Guanidino compounds in guanidinoacetate methyltransferase deficiency, a new inborn error of creatine synthesis

doi:10.1016/S0026-0495(97)90215-8

Metabolism

Volume 46, Issue 10, October 1997, Pages 1189-1193

https://doi.org/10.1016/S0026-0495(97)90215-8 Get rights and content

Abstract

The first inborn error of creatine metabolism (guanidinoacetate methyltransferase [GAMT] deficiency) has recently been recognized in an infant with progressive extrapyramidal movement disorder. The diagnosis was established by creatine deficiency in the brain as detected by in vivo magnetic resonance spectroscopy and by defective GAMT activity and two mutant GAMT alleles in a liver biopsy. Here, we describe characteristic guanidino-compound patterns in body fluids of this index patient with GAMT deficiency. Concentrations of guanidino compounds (creatine and guanidinoacetate) and creatinine were determined by cation-exchange chromatography and by color reaction with picric acid, respectively, in urine, plasma, and cerebrospinal fluid (CSF). Creatine concentrations were low in plasma, CSF, and urine while guanidinoacetate concentrations were markedly elevated. Daily urinary creatinine excretion was low, whereas creatinine concentrations in random urine samples were not always discriminative. Guanidino compound to creatinine ratios were not informative, as low creatinine concentrations resulted in high values for all determined compounds. During a 22-month period of oral treatment with creatine-monohydrate, plasma and urinary creatine concentrations increased to levels high above the normal range, and daily urinary creatinine excretion—proportional to total body creatine—became normalized. Guanidinoacetate concentrations remained elevated even during additional substitution of ornithine, which inhibits guanidinoacetate synthesis in vitro. The results indicate that GAMT deficiency can be recognized noninvasively by determination of guanidino compounds (creatine and guanidinoacetate) in body fluids. A deficiency of creatine, but not an accumulation of guanidinoacetate, can be corrected by treatment with oral creatine substitution.

References (21)

GL Cantoni et al.
Enzymatic mechanism of creatine synthesis
J Biol Chem
(1954)
S Stöckler et al.
Creatine replacement therapy in guanidinoacetate methyltransferase deficiency, a novel inborn error of metabolism
Lancet
(1996)
B Marescau et al.
Guanidino compounds in serum, urine, liver, kidney, and brain of man and some ureotelic animals
Metabolism
(1992)
DA Applegarth et al.
Creatinine excretion in children and the usefulness of creatinine equivalents in amino acid chromatography
Clin Chim Acta
(1968)
I Sipilä
Inhibition of arginine-glycine amidinotransferase by ornithine: A possible mechanism for the muscular and chorioretinal atrophies in gyrate atrophy of the choroid and retina with hyperornithinemia
Biochim Biophys Acta
(1980)
H Borsook et al.
The hydrolysis of phosphocreatine and the origin of urinary creatinine
J Biol Chem
(1947)
DM McGuire et al.
Repression of rat kidney l-arginine:glycine amidinotransferase synthesis by creatine at a pretranslational level
J Biol Chem
(1984)
Y Watanabe et al.
Synthesis of neuroactive guanidino compounds by rat kidney l-arginine:glycine amidinotransferase
Life Sci
(1994)
MM Daly
Guanidinoacetate methyltransferase activityin tissues and cultured cells
Arch Biochem Biophys
(1985)
JF Van Pilsum et al.
Determination of creatine, creatinine, arginine, guanidinoacetic acid, guanidine, and methylguanidine in biological fluids
J Biol Chem
(1956)

There are more references available in the full text version of this article.

Cited by (91)

Gene therapy for guanidinoacetate methyltransferase deficiency restores cerebral and myocardial creatine while resolving behavioral abnormalities
2022, Molecular Therapy Methods and Clinical Development
Citation Excerpt :
Despite optimal present-day medical therapy, including protein restriction and ornithine supplementation, chronically elevated GAA levels have plagued some children and are likely responsible for persistent seizures, autistic features, and other cognitive abnormalities.5,18 While it has been hypothesized that GAA interacts with GABAA receptors,4,28 the exact mechanism of brain injury has not been completely elucidated; both diminished creatine and elevated GAA likely contribute to the neurological phenotype.9,29 Here, we sought to explore and have demonstrated a gene therapy approach for GAMT deficiency that allows for normal and stable plasma creatine levels with the control of plasma GAA.
Creatine deficiency disorders are inborn errors of creatine metabolism, an energy homeostasis molecule. One of these, guanidinoacetate N-methyltransferase (GAMT) deficiency, has clinical characteristics that include features of autism, self-mutilation, intellectual disability, and seizures, with approximately 40% having a disorder of movement; failure to thrive can also be a component. Along with low creatine levels, guanidinoacetic acid (GAA) toxicity has been implicated in the pathophysiology of the disorder. Present-day therapy with oral creatine to control GAA lacks efficacy; seizures can persist. Dietary management and pharmacological ornithine treatment are challenging. Using an AAV-based gene therapy approach to express human codon-optimized GAMT in hepatocytes, in situ hybridization, and immunostaining, we demonstrated pan-hepatic GAMT expression. Serial collection of blood demonstrated a marked early and sustained reduction of GAA with normalization of plasma creatine; urinary GAA levels also markedly declined. The terminal time point demonstrated marked improvement in cerebral and myocardial creatine levels. In conjunction with the biochemical findings, treated mice gained weight to nearly match their wild-type littermates, while behavioral studies demonstrated resolution of abnormalities; PET-CT imaging demonstrated improvement in brain metabolism. In conclusion, a gene therapy approach can result in long-term normalization of GAA with increased creatine in guanidinoacetate N-methyltransferase deficiency and at the same time resolves the behavioral phenotype in a murine model of the disorder. These findings have important implications for the development of a new therapy for this abnormality of creatine metabolism.
Cross-talk between guanidinoacetate neurotoxicity, memory and possible neuroprotective role of creatine
2019, Biochimica et Biophysica Acta - Molecular Basis of Disease
Guanidinoacetate Methyltransferase deficiency is an inborn error of metabolism that results in decreased creatine and increased guanidinoacetate (GAA) levels. Patients present neurological symptoms whose mechanisms are unclear. We investigated the effects of an intrastriatal administration of 10 μM of GAA (0.02 nmol/striatum) on energy metabolism, redox state, inflammation, glutamate homeostasis, and activities/immunocontents of acetylcholinesterase and Na⁺,K⁺-ATPase, as well as on memory acquisition. The neuroprotective role of creatine was also investigated. Male Wistar rats were pretreated with creatine (50 mg/kg) or saline for 7 days underwenting stereotactic surgery. Forty-eight hours after surgery, the animals (then sixty-days-old) were divided into groups: Control, GAA, GAA + Creatine, and Creatine. Experiments were performed 30 min after intrastriatal infusion. GAA decreased SDH, complexes II and IV activities, and ATP levels, but had no effect on mitochondrial mass/membrane potential. Creatine totally prevented SDH and complex II, and partially prevented COX and ATP alterations. GAA increased dichlorofluorescein levels and decreased superoxide dismutase and catalase activities. Creatine only prevented catalase and dichlorofluorescein alterations. GAA increased cytokines, nitrites levels and acetylcholinesterase activity, but not its immunocontent. Creatine prevented such effects, except nitrite levels. GAA decreased glutamate uptake, but had no effect on the immunocontent of its transporters. GAA decreased Na⁺,K⁺-ATPase activity and increased the immunocontent of its α3 subunit. The performance on the novel object recognition task was also impaired. Creatine partially prevented the changes in glutamate uptake and Na⁺,K⁺-ATPase activity, and completely prevented the memory impairment. This study helps to elucidate the protective effects of creatine against the damage caused by GAA.
Magnetic Resonance Spectroscopy and its Clinical Applications: A Review
2017, Journal of Medical Imaging and Radiation Sciences
Citation Excerpt :
In contrast, some situations such as gliosis in white matter may increase its concentration slightly. The complete lack of Cr signal implies a deficiency in Cr production, as in guanidinoacetate methyltransferase imperfection [59–62] or in L-arginine glycine amidinotransferase shortcoming [63], or to a Cr transporter failure [64]. With short TE, some other signals can be observed.
In vivo NMR spectroscopy is known as magnetic resonance spectroscopy (MRS). MRS has been applied as both a research and a clinical tool in order to detect visible or nonvisible abnormalities. The adaptability of MRS allows a technique that can probe a wide variety of metabolic uses across different tissues. Although MRS is mostly applied for brain tissue, it can be used for detection, localization, staging, tumour aggressiveness evaluation, and tumour response assessment of breast, prostate, hepatic, and other cancers. In this article, the medical applications of MRS in the brain, including tumours, neural and psychiatric disorder studies, breast, prostate, hepatic, gastrointestinal, and genitourinary investigations have been reviewed.
La spectroscopie RMN in vivo est appelée spectroscopie par résonance magnétique (SRM) en clinique. La SRM a été utilisée autant comme outil de recherche que comme outil clinique pour la détection des anomalies visibles ou non. L’adaptabilité de la SRM en fait une technique qui peut examiner une grande variété d’utilisations métaboliques dans différents tissus. Bien que la SRM soit principalement utilisée pour les tissus cérébraux, elle peut être utilisée pour la détection, la localisation, la détermination du stade, l’évaluation du caractère agressif d’une tumeur et l’évaluation de la réponse tumorale dans le cancer du sein, de la prostate, du foie et d’autres organes. Cette étude, après un bref examen des fondements de la SRM, passe en revue les applications médicales de la SRM dans le cerveau, incluant les tumeurs, les applications médicales de la SRM, incluant les cancers et l’étude des troubles neurologiques et psychiatriques, ainsi que les examens du sein, de la prostate, du foie et des systèmes gastro-intestinal et génito-urinaire.
The Biochemistry of Creatine
2013, Magnetic Resonance Spectroscopy: Tools for Neuroscience Research and Emerging Clinical Applications
Creatine is a naturally occurring metabolite that is synthesized endogenously and absorbed from the diet. This chapter explores the biochemistry of creatine, its role in the creatine kinase/phosphocreatine energy shuttle and support of buffering, transport, and regulation of cellular energetics. Dysfunctional brain creatine metabolism occurs in creatine deficiency syndromes and other neurological disorders outlined in this chapter. The therapeutic potential of creatine supplementation to improve neural energy metabolism and the role of MRS in examining creatine energetics are discussed.
Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency
2009, Molecular Genetics and Metabolism
Guanidinoacetate methyltransferase (GAMT) deficiency is a disorder of creatine biosynthesis, characterized by excessive amounts of guanidinoacetate in body fluids, deficiency of creatine in the brain, and presence of mutations in the GAMT gene. We present here 8 new patients with GAMT deficiency along with their clinical, biochemical and molecular data. The age at diagnosis of our patients ranges from 0 to 14 years. The age of onset of seizures usually ranges from infancy to 3 years. However, one of our patients developed seizures at age 5; progressing to myoclonic epilepsy at age 8 years and another patient has not developed seizures at age 17 years. Five novel mutations were identified: c.37ins26 (p.G13PfsX38), c.403G > T (p.D135Y), c.507_521dup15 (p.C169_S173dup), c.402C > G (p.Y134X) and c.610_611delAGinsGAA (p.R204EfsX63). Six patients had the c.327G > A (last nucleotide of exon 2) splice-site mutation which suggests that this is one of the most common mutations in the GAMT gene, second only to the known Portuguese founder mutation, c.59G > C (p.W20S). Our data suggests that the clinical presentation can be variable and the diagnosis may be overlooked due to unawareness of this disorder. Therefore, GAMT deficiency should be considered in the differential diagnosis of progressive myoclonic epilepsy as well as in unexplained developmental delay or regression with dystonia, even if the patient has no history of seizures. As more patients are reported, the prevalence of GAMT deficiency will become known and guidelines for prenatal diagnosis, newborn screening, presymptomatic testing and treatment, will need to be formulated.
Liquid chromatographic analysis of guanidino compounds using furoin as a new fluorogenic reagent
2008, Journal of Pharmaceutical and Biomedical Analysis
Furoin, a benzoin analogue, was examined as novel fluorogenic reagent for the selective and sensitive LC determination of various guanidines after pre-column derivatization. The derivatization reaction was carried out at 100 °C for 5 min to give adducts that were separated on a Phenomenex Synergi MAX-RP column and detected at λ_em = 410 nm with λ_ex = 325 nm. The reagent showed to be useful both for determining together arginine (Arg) and creatine (CT) in dietary supplements under elution isocratic conditions and for the simultaneous analysis of a variety of guanidines in biological samples (human plasma and urine) under elution gradient conditions. The detection limits ranged from 7 to 25 fmol. Recovery studies showed good results for all determined guanidino compounds (85.6–106.2%; R.S.D. = 1.1–6.2%).

View all citing articles on Scopus

View full text

Guanidino compounds in guanidinoacetate methyltransferase deficiency, a new inborn error of creatine synthesis

Abstract

J Biol Chem

Lancet

Metabolism

Clin Chim Acta

Biochim Biophys Acta

J Biol Chem

J Biol Chem

Life Sci

Arch Biochem Biophys

J Biol Chem