is one that virtually all patients will require at some point. Our suggestion that monoamine oxidase B inhibitors or dopamine agonists are suitable for early therapy for the type of patients described and for the reasons given is in harmony with evidence-based reviews, national practice guidelines, and common clinical practice in movement disorders centers.1–3 Weiner and colleagues should not assume or insinuate a pejorative view simply because others might hold a different opinion to their own! Institute of Neurology and National Hospital for Neurology and Neurosurgery, University College London, London, UK; and 2Mount Sinai Medical School, New York, NY. References 1. Goetz CG, Poewe W, Rascol O, Sampaio C. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson’s disease: 2001 to 2004. Mov Disord 2005;20:523–539. Creatine Metabolism in Combined Methylmalonic Aciduria and Homocystinuria Disease Revisited Daria Younessi, B.S., Kathryn Moseley, MS, RD, and Shoji Yano, MD, PhD Bodamer and colleagues1 have reported a pathomechanism where an increased plasma guanidinoacetate (GAA) concentration may contribute to the neurological phenotype seen in patients with the combined methylmalonic aciduria and homocystinuria (cblC) disorder of intracellular cobalamin metabolism. The authors note that this phenotype overlaps with that seen in patients with a deficiency in creatine synthesis caused by a defective guanidinoacetate methyltransferase (GAMT). The authors suggest that patients with cblC disease may also have an impairment of the creatine biosynthesis pathway via two possible mechanisms: (1) A diminished pool of plasma S-adenosylmethionine (SAM), which provides labile methyl groups as a substrate for GAMT, can lead to decreased GAMT activity; and (2) plasma S-adenosylhomocysteine (SAH), a product of GAMT, can feedback to directly inhibit GAMT activity. Metabolites of the creatine synthesis pathway were measured in five patients with cblC disease. The authors report significantly increased GAA and homocysteine levels, and normal methionine and creatine levels. SAH was not significantly increased, but was in the high-normal range. There were no significant deviations in SAM or the SAM/SAH ratio from normal. The phenotype of these five patients includes developmental delay, seizures, microcephaly, hypotonia, and nystagmus.2 A significantly increased GAA level in cblC disease was a novel finding used to potentially explain the overlapping neurological phenotypes seen in patients with cblC disease and GAMT deficiency, because GAA is increased in GAMT deficiency. In light of these findings, we did a retrospective chart review of four patients with established early-onset cblC disease. Anthropometric, phenotypic, and metabolic data are reported in the Table. All four patients presented with the same phenotypic features as reported in the Bodamer series.2 Furthermore, we report increased homocysteine, a lownormal methionine, a normal GAA, and low-normal creatine levels in all four patients. The normal GAA level found in our patients contradicts the results that Bodamer and colleagues1 reported and raises questions regarding their conclusions. SAM or SAH levels were not measured in our patients because this is not clinically indicated in the routine management of patients with cblC disease. Bodamer implicates GAA, through its interaction with GABAA, as one of three possible sources of neurotoxicity to the developing brain. Two other sources include a decreased activity of methyltransferases required for neurotransmitter metabolism and an increased homocysteine level. Based on our findings, it is unlikely that GAA is responsible for the neuro- Annals of Neurology Vol 65 No 4 April 2009 481 Table. Anthropometric, Clinical, and Metabolic Data of Patients with Combined Methylmalonic Aciduria and Homocystinuria Characteristics Patient No. Age (yr) Sex Age at onset of first symptoms Current height (cm)/weight (kg) Protein intake, gm/kg/day Developmental delay Seizures Microcephaly Hypotonia Optic atrophy Nystagmus Homocysteine, mol/L (0–12) Methionine, mol/L (14–37) Guanidinoacetate, mol/L (0.4–3.7) Creatine, mol/L (20–110) 1 2 3 4 29 F ⬍6 mo 136/44 10 M ⬍6 mo 127/25 3 M 18 days 90/12 6 F 60 days 108/20 1.1 ⫹ ⫹ ⫹ ⫹ ⫹ ⫺ 50, 73 24, 22 3.3 ⫹ ⫺ ⫹ ⫹ ⫹ ⫺ 49, 45 13, 53 1.7 ⫹ ⫹ (hydrocephalus) ⫹ ⫹ ⫹ 110, 96 17 1.2 0.6 ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ 71, 83 12, 14, 13 0.8, 2 0.3 0.7 30 11, 48 39 24 logical phenotype seen in patients with cblC disease. Until further research demonstrates the true role of GAA in these patients, plasma GAA level should not be considered as a marker of metabolic control or as a potential therapeutic target. The pathological mechanisms responsible for the phenotype seen in patients with cblC remains unknown. Department of Pediatrics, Genetics Division, Keck School of Medicine of the University of Southern California, Los Angeles, CA Potential conflict of interest: Nothing to report. References 1. Bodamer OA, Sahoo T, Beaudet AL, et al. Creatine metabolism in combined methylmalonic aciduria and homocystinuria. Ann Neurol 2005;57:557–560. 2. Smith DL, Bodamer OA. Practical management of combined methylmalonic aciduria and homocystinuria. J Child Neurol 2002;17:353–356. DOI: 10.1002/ana.21571 Reply Olaf A. Bodamer, MD, FACMG,1 and Fernando Scaglia, MD, FACMG2 We read with great interest Dr Younessi and colleagues’1 report on creatine metabolism in combined methylmalonic aciduria and homocystinuria (cblC) disease. Although the findings of normal plasma guanidinoacetate (GAA) levels in their cblC patients appear to contradict our previous results,2 there may be several lines of explanation for this apparent discrepancy. Plasma GAA levels in our patients were increased 482 Annals of Neurology Vol 65 No 4 April 2009 throughout the whole study period, regardless of nutritional intake or timing of sampling,2 and were analyzed using isotope dilution tandem mass spectrometry as reported previously.3 Plasma GAA levels may depend on daily creatine intake as has been shown for patients with guanidinoacetate methyltransferase deficiency, an inborn error of creatine metabolism.4 Our patients were on a protein-restricted diet (0.7–1.5gm/kg/ day) without supplementation of amino acid mixtures, reflecting a lower creatine intake, although creatine intake was not formally assessed in them. Changes in dietary intake of creatine or timing of blood sampling may also be reflected in the GAA and creatine levels of Dr Younessi’s Patient 2, who shows marked fluctuation between measurements. We agree with Dr Younessi and coworkers1 that GAA may not be an ideal marker for metabolic control in cblC, but may instead reflect short-term changes in creatine metabolism. In fact, low to low-normal creatine plasma levels have been observed in our patients regardless of their protein intake, time of sampling, or both. Dr Younessi has confirmed this finding in her patients, which may lead to hypotheses that low creatine levels may indeed contribute to the neurological phenotype and the extent of homocystinuria observed in cblC disease. Moreover, additional studies on a larger cohort of patients with cblC are urgently needed to investigate the effects of creatine supplementation on homocysteine levels and the neurological phenotype observed in these patients. University Children’s Hospital, Paracelsus Medical University Salzburg, Salzburg, Austria, and 2Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX Potential conflict of interest: Nothing to report.