Physiol Rev. 2000 Jul;80(3):1107-213.
Creatine and creatinine metabolism.
Wyss M, Kaddurah-Daouk R.
F. Hoffmann-La Roche, Vitamins and Fine Chemicals Division, Basel, Switzerland.
[ Free full text ] (excellent review article)

The goal of this review is to present a comprehensive survey of the many intriguing facets of creatine (Cr) and creatinine metabolism, encompassing the pathways and regulation of Cr biosynthesis and degradation, species and tissue distribution of the enzymes and metabolites involved, and of the inherent implications for physiology and human pathology. Very recently, a series of new discoveries have been made that are bound to have distinguished implications for bioenergetics, physiology, human pathology, and clinical diagnosis and that suggest that deregulation of the creatine kinase (CK) system is associated with a variety of diseases. Disturbances of the CK system have been observed in muscle, brain, cardiac, and renal diseases as well as in cancer. On the other hand, Cr and Cr analogs such as cyclocreatine were found to have antitumor, antiviral, and antidiabetic effects and to protect tissues from hypoxic, ischemic, neurodegenerative, or muscle damage. Oral Cr ingestion is used in sports as an ergogenic aid, and some data suggest that Cr and creatinine may be precursors of food mutagens and uremic toxins. These findings are discussed in depth, the interrelationships are outlined, and all is put into a broader context to provide a more detailed understanding of the biological functions of Cr and of the CK system.

From the full text article:

In mammals, the highest concentrations of Cr and PCr and the highest specific CK activities are found in skeletal muscle. Consequently, it is thought that the CK/PCr/Cr system plays an important role in the energy metabolism of this tissue. In accordance with this concept, a multitude of experimental findings suggest a close relationship between disturbances of Cr metabolism and various muscle diseases.

On one hand, manipulations of the CK/PCr/Cr system were shown to induce myopathic changes. 1) Skeletal muscle of transgenic mice lacking MM-CK and/or sarcomeric Mi-CK displayed structural and functional alterations such as impaired burst activity, decreased rate constants for changes in muscle tension, and abnormal Ca2+ handling (see sect. VIID). The facts that these mice survive and reproduce, and that the phenotype is milder than previously suspected, may indicate that other systems (e.g., adenylate kinase) take over in part the function of CK (see sect. VIID). 2) With the caveat that the reagent may not be sufficiently specific, injection of the CK inhibitor 2,4-dinitrofluorobenzene (DNFB) into the aorta of rats caused a metabolic myopathy characterized by spontaneous muscle contractures in the hindlimbs and by selective destruction of type I fibers in both soleus and gastrocnemius muscles (233). 3) When fed to experimental animals, the Cr analog GPA competes with Cr for uptake into muscle and therefore results in considerable depletion of the muscle stores of Cr and PCr. In line with the fact that GPA and its phosphorylated counterpart PGPA represent poor CK substrates, a variety of pathological changes have been observed in skeletal muscles of these animals (see sect. VIIIB) (741, 1125).

On the other hand, many (neuro)muscular diseases with different underlying defects are accompanied by a variety of disturbances in Cr metabolism. Examples are Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), facioscapulohumeral dystrophy, limb-girdle muscular dystrophy, myotonic dystrophy, spinal muscle atrophy, amyotrophic lateral sclerosis, myasthenia gravis, poliomyelitis anterior, myositis, or diabetic myopathy, to name just a few (for references, see Refs. 639, 826, 955, 1002, 1123). Common findings are increased Cr concentrations in serum and urine; stimulation of creatinuria by oral supplementation with Gly or Cr; decreased urinary Crn excretion; depressed muscle levels of Cr, PCr, Pi, glycogen, and ATP; increased serum CK activities; as well as an increased MB-/MM-CK ratio in skeletal muscle, with the latter suggesting induction of B-CK expression in regenerating muscle fibers. In addition, a 67-86% decrease in Mi-CK activity or mRNA levels was reported for chickens with hereditary muscular dystrophy and rats with diabetic myopathy (585, 955). Depending on the particular muscle disease, these disturbances are more or less pronounced. Unfortunately, no sufficiently detailed studies have been published in recent years, whereas the older investigations were performed mostly with rather nonspecific analytical methods. Therefore, the above-mentioned findings await corroboration and expansion, which will hopefully allow us to unravel potential causal links between individual muscle diseases and disturbances of Cr metabolism.

In DMD, increased plasma membrane fragility and subsequent leakage of cytosolic components due to dystrophin deficiency are generally accepted to be the primary defects. The muscle concentrations of Cr, PCr, and ATP, the ATP/ADP, PCr/Cr, and PCr/ATP ratios, as well as the phosphorylation potential are significantly decreased, whereas the calculated ADP concentration and intracellular pH are increased (88, 143, 211, 472). Conversely, serum [Cr] is increased, resulting in creatinuria, in considerably reduced tolerance toward orally administered Cr, and, very likely due to competition of Cr and GAA for reabsorption in the kidney, in elevated urinary excretion of GAA. The total bodily Cr pool is reduced because of both muscle wasting and a reduced Cr concentration in the remaining muscle mass, with the consequence that Crn production and urinary Crn excretion are largely decreased. By use of radioactively labeled Cr, Cr turnover was shown to be increased in DMD patients relative to controls, with half times for the decrease in isotope content of 18.9 ± 5.1 and 39.8 ± 2.6 days, respectively (245). This latter finding may be due either to impaired Cr uptake into muscle (57) or to an impaired ability of muscle to retain Cr.

Most probably due to leakage of the plasma membrane and to continued necrosis of immature muscle fibers, both the total CK activity and the proportion of MB-CK in serum are dramatically increased (79, 190, 222, 755). Finally, disturbances of ion gradients across the plasma membrane were observed in skeletal muscle from DMD patients. The muscle concentration of Na+ as well as the free intracellular [Ca2+] are increased, whereas the muscle levels of K+ and Pi are decreased. In serum, on the other hand, [K+], [Ca2+], and [Pi] are increased, whereas [Na+] and [Cl] are decreased (see Refs. 143, 199, 755).

Disturbances very similar to those seen in DMD were observed in mdx mice that display the same primary defect as DMD patients, namely, dystrophin deficiency, and in other dystrophic animal strains (see Refs. 143, 199, 201-203, 790, 799). Additionally, in skeletal muscles of mdx mice, the resting membrane potential was shown to be "decreased" from 70 to 59 mV (see Ref. 199). Remarkably, all pathological changes, i.e., muscle fiber necrosis as well as the disturbances in membrane permeability, in Cr and high-energy phosphate metabolism, and in serum CK activities, were not evident in mdx mice at birth, but only developed after 2-6 wk of life (202, 799, 982). Consequently, dystrophin deficiency alone does not seem to be sufficient to induce muscle damage, thus calling for other factors that may act in conjunction with dystrophin deficiency to bring about plasma membrane damage and muscle cell necrosis.

Two hypotheses may be put forward to explain how disturbances in Cr metabolism may contribute to the progression of DMD and of other muscle diseases (see also Ref. 1123). 1) Loike et al. (571) have shown that increasing concentrations of extracellular Cr downregulate Cr transport activity in rat and human myoblasts and myotubes. Similarly, Cr supplementation of the diet downregulates Cr transporter expression in rat skeletal muscle (317). In muscle diseases that are characterized by decreased tissue levels of Cr and PCr, the muscle should respond to this deficit by an increased Cr uptake across the plasma membrane. However, because of the chronically increased serum concentration of Cr that is observed in many muscle diseases, the Cr transport activity may even be depressed, thereby resulting in a further depletion of the muscle stores of Cr and PCr. This progressive Cr depletion would likely compromise the energy metabolism of muscle and would make the muscle cells more vulnerable to (membrane) damage upon further use. 2) Let us assume that the changes in membrane permeability and the concomitant disturbances of ion gradients across the plasma membrane represent early events in pathological muscle fiber degeneration. Because the Cr transporter is driven by the electrochemical gradients of Na+ and Cl across the plasma membrane (see sect. IVB), the consequences would be a diminished rate of Cr uptake into muscle and partial depletion of the intracellular high-energy phosphate stores which, in turn, may further deteriorate ion homeostasis. If either of these purported vicious circles 1 or 2 were in fact operative, oral Cr supplementation may represent a promising strategy to alleviate the clinical symptoms and/or to slow or even halt disease progression. If only hypothesis 2 is correct, continuous supplementation with Cr is indicated. If, however, hypothesis 1 is valid, intermittent short-term supplementation with high doses of Cr is expected to provide superior results. In support of these hypotheses, preincubation of primary mdx muscle cell cultures for 6-12 days with 20 mM Cr prohibited the increase in intracellular Ca2+ concentration induced by either high extracellular [Ca2+] or hyposmotic stress (790). Furthermore, Cr enhanced mdx myotube formation and survival.

Patients with chronic renal failure commonly present with muscle weakness and display disturbances in muscular Cr metabolism (see Refs. 93, 716). Histochemical studies revealed type II muscle fiber atrophy. In skeletal muscle of uremic patients, [ATP], [PCr], and [ATP]/[Pi] are significantly decreased both before and after hemodialysis, whereas [Cr] and [Pi] may either be unchanged or increased. Disturbances in ion homeostasis similar to those observed in DMD were also reported for uremic myopathy (99) and may be due, in part, to depressed Na+-K+-ATPase activity (648, 950). Nevertheless, the benefit of oral Cr supplementation for uremic subjects has to be questioned, since the plasma level of Cr most likely is normal, and since an increase in the total body Cr pool would be paralleled by a further increase in the plasma concentration of Crn which, in turn, is a precursor of the potent nephrotoxin methylguanidine (see sect. IXH).

In gyrate atrophy of the choroid and retina, the disturbances of Cr metabolism seem to be brought about by a different series of events (Fig. 11). Gyrate atrophy is an autosomal recessive tapetoretinal dystrophy. The clinical phenotype is mainly limited to the eye, beginning at 5-9 yr of age with night blindness, myopia, and progressive constriction of the visual fields. By age 20-40 yr, the patients are practically blind. In addition to the retinal degeneration, type II muscle fiber atrophy, an increase in the proportion of type I muscle fibers with age, as well as the formation of tubular aggregates in affected type II fibers were observed in vastus lateralis muscle of gyrate atrophy patients (900). The underlying primary defect is a deficiency in mitochondrial matrix L-ornithine:2-oxo-acid aminotransferase (OAT; EC 2.6.1.13), the major enzyme catabolizing ornithine (see Refs. 95, 398, 792). Because of this deficiency, ornithine accumulates in the body, with the plasma concentration being raised 10- to 20-fold (450-1,200 µM vs. ~40-60 µM in controls) (897, 899). Ornithine, in turn, inhibits AGAT (Ki = 253 µM) (897), the rate-limiting enzyme for Cr biosynthesis, and therefore slows production of both GAA and Cr (899). Accordingly, [GAA] is decreased in plasma and urine by a factor of 5 and 20, respectively. Similarly, [Cr] is reduced in plasma, urine, cerebrospinal fluid, erythrocytes, and vastus lateralis muscle by a factor of 2-6 (901).

The effects of oral Cr supplementation (0.75-1.5 g/day) have been tested in 13 patients with gyrate atrophy for periods of 12 mo (898) and 5 yr (1052). Cr supplementation caused the disappearance of tubular aggregates in type II muscle fibers as well as an increase in the diameter of type II muscle fibers from 34 to 49 µm. In contrast, there was no significant increase in the diameter of type I fibers. In the few patients that discontinued Cr supplementation, the pathological muscle changes promptly reappeared. Somewhat less promising results were obtained with regard to eye pathology. Although during the first 12 mo of therapy no further constriction of the visual fields became apparent, the 5-yr follow-up study demonstrated continued deterioration of visual function in all of the patients. The velocity of the progression varied considerably between individuals and was, in general, rapid in young patients and slow at more advanced stages. It remains to be established whether the apparent discrepancy between the effects of Cr supplementation on muscle and eye pathology are due to limited permeability of the blood-eye barrier for Cr.

The finding of hyperornithinemias that are not accompanied by gyrate atrophy casts doubt on a potential causal link between disturbances in Cr metabolism on one hand and muscle and eye pathology on the other hand in gyrate atrophy of the choroid and retina (see Refs. 189, 350, 898). Unfortunately, it has not been established so far whether Cr biosynthesis is depressed in all of these hyperornithinemias. For example, it might be anticipated that hyperornithinemia is caused by a defect of ornithine transport across the mitochondrial membranes (234). In this case, the intramitochondrial concentration of ornithine and therefore also the rates of GAA and Cr formation may be normal. As an alternative, it has been proposed that the clinical symptoms of gyrate atrophy are caused by proline deficiency rather than Cr deficiency. Only by further investigation will it be possible to discriminate between these and further possibilities.

Mitochondrial (encephalo-) myopathiese.g., chronic progressive external ophthalmoplegia (CPEO); mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS); and Kearns-Sayre syndromedeserve special attention. They commonly display a phenotype of so-called ragged-red fibers that are characterized by an accumulation of abnormal and enlarged mitochondria as well as by the occurrence of highly ordered crystal-like inclusions in the intermembrane space of these mitochondria (see Refs. 463, 751, 760, 936, 1046, 1079). Remarkably, investigation by enzyme cytochemistry, immunoelectron microscopy, and optical diffraction of electron micrographs demonstrated that Mi-CK represents the major constituent of these intramitochondrial inclusions (906, 936; see also Refs. 281, 1124, 1125). There is evidence that in muscles displaying ragged-red fibers and/or Mi-CK-containing intramitochondrial inclusions, the specific Mi-CK activity relative to both protein content and citrate synthase activity is increased (89, 906). Further hints as to the pathogenesis of the inclusions come from a comparison with two additional sets of experiments. Cr depletion through feeding of rats with GPA caused the appearance of mitochondrial intermembrane inclusions immunoreactive for sarcomeric Mi-CK in skeletal muscle and heart (719, 720). Similarly, in cultured adult rat cardiomyocytes, large, cylindrical mitochondria displaying crystal-like inclusions that are highly enriched in Mi-CK appear when the cells are cultured in a Cr-free medium, or when the intracellular Cr stores are depleted through incubation with GPA (228). The large mitochondria and the Mi-CK crystals rapidly disappear when the cardiomyocytes are resupplied with external Cr. Therefore, it seems plausible to postulate that in both the rat cardiomyocyte model and in human mitochondrial myopathies, an initial depletion of intracellular Cr pools causes compensatory upregulation of Mi-CK expression. Although, at first, overexpression of Mi-CK may be a physiological adaptation process, it becomes pathological when, at a given limit, Mi-CK starts to aggregate and forms the highly ordered intramitochondrial inclusions. Inherent in this hypothesis are the postulates that in the respective myopathies, the muscle concentrations of Cr, PCr, and total Cr are decreased; that Cr supplementation reverses crystal formation (see Ref. 502); and that Cr supplementation may alleviate some of the clinical symptoms. In fact, in a 25-yr-old male MELAS patient, Cr supplementation resulted in improved muscle strength and endurance, reduced headache, better appetite, and an improved general well-being (323). Similarly, a randomized, controlled trial of Cr supplementation in patients with mitochondrial myopathies (mostly MELAS) revealed increased strength in high-intensity anaerobic and aerobic type activities, but no apparent effects on lower intensity aerobic activities (986). It will be interesting to investigate whether intramitochondrial inclusions seen in other myopathies are also enriched in Mi-CK, e.g., in ischemic myopathy (464), HIV-associated or zidovudine-induced myopathy (557, 667), congenital myopathy (783), oculopharyngeal muscular dystrophy (1116), inclusion body myositis (31, 732), hyperthyroid myopathy (567), mitochondrial myopathy of transgenic mice lacking the heart/muscle isoform of the adenine nucleotide translocator (300), in the diaphragm of patients with chronic obstructive pulmonary disease (566), in cultured human muscle fibers overexpressing the -amyloid precursor protein (31), or in myocytes of isolated rat hearts exposed to oxygen radicals (352). Remarkably, ragged-red fibers of patients with mitochondrial encephalomyopathies were recently shown to overexpress the neuronal and endothelial isoenzymes of NO synthase (NOS) in the subsarcolemmal region (728). Therefore, it might be interesting to test the hypothesis that ragged-red fibers are exposed to oxidative stress, that Mi-CK (which is sensitive to oxidative inactivation; see sect. VIID) is inactivated by NO or peroxynitrite, and that the modified Mi-CK displays an increased tendency to form crystalline aggregates in subsarcolemmal mitochondria. This interpretation would be in line with a similar conclusion by O'Gorman et al. (720).

In patients with muscle hypotonotrophy of the thigh due to knee osteoarticular lesions, intravenous injection of 1 g PCr daily during the rehabilitation phase significantly accelerated recovery of muscle strength and power peak torque (847). After 30 days of treatment, the difference between PCr-treated and nontreated patients was 13% in muscle flexion and 18% in extension. Intramuscular injection of PCr in the rat before 4 h of ischemia followed by 30 min of reperfusion prevented the increase in membrane ion conductance and the loss of excitability of the muscle fibers upon reperfusion (1016).

Finally, recent gene localization studies revealed interesting relationships. The gene for the Cr transporter is localized on human chromosome Xq28, a locus to which several (neuro)muscular disorders have been mapped, for example, Emery-Dreifuss muscular dystrophy, Barth syndrome, or myotubular myopathy (see Refs. 309, 317, 691). Similarly, the gene for M-CK on human chromosome 19q13.2-19q13.3 is one of the most tightly linked markers of myotonic dystrophy (101, 506). The genes for ubiquitous Mi-CK and AGAT on human chromosome 15q15.3 and for sarcomeric Mi-CK on human chromosome 5q13.3 are in close proximity to the genes for limb-girdle muscular dystrophy type 2A (LGMD2A) and for proximal spinal muscular atrophy, respectively (260, 805, 940). So far, however, evidence is lacking that mutations in the Cr transporter, CK, or AGAT genes may be the cause of the respective muscle diseases (see, e.g., Ref. 42).

To conclude, a wealth of experimental evidence suggests that muscle diseases and disturbances of Cr metabolism are related. However, little is known so far about the causal links, either direct or indirect, between the disturbances of Cr metabolism on one hand and the primary defects or the clinical expression of the disease on the other hand. Future studies should not only provide the missing links but may also hint at alternative therapeutic approaches for muscle diseases. Possibly, oral Cr supplementation may turn out to be a simple and practicable way for alleviating at least some of the clinical symptoms in a broad range of muscle diseases. Just very recently, Tarnopolsky and Martin (985) provided experimental support for this hypothesis, in that Cr supplementation in fact increased handgrip, dorsiflexion, and knee extensor strength in more than 80 patients with neuromuscular disease (mitochondrial cytopathies, neuropathic disorders, dystrophies/congenital myopathies, inflammatory myopathies, and miscellaneous conditions), with no obvious differences between subgroups.

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Total CK activity and Cr content are lower in brain than in skeletal muscle or heart. Even though it might be concluded that, therefore, the CK system plays a less prominent role in brain physiology, there is ample evidence for close correlations between Cr metabolism and CK function on one hand and proper brain function on the other hand. In chicken and rat brain, the B-CK, M-CK, and Mi-CK isoforms were localized specifically to cell types for which high and fluctuating energy demands can be inferred (e.g., cerebellar Bergmann glial cells, Purkinje neurons, and glomerular structures) (450, 1081). Substantial evidence supports a direct coupling of CK (or ArgK) with growth cone migration (1087), with Na+-K+-ATPase and neurotransmitter release, as well as an involvement of CK in the maintenance of membrane potentials, calcium homeostasis, and restoration of ion gradients before and after depolarization (1081). CK and Cr were also suggested to participate in inhibition of mitochondrial permeability transition (64, 717), which is thought to be linked to both apoptotic and necrotic neuronal cell death.

Although the situation may be somewhat different in the rat and piglet brain (375, 1102), the PCr and total Cr concentrations as well as the flux through the CK reaction are significantly higher in gray than in white matter of the human brain (105, 573, 594, 784, 1086). These findings parallel the higher rate of ATP turnover in cerebral gray compared with white matter. Furthermore, electroencephalogram (EEG) activity increases considerably in the first 2-3 wk of life in the rat. Large increases in the response of rat cortical slice respiration to electrical stimulation, hyperthermia, or increased extracellular [KCl] occur in particular between 12 and 17 days of age (see Ref. 377). Interestingly, in this same developmental interval, the proportion of Mi-CK and the flux through the CK reaction increase by a factor of 4 (377, 1018). On the other hand, both CK activity and flux through the CK reaction were shown to be decreased in aged rats and humans (see Ref. 909), and it is tempting to speculate that this may correlate with the cognitive decline in the elderly.

In rats in which EEG activity was varied over a fivefold range by either bicuculline stimulation or thiopental inhibition, the forward rate constant of the CK reaction (kf) measured by 31P-NMR saturation transfer was linearly correlated with EEG intensity (849). A linear correlation was also observed in the brain between kf and the accumulation of deoxyglucose-6-phosphate after intraperitoneal administration of deoxyglucose, which is a measure of glucose uptake and utilization in brain. In contrast, brain ATP concentration remained constant over the whole range of EEG intensities studied, and PCr concentration only decreased at high EEG intensities. These findings suggest that kf is a more sensitive and reliable indicator of brain activity than [ATP] or [PCr]. In a similar study on the rat brain, the dihydropyridine calcium antagonist isradipine slowed ATP depletion during global ischemia, which was paralleled by a decrease in the flux through the CK reaction by ~25% (825).

By increasing the ATP-regenerating capacity via the CK reaction before oxygen deprivation, it might be possible to delay ATP depletion and, thereby, to protect the brain from ischemic or anoxic damage. As a matter of fact, in hippocampal slices of the guinea pig brain exposed to 5-30 mM Cr for 0.5-3 h before anoxia, PCr accumulation in the slices increased with Cr concentration and incubation time, synaptic transmission measured with electrophysiological methods survived up to three times longer during anoxia, and postanoxic recovery of both high-energy phosphates and of the postsynaptic potential was considerably improved relative to control slices (see Refs. 563, 730). Similarly, preincubation of rat neocortical slices with 25 mM Cr for 2 h had a pronounced protective effect on excitatory and inhibitory synaptic transmission during brief periods of hypoxia (579), and preincubation of rat hippocampal slices with 0.03-25 mM Cr slowed ATP depletion, prevented the impairment of protein synthesis, reduced neuronal death during anoxia in a dose-dependent manner, and delayed anoxic depolarization (43, 112). In brain stem slices of Cr-pretreated neonatal mice, and in slices of nonpretreated neonatal mice incubated for 3 h with 0.2 mM Cr, ATP depletion was delayed and hypoglossal activity enhanced and stabilized relative to controls during 30 min of anoxia (1105).

The susceptibility to seizures is highest in human term newborns and 10- to 12-day-old rats, and it has been suggested that the low Cr and PCr concentrations in the metabolically immature brain may critically influence susceptibility to hypoxic seizures (376). As a matter of fact, injection of Cr into rat pups for 3 days before exposing them to hypoxia on postnatal day 10 increased brain PCr-to-nucleoside triphosphate ratios, decreased hypoxia-induced seizures and deaths, and enhanced brain PCr and ATP recoveries after hypoxia.

As in skeletal muscle and heart (see sects. VIIIA and IXC), long-term feeding of mice with the Cr analog cCr increased the total high-energy phosphate pool in the brain and slightly delayed ATP depletion during brain ischemia (1119), but did not improve the hypoxic survival time of the mice (30). The rate of cCr accumulation in the brain was relatively slow when the compound was supplied in the diet but could be increased by circumventing the blood-brain barrier, or when the compound was given intravenously (R. Kaddurah-Daouk, unpublished data). Feeding of mice with the Cr analog GPA resulted in the accumulation of PGPA, decreased the flux through the CK reaction in the brain in vivo by ~75%, and enhanced survival during hypoxia (371, 372, 374).

Recently, GAMT deficiency was identified as the first inborn error of Cr metabolism in three children presenting with neurological symptoms (276, 867, 946-949). One of the male patients exhibited an extrapyramidal movement disorder starting at the age of 5 mo. At the age of 22 mo, he displayed severe muscular hypotonia and developmental delay. The EEG showed abnormally low background activity with multifocal spikes. Another patient, a girl aged 4 yr, presented a dystonic-dyskinetic syndrome, developmental delay, and epilepsy with myoclonic and astatic seizures and grand mal. The third patient, a 5-yr-old boy, displayed global developmental delay and experienced frequent tonic seizures, associated with apnea. GAMT deficiency was identified as the underlying metabolic basis of the disease by finding considerably increased brain, cerebrospinal fluid, serum, and urine concentrations of guanidinoacetate; low Cr concentrations in plasma, cerebrospinal fluid, and urine; a virtual absence of Cr and PCr in the brain (0.2-0.3 vs. 5.1-5.5 mM in controls); strongly depressed Crn concentrations in serum and urine; as well as a drastically reduced GAMT activity in liver biopsies (0.5-1.35 vs. 36.4 nmol · h1 · g1 in controls). In addition, oral supplementation with Arg resulted in an increase in brain guanidinoacetate concentration but did not elevate cerebral Cr levels. The nucleic acid mutations causing GAMT deficiency were characterized and include base substitutions, insertions, and deletions (948).

Oral supplementation with 4-8 g Cr/day or 2 g · kg1 · day1 slowly normalized the concentration of Cr in the brain (276, 867, 946, 947). After 6 wk, brain Cr had reached almost 50% of its normal concentration, whereas after 25 mo on treatment, brain [Cr] was nearly normal. The slow increase in brain [Cr] is a further indication for the limited permeability of the blood-brain barrier for Cr. Oral Cr supplementation also improved serum and urinary Crn concentrations, brain guanidinoacetate concentration, as well as EEG activity. Most importantly, Cr supplementation resulted in substantial clinical improvement, both with regard to muscle tone and extrapyramidal symptoms. Although the plasma concentration of Cr increased to supranormal levels (270-763 µM), the plasma concentrations of guanidinoacetate and homoarginine remained elevated even after 22 mo of Cr supplementation (949). This is noteworthy for two reasons: 1) it cannot yet be excluded that guanidinoacetate at the still elevated concentrations is neurotoxic and is responsible, instead of Cr deficiency, for the neurological symptoms associated with GAMT deficiency. 2) Increased serum concentrations of Cr due to supplementation should downregulate AGAT activity in kidney and pancreas and therefore result in subnormal guanidinoacetate concentrations. The opposite finding in a patient with GAMT deficiency suggests that the serum concentration of Cr may not be the sole signal for the downregulation of AGAT activity (see sect. IV).

Four points deserve further consideration. 1) Despite sharing the same primary defect, the three patients with GAMT deficiency, for unknown reasons, displayed strikingly different clinical symptoms. 2) Arginine restriction of the diet for 15 days while maintaining Cr supplementation tended to increase rather than decrease the plasma concentration and urinary excretion of guanidinoacetate (868). Therefore, early institution of Cr supplementation is so far the only successful therapeutic strategy in GAMT deficiency. 3) GAMT knock-out animals may become a valuable model for studying the relevance of the CK system at different developmental stages. Cr can be supplied through the diet during both pregnancy and postnatal development. At any developmental stage, Cr can be withdrawn from the diet and the accompanying changes in brain and muscle function studied. That Cr is in fact provided to the fetus in utero is supported by the lack of neurological symptoms in patients with GAMT deficiency during the first few months of life and by the demonstration of maternofetal transport of Cr in the rat (157). 4) Cr supplementation may prove beneficial in other diseases presenting with both neurological symptoms and reduced tissue concentrations of Cr. For example, Cr excretion was reported to be lowered in the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, which is characterized by clinical symptoms such as vomiting, lethargy, coma, seizures, ataxia, and various degrees of mental retardation (189). Arg or citrulline supplementation normalized Cr excretion and seemed to have favorable clinical effects.

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Categories: 2000, Creatine, Mitochondria, Cardiac, Cancer, Energy metabolism, Creatine synthesis and transport disorders