Creatine replacement therapy in guanidineoacetate methyltransferase deficiency, a novel inborn error of metabolism

doi:10.1016/S0140-6736(96)04116-5

The Lancet

Volume 348, Issue 9030, 21 September 1996, Pages 789-790

https://doi.org/10.1016/S0140-6736(96)04116-5 Get rights and content

Summary

Background

The creatine/creatine-phosphate system is essential for the storage and transmission of phosphate-bound energy in muscle and brain. In infants, inefficiency or failure of this metabolic pathway can impair the development of motor control and mentation.

Methods

We studied and treated an infant with extrapyramidal signs who was shown–by assay for urinary creatinine and by analysis of brain metabolites with use of nuclear magnetic resonance spectra–to have depletion of body and brain creatine, due to inborn deficiency of guanidinoacetate methyltransferase (GAMT).

Findings

Long-term oral administration of creatine-monohydrate (4-8 g per day) to this index patient resulted in substantial clinical improvement, disappearance of magnetic resonance (MRI) signal abnormalities in the globus pallidus, and normalisation of slow background activity on the electroencephalogram (EEG). During the 25-month treatment period, both brain and total body creatine concentrations became normal.

Interpretation

Oral creatine replacement has proved to be effective in one child with an inborn error of GAMT. It may well be effective in the treatment of other disorders of creatine synthesis.

Introduction

The creatine/creatine-phosphate system plays an important role in the storage and transmission of phosphate-bound energy. Creatine is mainly synthesised in the liver and the pancreas, in reactions catalysed by arginine:glycine amidinotransferase and guanidinoacetate methyltransferase (GAMT). It is utilised in muscle and brain, where the pool of creatine/creatine-phosphate, with creatine kinase and ATP/ADP, provide a high-energy phosphate buffering system. Creatine is converted by non-enzymatic cyclisation to creatinine, with a daily catabolisation of 1-5% of body creatine. For maintenance of the body pool, 1-2 g (7-6-15-2 mmol) of creatine- equivalent to the daily urinary excretion of creatinine — must be provided from endogenous synthesis or from dietary sources.¹ In 1994 we described a child with a newly recognised inborn error of creatine metabolism,² and we now describe his response to creatine therapy.

Section snippets

Patient and methods

In an infant (age 22 months) with progressive extrapyramidal signs and severe developmental delay, systemic depletion of body creatine was indicated by low urinary creatinine excretion, and by the absence of brain creatine and creatine-phosphate signals in proton and phosphorus magnetic resonance in vivo spectra.2 Simultaneous accumulation of guanidinoacetate, the immediate precursor of creatine, suggested an inborn error of creatine synthesis, which was confirmed by defective GAMT activity in

Results

After 2 months on creatine replacement the infant's extrapyramidal signs had resolved and he had begun to make substantial developmental progress. Before therapy he had been unable to roll over and to hold his head. Now, he had learned to sit and to crawl. At age 48 months he was able to pull himself up to standing position, was eager to experience his surroundings, enjoyed the company of other children, and understood simple phrases. At age 4-5 years he is able to walk with support and can

Discussion

There are two known transport processes for the cellular uptake of creatine in the brain: a high-capacity, saturable, sodium-dependent process, and a low-capacity, sodium-independent, diffusion process.⁸ Poor accessibility of extracellular creatine to cell types such as neurones that lack the high capacity transport process⁹ might explain the observation of a biphasic pattern for replenishment of the brain creatine pool in our patient.

GAMT deficiency is the first human model of systemic

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Influence of oral creatine supplementation on muscle torque during repeated bouts of maximal voluntary exercise in man
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Creatine supplementation research fails to support the theoretical basis for an effect on cognition: Evidence from a systematic review
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Creatine supplementation has been put forward as a possible aid to cognition, particularly for vegans, vegetarians, the elderly, sleep deprived and hypoxic individuals. However, previous narrative reviews have only provided limited support for these claims. This is despite the fact that research has shown that creatine supplementation can induce increased brain concentrations of creatine, albeit to a limited extent. We carried out a systematic review to examine the current state of affairs. The review supported claims that creatine supplementation can increases brain creatine content but also demonstrated somewhat equivocal results for effects on cognition. It does, however, provide evidence to suggest that more research is required with stressed populations, as supplementation does appear to significantly affect brain content. Issues with research design, especially supplementation regimens, need to be addressed. Future research must include measurements of creatine brain content.
Current and potential new treatment strategies for creatine deficiency syndromes
2022, Molecular Genetics and Metabolism
Creatine deficiency syndromes (CDS) are inherited metabolic disorders caused by mutations in GATM, GAMT and SLC6A8 and mainly affect central nervous system (CNS). AGAT- and GAMT-deficient patients lack the functional brain endogenous creatine (Cr) synthesis pathway but express the Cr transporter SLC6A8 at blood-brain barrier (BBB), and can thus be treated by oral supplementation of high doses of Cr. For Cr transporter deficiency (SLC6A8 deficiency or CTD), current treatment strategies benefit one-third of patients. However, as their phenotype is not completely reversed, and for the other two-thirds of CTD patients, the development of novel more effective therapies is needed. This article aims to review the current knowledge on Cr metabolism and CDS clinical aspects, highlighting their current treatment possibilities and the most recent research perspectives on CDS potential therapeutics designed, in particular, to bring new options for the treatment of CTD.
Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials
2018, Experimental Gerontology
Citation Excerpt :
The importance of creatine in brain function is suggested by the presence of creatine kinase (CK) isoforms in multiple brain areas including the cerebellum, hippocampus, pontine reticular formation, red nucleus, cerebral cortex and choroid plexus (Kaldis et al., 1996; Friedman and Roberts, 1994) (see also the brain distribution of CKMT1A (Anon, 2018a); and the Allen Human Brain Atlas (Anon, 2018b)). On the other hand, inborn errors of metabolism that result in deficiency of creatine transporter or creatine itself are characterized by cognitive and neurodevelopmental defects (Stöckler et al., 1996; Salomons et al., 2003), which may be reversed by creatine supplementation (Stöckler et al., 1996). In addition, experimental deletion of CK in rodents results in learning problems (Jost et al., 2002).
Creatine is a supplement used by sportsmen to increase athletic performance by improving energy supply to muscle tissues. It is also an essential brain compound and some hypothesize that it aids cognition by improving energy supply and neuroprotection. The aim of this systematic review is to investigate the effects of oral creatine administration on cognitive function in healthy individuals.
A search of multiple electronic databases was performed for the identification of randomized clinical trials (RCTs) examining the cognitive effects of oral creatine supplementation in healthy individuals.
Six studies (281 individuals) met our inclusion criteria. Generally, there was evidence that short term memory and intelligence/reasoning may be improved by creatine administration. Regarding other cognitive domains, such as long-term memory, spatial memory, memory scanning, attention, executive function, response inhibition, word fluency, reaction time and mental fatigue, the results were conflicting. Performance on cognitive tasks stayed unchanged in young individuals. Vegetarians responded better than meat-eaters in memory tasks but for other cognitive domains no differences were observed.
Oral creatine administration may improve short-term memory and intelligence/reasoning of healthy individuals but its effect on other cognitive domains remains unclear. Findings suggest potential benefit for aging and stressed individuals. Since creatine is safe, future studies should include larger sample sizes. It is imperative that creatine should be tested on patients with dementias or cognitive impairment.
A pilot study to estimate incidence of guanidinoacetate methyltransferase deficiency in newborns by direct sequencing of the GAMT gene
2016, Gene
Citation Excerpt :
Clinical features include global developmental delay (GDD), hypotonia and seizures in infants and intellectual disability, movement disorder, epilepsy and behavioral problems in children (Mercimek-Mahmutoglu et al., 2009; Viau et al., 2013). Treatment consists of high dose creatine to replenish cerebral creatine deficiency and ornithine supplementation and arginine restricted diet to decrease neurotoxic GAA accumulation in the central nervous system (CNS) (Stöckler et al., 1996a; Schulze et al., 2001; Mercimek-Mahmutoglu et al., 2006, 2009). The current treatment is successful to treat epilepsy and the movement disorder, but not GDD or intellectual disability occurring prior to diagnosis (Stöckler et al., 1996a; Schulze et al., 2001; Mercimek-Mahmutoglu et al., 2006, 2009, 2012a, 2014a; Viau et al., 2013; Stockler-Ipsiroglu et al., 2014).
GAMT deficiency is an autosomal recessive disorder of creatine biosynthesis causing developmental delays or intellectual disability in untreated patients as a result of irreversible brain damage occurring prior to diagnosis. Normal neurodevelopmental outcome has been reported in patients treated from neonatal period highlighting the importance of early treatment.
Five hundred anonymized newborns from the National Newborn Screening Program of The Netherlands were included into this pilot study. Direct sequencing of the coding region of the GAMT gene was applied following DNA extraction. The disease causing nature of novel missense variants in the GAMT gene was studied by overexpression studies. GAA and creatine was measured in blood dot spots.
We detected two carriers, one with a known common (c.327G>A) and one with a novel mutation (c.297_309dup (p.Arg105Glyfs*) in the GAMT gene. The estimated incidence of GAMT deficiency was 1:250,000. We also detected five novel missense variants. Overexpression of these variants in GAMT deficient fibroblasts did restore GAMT activity and thus all were considered rare, but not disease causing variants including the c.131G>T (p.Arg44Leu) variant. Interestingly, this variant was predicted to be pathogenic by in silico analysis. The variants were included in the Leiden Open Variation Database (LOVD) database (www.LOVD.nl/GAMT). The average GAA level was 1.14 μmol/L ± 0.45 standard deviations. The average creatine level was 408 μmol/L ± 106. The average GAA/creatine ratio was 2.94 ± 0.136.
The estimated incidence of GAMT deficiency is 1:250,000 newborns based on our pilot study. The newborn screening for GAMT deficiency should be implemented to identify patients at the asymptomatic stage to achieve normal neurodevelopmental outcome for this treatable neurometabolic disease. Biochemical investigations including GAA, creatine and GAMT enzyme activity measurements are essential to confirm the diagnosis of GAMT deficiency. According to availability, all missense variants can be assessed functionally, as in silico prediction analysis of missense variants is not sufficient to confirm the pathogenicity of missense variants.
Creatine biosynthesis and transport in health and disease
2015, Biochimie
Creatine is physiologically provided equally by diet and by endogenous synthesis from arginine and glycine with successive involvements of arginine glycine amidinotransferase [AGAT] and guanidinoacetate methyl transferase [GAMT]. A specific plasma membrane transporter, creatine transporter [CRTR] (SLC6A8), further enables cells to incorporate creatine and through uptake of its precursor, guanidinoacetate, also directly contributes to creatine biosynthesis. Breakthrough in the role of creatine has arisen from studies on creatine deficiency disorders. Primary creatine disorders are inherited as autosomal recessive (mutations affecting GATM [for glycine-amidinotransferase, mitochondrial]) and GAMT genes) or X-linked (SLC6A8 gene) traits. They have highlighted the role of creatine in brain functions altered in patients (global developmental delay, intellectual disability, behavioral disorders). Creatine modulates GABAergic and glutamatergic cerebral pathways, presynaptic CRTR (SLC6A8) ensuring re-uptake of synaptic creatine. Secondary creatine disorders, addressing other genes, have stressed the extraordinary imbrication of creatine metabolism with many other cellular pathways. This high dependence on multiple pathways supports creatine as a cellular sensor, to cell methylation and energy status. Creatine biosynthesis consumes 40% of methyl groups produced as S-adenosylmethionine, and creatine uptake is controlled by AMP activated protein kinase, a ubiquitous sensor of energy depletion. Today, creatine is considered as a potential sensor of cell methylation and energy status, a neurotransmitter influencing key (GABAergic and glutamatergic) CNS neurotransmission, therapeutic agent with anaplerotic properties (towards creatine kinases [creatine–creatine phosphate cycle] and creatine neurotransmission), energetic and antioxidant compound (benefits in degenerative diseases through protection against energy depletion and oxidant species) with osmolyte behavior (retention of water by muscle). This review encompasses all these aspects by providing an illustrated metabolic account for brain and body creatine in health and disease, an algorithm to diagnose metabolic and gene bases of primary and secondary creatine deficiencies, and a metabolic exploration by ¹H-MRS assessment of cerebral creatine levels and response to therapeutic measures.
Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes
2023, Turkish Archives of Pediatrics

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Early ReportCreatine replacement therapy in guanidineoacetate methyltransferase deficiency, a novel inborn error of metabolism

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patient and methods

Results

Discussion

Clin Chim Acta

Creatine: biosynthesis, regulation, and function

Adv Enzymol

Creatine deficiency in the brain: a new, treatable inborn error of metabolism

Pediatr Res

Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man

Am JHum Genet

Influence of oral creatine supplementation on muscle torque during repeated bouts of maximal voluntary exercise in man

Clin Sci

Early Report
Creatine replacement therapy in guanidineoacetate methyltransferase deficiency, a novel inborn error of metabolism