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Creatine metabolism in combined methylmalonic aciduria and homocystinuria disease revisited.

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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.
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