Creatine deficiency syndromes …

Andreas Schulze MD PhD

Neurogenetic Disorders

Updated 09.23.2025
Released 09.23.2025
Expires For CME 09.23.2028

Creatine deficiency syndromes

Author: Andreas Schulze MD PhD

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Editor: Deepa S Rajan MD

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Creatine deficiency syndromes

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Introduction

Overview

Creatine deficiency syndromes compromise a group of inborn errors of creatine metabolism that cause a severe neurodevelopmental disorder (39).

GAMT deficiency (GAMT-D, guanidinoacetate N-methyltransferase deficiency, OMIM #612736) is the most severe creatine deficiency syndrome. In addition to cerebral creatine deficiency, there is the buildup of guanidinoacetate. The latter is neurotoxic and responsible for treatment-refractory seizures. Available treatments, when started in the presymptomatic phase, effectively allow normal development for affected babies, which is why a growing number of newborn screening programs are adding GAMT deficiency to the screened conditions.

AGAT deficiency (AGAT-D, L-argine:glycine amidinotransferase deficiency, OMIM #612718) is the rarest condition but well treatable through supplementation with creatine.

Creatine transporter deficiency (CTD, OMIM #300352) is the most frequent condition, and males are primarily affected. No effective causative treatment is available for creatine transporter deficiency.

Key points

	• Creatine deficiency syndromes are easy to miss because the symptoms, although severe, are nonspecific.
	• Children and adults with a combination of global developmental delays, intellectual disability, speech impairment, epileptic seizures, behavioral disorder, and movement disorder must be tested for creatine deficiency syndromes, especially because some of them are amenable to treatment.
	• Clinical diagnosis can be established with blood and urine testing of creatine, creatinine, and guanidinoacetate; targeted sequencing of the genes GATM, GAMT, or SLC6A8 or whole-exome/genome sequencing; or brain MR spectroscopy. Brain MR spectroscopy with evidence of cerebral creatine depletion is the most sensitive test (41).
	• Treatment of GAMT includes supplementation with creatine and reduction of guanidinoacetate with pharmacological doses of ornithine and an arginine-restricted diet. Creatine supplementation is effective and sufficient for AGAT deficiency. In creatine transporter deficiency, none of the treatment approaches has proven efficient.
	• Newborn screening for GAMT deficiency is available in several jurisdictions. It is included in the Recommended Screening Panel in the United States.
	• Novel treatments, including gene delivery and alternative formulation and route of application for creatine, are emerging.

Historical note and terminology

The first two patients with a creatine deficiency syndrome, both with GAMT deficiency, were diagnosed almost at the same time in two separate metabolic centers in Germany (47; 45). The unrelated patients, a boy and a girl, were noted to have severe neurologic deficits. Both were identified through brain MR spectroscopy due to a missing creatine peak and diagnosed as having GAMT deficiency. Six years after the discovery of the first primary creatine deficiency in man, GAMT deficiency, a boy found to be lacking creatine on a brain MRS in Cincinnati was diagnosed as the first patient with creatine transporter deficiency (09; 35), and two Italian sisters were diagnosed as the first patients with AGAT deficiency (05; 18). This group of disorders, including AGAT deficiency, GAMT deficiency, and creatine transporter deficiency, was termed creatine deficiency syndromes (39) and later named CCDS1-3 (where the first letter C stands for cerebral) by the OMIM authors. Although the neurologic manifestations dominate the clinical presentation in creatine deficiency syndromes, it is a multisystemic disorder that affects extracerebral tissues and organs and has associated symptoms as well. Therefore, the term creatine deficiency syndrome is preferred over CCDS. Furthermore, it is important to distinguish the enzyme name and the gene name; although GAMT enzyme and GAMT gene are easy to comprehend, for the AGAT enzyme, the encoding gene’s name is GATM, which could easily be confused with GAMT.

Clinical manifestations

Presentation and course

GAMT deficiency. Global developmental delay or intellectual disability with speech and language delay and behavioral problems are the domains most affected in patients with GAMT deficiency (49).

The combination of cerebral creatine depletion with the buildup of neurotoxic guanidinoacetate makes this condition the most severe of the creatine deficiency syndromes. Affected babies are asymptomatic at birth and during the first few months of life. Parents usually observe some delays in achieving the first milestones of development, but clinical suspicion rises most often only in the second year of life when the first seizures can occur. The seizures become treatment refractory over time and include generalized tonic-clonic seizures as well as frequent absence seizures, drop attacks, and other astatic seizures. Patients on the severe end of the clinical spectrum do not develop expressive speech. Their comprehensive speech capabilities are very limited. Dystonic and hemiballistic movements and spasticity are further symptoms of the disease. The behavioral abnormalities have been described as autistic but might be related to intellectual disability and the lack of social interaction due to speech impairment.

Besides the severe form described above, there are also milder presentations likely due to higher residual enzyme activity of GAMT.

The onset of symptoms is typically between 3 and 12 months but can be up to 3 years in milder cases (39; 25). Often, parents note that their children are delayed in early developmental milestones, but it is the onset of seizures in the second to third year of life that spurs them to seek medical attention. The lack of active speech acquisition becomes obvious in the third year of life (39).

The disease doesn’t seem to be progressive in nature. Adults with the condition have been identified (39), but the life expectancy of those with GAMT deficiency is unknown. The disease course is mainly determined by the extent of seizure activity, frequency, and severity (41). Control of seizures significantly improves the general clinical status, although it doesn’t seem to have much impact on improving intellectual capabilities and speech.

AGAT deficiency. AGAT deficiency seems to have the least severe clinical manifestation of the three creatine deficiency syndromes. AGAT deficiency is also the rarest among them, at least judging from the number of patients, less than 20, who have been identified with AGAT deficiency. However, this is likely a gross underestimate as many may be missed because of unspecific presentation and unlikely diagnosis by biochemical testing. Symptom onset is later than in GAMT and creatine transporter deficiency, often not before the second year of life. The first symptoms are delays in global development and speech (50). Seizures are not associated with the disease, although febrile seizures in infancy have been reported. Delayed and impaired speech, again mostly expressive and to a lesser degree comprehensive, combined with global developmental delays and muscular hypotonia, are the hallmarks of the disease (48).

Creatine transporter deficiency. Besides fragile X, creatine transporter deficiency is considered the most frequent cause of X-linked intellectual disability. Affected boys demonstrate delays in all areas of global development. The onset of symptoms is typically between 6 and 18 months (52), with a delay in developmental milestones. The disease becomes more obvious when the children show a distinct lack of expressive speech. Comprehension is also much affected. Quite often, parents, teachers, and doctors describe the child’s behavior as autistic. Epileptic seizures can occur but are usually controllable with antiseizure medications. Gastrointestinal symptoms, like diarrhea and obstruction, have been observed. Muscle weakness can occur but is not predominant.

In females carrying one pathogenic variant in SLC6A8, the disease can present as a spectrum from asymptomatic to the full manifestation of symptoms seen in boys. Female carriers most often have a history of mild learning deficiencies. However, many mothers of boys with creatine transporter deficiency may not be affected because the creatine transporter deficiency in their sons is caused by de-novo pathogenic variants and mosaicism in 30% and 7% of cases, respectively (52).

Prognosis and complications

GAMT deficiency. Nonprogressive in nature, the disease prognosis depends mainly on the severity of the seizure disorder. The untreated condition is debilitating. Patients might be wheelchair-bound due to the frequent absences and drop attacks. Often, they cannot attend school or receive other forms of education. Because standard antiseizure treatments, even in a multitude of combinations, fail to control the seizures, the specific treatment for GAMT deficiency is the only proven option to achieve seizure freedom. In turn, even adult patients with GAMT deficiency who have suffered from seizures their entire lives will benefit dramatically. They can leave the wheelchair and walk without dropping. They can attend kindergarten or similar early learning options. Identifying and treating patients with GAMT deficiency will benefit them greatly at any stage in their lives.

Early GAMT deficiency-specific treatment, described in detail below, changes the disease outcome dramatically (Caspi et al, Neurology: Genetics, submitted); therefore, early identification of affected individuals is paramount. Starting treatment in the presymptomatic period of the disease postnatally and during early infancy enables normal development and seizure freedom, which is distinctly different from the outcome of treatment initiated in the symptomatic stage in affected individuals. Universal screening of all newborns is the only option to detect affected babies and enable presymptomatic treatment. A growing number of screening programs worldwide are adding GAMT deficiency to their disease panels. In the United States, the condition has been added to the Recommended Universal Screening Panel.

Undiagnosed individuals with GAMT deficiency are prone to the typical complications that are common to all debilitating neurocognitive disorders.

AGAT deficiency. There are no specific complications in this condition. The prognosis is good if creatine supplementation is started in early infancy. Untreated patients may develop intellectual disability and may have a lower seizure threshold.

Creatine transporter deficiency. The disease prognosis is likely determined by the general consequences of intellectual disability and behavioral disorder. Early intervention, even if not disease-specific, like occupational therapies, physiotherapy, and speech-language therapy, may improve the prognosis. Seizures may occur but are usually well controlled by antiepileptics. Gastrointestinal complications associated with diarrhea or constipation may occur.

Undiagnosed individuals with creatine transporter deficiency are prone to the typical complications common in all severe neurocognitive disorders.

Biological basis

Etiology and pathogenesis

Creatine deficiency syndromes are inherited disorders affecting the synthesis and cellular uptake of creatine. Creatine is essential for providing and buffering energy in all cells and tissues of the human body. Creatine from food, especially meat and fish, provides approximately 50% of the daily creatine needs in a typical Western diet. The other half is provided by endogenous creatine synthesis through two enzymes, AGAT and GAMT. The kidney, pancreas, and liver are the main organs for creatine synthesis (56). The brain is most likely self-sufficient in creatine synthesis and, therefore, less dependent on circulating creatine. Interestingly, even with zero creatine supply from food, as in strict vegan diets, the body can compensate via endogenous creatine synthesis. In contrast, the inability to synthesize creatine because of a deficiency in one of the two necessary enzymes, AGAT and GAMT, or the inability to transport creatine into the cells across the cell membrane and against a large concentration gradient in creatine transporter deficiency leads to the severe neurodevelopmental disorders described in this article.

The depletion of creatine in the brain is the obvious pathomechanism in creatine deficiency syndromes. It is present in all three conditions. Additionally, in GAMT deficiency, the neurotoxicity of guanidinoacetate complicates the disease.

Biochemistry

GAMT deficiency. Guanidinoacetate N-methyltransferase (EC 2.1.1.2) catalyzes the methyl group transfer from S-adenosylmethionine to guanidinoacetate, forming creatine and S-adenosylhomocysteine. The cytosolic enzyme is a heterodimer, with each subunit’s molecular weight of 26 KD (30). The enzyme is mainly expressed in the liver, pancreas, kidney, gastrointestinal tract, and reproductive tissue (www.proteinatlas.org/about/releases#24.0 2024). In the CNS (rat cortex), GAMT is found in approximately one third of neurons as well as in oligodendrocytes and astrocytes (08).

Biochemically, the disorder is characterized by creatine depletion and accumulation of guanidinoacetate in tissues and body fluids.

AGAT deficiency. L-Arginine:glycine amidinotransferase (AGAT; EC 2.1.4.1) catalyzes the transfer of a guanidino group from L-arginine to L-glycine, forming guanidinoacetate and L-ornithine. The AGAT reaction is the rate-limiting step in creatine synthesis. The enzyme has two iso-enzymes; the main form is localized at the outer side of the inner mitochondrial membrane (16; 22), and the other form is cytosolic. AGAT is a homodimer, and the molecular weight of the monomer is approximately 41 to 46 kD. The enzyme is mainly expressed in the kidneys, liver, and pancreas (www.proteinatlas.org/about/releases#24.0 2024). In the CNS (rat cortex), AGAT is found in approximately one third of neurons as well as in oligodendrocytes and astrocytes (08).

Biochemically, the disorder is characterized by creatine depletion and reduced guanidinoacetate in tissues and body fluids.

Creatine transporter deficiency. The creatine transporter (CrT1; OMIM 300036) is a member of solute carrier family 6, a large family of membrane transporters that mediate the translocation of a range of solutes across plasma membranes through the co-transport of sodium and chloride down their electrochemical gradients (10). Mammalian CrTs from mouse, rat, rabbit, cow, and man contain 635 amino acids and are approximately 96% identical at the amino acid level. Each is predicted to contain 12 transmembrane-spanning domains. The CrT transports creatine into the cells against a large concentration gradient of almost three magnitudes (55). CrT1 is most abundant in tissues with high energy demands, such as skeletal muscle, heart, brain, or retinae, or with absorptive function, such as kidney and intestine (17; 15; 38; 36; 31; www.proteinatlas.org/about/releases#24.0 2024). In situ hybridization studies in adult rat brains revealed the presence of the CrT1 in neurons and oligodendrocytes but not in astrocytes (07).

Biochemically, the disorder is characterized by creatine depletion in tissues and increased creatine-to-creatinine ratio in urine.

Genetics

GAMT deficiency. Biallelic loss of function mutations in the GAMT gene lead to impaired function of GAMT. The result is creatine depletion and accumulation of guanidinoacetate.

Autosomal-recessive inheritance. The GAMT gene is located on chromosome 19p13.3, has six exons, and is 4.46 kB large. Two pathogenic variants, c.59G>C (p.W20S) (=Portuguese Founder mutation) and c.327G>A (splice site), account for 50% of the 60 reported mutations. Sixty-five percent were null mutations, and 35% were missense variants (13). A variant classification revealed 72 GAMT variants, among them 55% missense (14).

AGAT. Biallelic loss of function mutations in the GATM gene leads to impaired function of AGAT. The result is creatine depletion and reduced guanidinoacetate.

Autosomal-recessive inheritance. The GATM gene is located on chromosome 15q15.3, has nine exons, and is 16.8 kB large. Variant classification revealed 45 GATM variants, among them 42% missense (14).

SLC6A8 . CrT is encoded by the gene SLC6A8 on the X-chromosome. Hemizygote loss of function mutations in males cause creatine depletion, and heterozygote loss of function mutations in females can cause creatine depletion depending on the degree of X-inactivation.

X-linked inheritance. The SLC6A8 gene is located on chromosome Xq28, has 13 exons, and is 8.4 kB large.

Variant classification revealed 64 SLC6A8 variants, among them 42% missense and 23% frameshift (14).

Cell biology. Creatine homeostasis is critical for energy transduction, buffering, and storage in mammalian cells (04; 54; 57). The cellular creatine provision is established through extracellular uptake and endogenous synthesis. Creatine homeostasis is species- and tissue-specific and requires a coordinated system of creatine uptake and synthesis to set and maintain stable creatine levels. The main contributors are the creatine transporter (CrT, gene: SLC6A8 ) and AGAT, the rate-limiting enzyme in creatine synthesis.

Cellular creatine homeostasis

Rates of CT synthesis and uptake determine tissue-specific CT content. The rate-limiting step in CT synthesis, arginine:glycine amidinotransferase (AGAT), is controlled by product inhibition (1), and CT negative feedback loop (...

Pathology

A summary and comparison of pathology is shown Table 1.

Table 1. Comparison of Symptoms in Creatine Deficiency Syndromes

	GAMT	AGAT	CrT
Developmental delay	+++	+++	+++
Speech and language delay
Expressive	+++	+++	+++
Comprehensive	++	++	++
Intellectual disability	+++	++	+++
Therapy refractory epilepsy	+/-	-	-
Mild epilepsy or EEG abnormalities	+	+/-	+/-
Movement disorder	+/-	-	+/-
Autistic, self-aggressive behavior	+	+/-	+
Muscular hypotonia	+	+/-	+
Mild learning disability in females	-	-	+/-
X-chromosomal trait	-	-	+
From (41)

GAMT deficiency.

Clinical. GAMT deficiency has the most severe clinical phenotype, including extrapyramidal movements and drug-resistant epilepsy. Severely affected patients present with developmental delay noticed at 3 to 12 months of age, muscular hypotonia, dyskinetic or dystonic involuntary movements or ataxia, and autistic or self-aggressive behavior. The onset of the seizure disorder, mostly refractory to antiepileptic drugs and accompanied by developmental regression or arrest, usually occurs in the second or third year of life. Speech and language development, if any, is restricted to an understanding of simple instructions. Most children have no active speech and suffer from marked intellectual disability. Milder affected patients may present with developmental delay, speech delay, and mild epilepsy or EEG changes (39; 13; 41; 24; 49).

EEG or seizures. Seizures usually develop after the first year of life (10 months to 3 years). These include myoclonic, generalized tonic-clonic, and sporadic partial complex seizures, head nodding, and drop attacks (25). In severe cases, the seizures are refractory to anticonvulsant treatment. EEG findings have been described as diffuse or multifocal epileptic activity, diffuse slow spike waves, slow background activity, bilateral frontal spike and slow waves, and sharp waves with secondary incomplete generalization (41).

EEGs before and 8 weeks after treatment of a patient with GAMT-D

Electroencephalograms (common reference leads) before (upper record) and 8 weeks after (lower record) treatment of a patient with GAMT deficiency. The first record shows a continuous generalized slow spike-wave activity of high...

Neuroimaging. Delayed myelination or bilateral hyperintensity in the globus pallidus are common findings. The earliest changes were observed 17 months after the onset of symptoms. In some patients, pallidal changes occur after retarded myelination has resolved. There is no correlation of MRI findings to either the duration or the severity of the disease. MRI abnormalities were observed in five of eight patients (39). In a series of 22 patients, six had abnormal bilateral signal intensity in the pallidum, and the remainder either had a delay of myelination or were normal (25). Another series of seven patients revealed a normal MRI in four patients and abnormalities in three patients, one with pallidal changes, one with small corpus callosum and delayed myelination and pallidal changes, and one with 2 mm T2 hyperintensity in the pons (13; 41).

Creatine transporter deficiency.

Clinical. Patients with creatine transporter deficiency present with developmental delay, severe language impairment, and marked intellectual disability. Focal seizures, failure to thrive, behavioral abnormalities, and muscular hypotonia are part of the clinical spectrum (12). The speech disorder has been characterized as expressive dysphasia and mild comprehension impairment. Children learn single words but reach no further language skills. Their behavior abnormalities have been described as compulsive, in part aggressive, with some autistic features in the area of social contact. Five adults in one family presented with facial dysmorphism described as midface hypoplasia and, in one case, a protruding forehead, short nose, and low-set eyebrows. Gastrointestinal symptoms like constipation or high-frequency watery stools seem to be quite frequent. Symptoms of creatine transporter deficiency develop during infancy and childhood, with no obvious progression thereafter. A variety of other organ manifestations can develop in elderly people, such as chronic constipation, megacolon, gastric and duodenal ulcers, and myopathic facies. Females can be asymptomatic or may have mild cognitive delay and behavioral problems. At least one girl presenting with intractable epilepsy at 3 years of age was diagnosed with creatine transporter deficiency (23; 41; 52).

EEG or seizures. The epileptic disorder observed in creatine transporter deficiency is generally described as mild, with infrequent seizures and a favorable response to common antiepileptic drugs. In those patients with seizures, the onset is usually in the second year of life. First presenting as atypical febrile seizures or partial status epilepticus, they can later turn into generalized tonic-clonic seizures. Severe seizures refractory to antiepileptic treatment are uncommon but have been reported in two patients (41; 52).

Neuroimaging. Brain imaging is normal in most patients. In single cases, abnormalities have been reported, such as generalized, in part progressive brain atrophy, cerebellar vermis atrophy, myelination delay, thinning of the corpus callosum, and signal changes in the pallidum and paratrigonal white matter (41; 52).

AGAT deficiency.

Clinical. AGAT deficiency seems to have the mildest clinical phenotype among creatine deficiency syndromes. The symptoms are nonspecific and include developmental delay in the first year of life, followed by delayed speech acquisition and mild to moderate intellectual deficits. The first cases, two sisters from Italy, 4 and 6 years old, presented with mild intellectual deficits but significant speech delay (05). A third girl in this family was diagnosed at birth and had a normal development since early treatment had been initiated (02). One affected cousin presented at 2 years of age with severe developmental delay, mild generalized hypotonia, poor social contact, short attention span, stereotyped movements of the hands, and speech delay (03). A girl of Chinese descent presented at 10 months of age with moderate central hypotonia, failure to thrive, and speech delay (28; 41).

EEG or seizures. Except for mild febrile seizures in one patient, seizures or EEG abnormalities have not been observed.

Neuroimaging. No abnormalities have been reported.

Pathophysiology

The depletion of creatine in the brain is considered the obvious pathomechanism in creatine deficiency syndromes. Creatine depletion is present in all three conditions. In addition, the neurotoxicity of guanidinoacetate complicates the disease in GAMT deficiency.

Creatine depletion. The cerebral creatine deficiency in GAMT deficiency and AGAT deficiency can be explained if one accepts that the brain serves its own creatine homeostasis through the interplay between the local creatine synthesis and the transport of creatine and its precursor guanidinoacetate. The blood-brain barrier is basically impermeable for creatine because the astrocytes covering the endothelial cells do not have functional creatine transport abilities. Astrocytes do not express the CrT. Neurons and oligodendrocytes express all three proteins, AGAT, GAMT, and CrT, enabling these cells to synthesize and transport creatine and guanidinoacetate between the cells. Interestingly, not all neurons co-expresses the three proteins. Based on observations in rat brain cells, one can assume that only one third of neurons express all three proteins, one third express two proteins, and one third only one protein (07). The job sharing of different neuron populations may allow dynamic calibration of creatine demands in a spatial and temporal manner in the brain. One can hypothesize that this dynamic calibration is of special importance during brain development and differentiation.

In creatine transporter deficiency, the local creatine synthesis is supposed to be intact. However, because the CrT transports not only creatine but also guanidinoacetate in the neurons (06), the lack of CrT activity deprives those neurons of guanidinoacetate, which doesn’t express AGAT and, therefore, hampers their ability to produce creatine even if they express the GAMT enzyme. The combination of reduced capability for creatine synthesis combined with the primary inability to take creatine from across the blood-brain barrier explains why patients with creatine transporter deficiency have cerebral creatine deficiency. It also explains why creatine supplementation is not effective for them.

Guanidinoacetate neurotoxicity. The exceptional clinical disease severity of GAMT deficiency can be explained by the action of guanidinoacetate. Guanidinoacetate is one of the guanidino compounds associated with epileptogenic activity (26). It has been shown that guanidinoacetate evokes picrotoxin- and bicuculline-sensitive GABAA receptor-mediated chloride currents in cortical neurons. It also hyperpolarizes globus pallidus neurons and reduces their spontaneous spike frequency. Guanidinoacetate acts as a partial agonist at heterologyously expressed GABAA but not GABAB receptors (29). Experiments with GAMT mutant mice revealed that systemic availability of guanidinoacetate affects GABAA receptor function and seizure thresholds. Ornithine treatment or picrotoxin (PTX, GABAA antagonist) administration led to a relative normalization of the GAMT mutant electrocortigraphic phenotype. Although GAMT wild-type mice on PTX exhibited electro-behavioral seizures, the GAMT mutant mice did not have PTX-induced seizures at the same PTX dose. GAMT mutant mice treated with both ornithine and PTX did not show electro-behavioral seizures, whereas ornithine elevated the PTX seizure threshold of GAMT mutant mice even further (46).

Diagnostic workup

	• Investigating creatine metabolites, including creatine, creatinine, and guanidinoacetate, in urine allows detection and differentiation of the three creatine deficiency syndromes.
	• The lack of creatine in the brain identified through MR spectroscopy has 100% sensitivity in all three creatine deficiency syndromes.

GAMT deficiency. Elevation of guanidinoacetate and decrease of creatine are the hallmarks for diagnosing GAMT deficiency. Biochemical abnormalities can be detected in urine, blood, CSF, and brain (45; 39).

Urine testing for creatine metabolites is offered in several specialized metabolic laboratories and is the least invasive method to diagnose GAMT deficiency. However, the test may lack some sensitivity in the postnatal period. Another test that would not require a special laboratory and could be applied everywhere is the determination of the daily excretion of creatinine in urine. Although rarely reported or done, the decreased creatinine excretion per kg body weight and day seems to have very high sensitivity but requires collection of a 24-hour urine sample.

Sequencing of the GAMT gene or genome-wide sequencing revealing biallelic pathogenic variants is diagnostic, but the diagnostic sensitivity is less than 95%.

Enzyme testing is no longer available in clinical laboratories.

Proton MR spectroscopy identifies the near absence of the total creatine peak at 3.0 ppm (ie, the sum of creatine and phosphocreatine) in the brain of all individuals affected by GAMT deficiency. Combining high-field MR scanners with reliable expertise allows the detection of elevated guanidino acetate at 3.8 ppm in the brain (53).

Creatine transporter deficiency. Finding elevated creatine-to-creatinine in urine is the most likely way to diagnose creatine transporter deficiency. Although not very specific because there are many other circumstances in which the ratio is elevated, a normal ratio excludes creatine transporter deficiency (27).

Sequencing of the SLC6A8 gene or genome-wide sequencing revealing a pathogenic variant in males is diagnostic, but the diagnostic sensitivity is less than 90%.

The activity of the CrT can be determined by creatine uptake studies in fibroblasts (19).

Proton MR spectroscopy identifies the near absence of the total creatine peak at 3.0 ppm (ie, the sum of creatine and phosphocreatine) in the brain of all individuals affected by creatine transporter deficiency.

AGAT deficiency. Proton MR spectroscopy identifies the near absence of the total creatine peak at 3.0 ppm (ie, the sum of creatine and phosphocreatine) in the brain of all individuals affected by AGAT deficiency.

Sequencing of the GATM gene that encodes for AGAT or genome-wide sequencing revealing biallelic pathogenic variants is diagnostic, but the diagnostic sensitivity is less than 95%.

Enzyme testing is no longer available in clinical laboratories but can be done on a research basis (20).

Management

	• Treatment to replenish creatine and reduce guanidinoacetate has changed the outcome of GAMT deficiency for all affected individuals, with almost normal development and no symptoms when started in the early postnatal period.
	• Supplementation with creatine seems to be very successful in ameliorating or preventing symptoms in AGAT deficiency.
	• Creatine transporter deficiency, despite attempts to improve brain creatine by creatine supplementation or the addition of creatine precursors, lacks efficacy.

GAMT deficiency. Increasing creatine and lowering guanidinoacetate are equally important for successfully managing patients with GAMT deficiency.

To increase creatine, daily supplementation of 200 to 400 mg creatine per kg is recommended (50).

To lower the neurotoxic guanidinoacetate, different strategies can be applied or combined. Creatine supplementation alone lowers circulating guanidinoacetate by approximately 50% (40). Treatment with pharmacological doses of L-ornithine adds to this effect and is the most effective treatment. With doses of 400 mg/kg/day in adults and 800 mg/kg/day in children, guanidinoacetate decreases, and seizures stop (44; 39). An orthogonal or additional approach is substrate reduction with an arginine-restricted diet. Treatment with sodium benzoate to reduce glycine has not yet been proven effective in patients but is used by some metabolic experts (50).

Creatine transporter deficiency. Supplementation of creatine (100 to 400 mg/kg/day) or creatine precursors L-arginine (400 mg/kg/day), L-glycine (150 mg/kg/day) and S-adenosylmethionine (20 to 100 mg/kg/day) have not shown any convincing treatment effects (50). However, one would want to try these treatments in very young children to capitalize on the potential benefits during brain differentiation. Also, symptomatic female patients with creatine transporter deficiency may benefit from these treatments.

More recently, a report of two adult brothers with creatine transporter deficiency who showed remarkable improvements in their behavior while taking an undefined supplement pointed to the potential benefits of betaine (37). Betaine provides the brain with methyl groups that can be used by GAMT to synthesize creatine. The advantage of betaine over S-adenosylmethionine is that we can use higher doses of up to 250 mg/kg/day. Several experts in the field of creatine deficiency disorders (including this author) recommend the use of betaine.

AGAT deficiency. Daily supplementation with creatine has been proven very effective. The doses vary between 100 to 400 mg/kg/day, but the lower dose is most likely effective, making higher dosing unnecessary (50).

Outcomes

GAMT deficiency. Treatment of neonates or treatment initiation in the first few months of life has proven to lead to favorable outcomes. Those children who have been treated early do not develop seizures, have normal speech development and cognitive function, and score better in all domains of development than later-treated patients (Caspi et al, Neurology: Genetics, submitted).

Despite the superior outcome of early treatment, patients whose treatment is started at a later time still benefit from the treatment significantly. Treatment leads to improved cognitive functioning, and, most importantly, it enables seizure control. The latter is usually not attainable with antiepileptic mono- or combination therapies and represents the largest burden of the disease for patients and their families (44; 39).

Creatine transporter deficiency. Although not progressive in nature, the cognitive and behavioral deficiencies become more burdensome and pronounced with age. The current treatments seem to have no impact on that.

AGAT deficiency. Creatine supplementation started in the first month of life seems to lead to favorable outcomes with normal development. Treatment started later seems to ameliorate disease symptoms significantly (01).

References

01: Battini R, Alessandri MG, Casalini C, Casarano M, Tosetti M, Cioni G. Fifteen-year follow-up of Italian families affected by arginine glycine amidinotransferase deficiency. Orphanet J Rare Dis 2017;12(1):21. PMID 28148286
02: Battini R, Alessandrì MG, Leuzzi V, et al. Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: early treatment can prevent phenotypic expression of the disease. J Pediatr 2006;148(6):828-30. PMID 16769397
03: Battini R, Leuzzi V, Carducci C, et al. Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree. Mol Genet Metab 2002;77(4):326-31. PMID 12468279
04: Bessman SP, Geiger PJ. Transport of energy in muscle: the phosphorylcreatine shuttle. Science 1981;211(4481):448-52. PMID 6450446
05: Bianchi MC, Tosetti M, Fornai F, et al. Reversible brain creatine deficiency in two sisters with normal blood creatine level. Ann Neurol 2000;47(4):511-3. PMID 10762163
06: Braissant O, Béard E, Torrent C, Henry H. Dissociation of AGAT, GAMT, and SLC6A8 in CNS: relevance to creatine deficiency syndromes. Neurobiol Dis 2010;37(2):423-33. PMID 19879361
07: Braissant O, Henry H, Loup M, Eilers B, Bachmann C. Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study. Brain Res Mol Brain Res 2001;86(1-2):193-201. PMID 11165387
08: Braissant O, Henry H. AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: a review. J Inherit Metab Dis 2008;31(2):230-9. PMID 18392746
09: Cecil KM, Salomons GS, Ball WS Jr, et al. Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect? Ann Neurol 2001;49(3):401-4. PMID 11261517
10: Chen NH, Reith ME, Quick MW. Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6. Pflugers Arch 2004;447(5):519-31. PMID 12719981
11: Clark AJ, Rosenberg EH, Almeida LS, et al. X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology. Hum Genet 2006;119(6):604-10. PMID 16738945
12: deGrauw TJ, Salomons GS, Cecil KM, et al. Congenital creatine transporter deficiency. Neuropediatrics 2002;33(5):232-8. PMID 12536364
13: Dhar SU, Scaglia F, Li FY, et al. Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab 2009;96(1):38-43. PMID 19027335
14: Goldstein J, Thomas-Wilson A, Groopman E, et al. ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes. Mol Genet Metab 2024;142(1):108362. PMID 38452609
15: Gonzalez AM, Uhl GR. 'Choline/orphan V8-2-1/creatine transporter' mRNA is expressed in nervous, renal and gastrointestinal systems. Brain Res Mol Brain Res 1994;23(3):266-70. PMID 8057783
16: Grazi E, Magri E, Balboni G. On the control of arginine metabolism in chicken kidney and liver. Eur J Biochem 1975;60(2):431-6. PMID 1204649
17: Guimbal C, Kilimann MW. A Na(+)-dependent creatine transporter in rabbit brain, muscle, heart, and kidney: cDNA cloning and functional expression. J Biol Chem 1993;268(12):8418-21. PMID 8473283
18: Item CB, Stöckler-Ipsiroglu S, Stromberger C, et al. Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet 2001;69(5):1127-33. PMID 11555793
19: Joncquel-Chevalier Curt M, Bout MA, Fontaine M, et al. Functional assessment of creatine transporter in control and X-linked SLC6A8-deficient fibroblasts. Mol Genet Metab 2018;123(4):463-71. PMID 29478817
20: Lee A, Anderson L, Tkachyova I, Tropak MB, Wang D, Schulze A. Validation and optimization of a stable isotope-labeled substrate assay for measuring AGAT activity. Int J Mol Sci 2024;25(23):12490. PMID 39684202
21: Lichter-Konecki U, Broman KW, Blau EB, Konecki DS. Genetic and physical mapping of the locus for autosomal dominant renal Fanconi syndrome, on chromosome 15q15.3. Am J Hum Genet 2001;68(1):264-8. PMID 11090339
22: Magri E, Baldoni G, Grazi E. On the biosynthesis of creatine: intramitochondrial localization of transamidinase from rat kidney. FEBS Lett 1975;55(1):91-3. PMID 1140432
23: Mercimek-Mahmutoglu S, Connolly MB, Poskitt KJ, et al. Treatment of intractable epilepsy in a female with SLC6A8 deficiency. Mol Genet Metab 2010;101(4):409-12. PMID 20846889
24: Mercimek-Mahmutoglu S, Ndika J, Kanhai W, et al. Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene. Hum Mutat 2014;35(4):462-9. PMID 24415674
25: Mercimek-Mahmutoglu S, Stoeckler-Ipsiroglu S, Adami A, et al. GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis. Neurology 2006;67(3):480-4. PMID 16855203
26: Mori A. Biochemistry and neurotoxicology of guanidino compounds: history and recent advances. Pavlov J Biol Sci 1987;22(3):85-94. PMID 2821470
27: Morkrid L, Rowe AD, Elgstoen KB, et al. Continuous age- and sex-adjusted reference intervals of urinary markers for cerebral creatine deficiency syndromes: a novel approach to the definition of reference intervals. Clin Chem 2015;61(5):760-8. PMID 25759465
28: Ndika JD, Johnston K, Barkovich JA, et al. Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency. Mol Genet Metab 2012;106(1):48-54. PMID 22386973
29: Neu A, Neuhoff H, Trube G, et al. Activation of GABA(A) receptors by guanidinoacetate: a novel pathophysiological mechanism. Neurobiol Dis 2002;11(2):298-307. PMID 12505422
30: Ogawa H, Date T, Gomi T, et al. Molecular cloning, sequence analysis, and expression in Escherichia coli of the cDNA for guanidinoacetate methyltransferase from rat liver. Proc Natl Acad Sci U S A 1988;85(3):694-8. PMID 3277179
31: Peral MJ, Garcia-Delgado M, Calonge ML, et al. Human, rat and chicken small intestinal Na+ - Cl- -creatine transporter: functional, molecular characterization and localization. J Physiol 2002;545(1):133-44. PMID 12433955
32: Puusepp H, Kall K, Salomons GS, et al. The screening of SLC6A8 deficiency among Estonian families with X-linked mental retardation. J Inherit Metab Dis 2010;33 Suppl 3:S5-11. PMID 24137762
33: Reichold M, Klootwijk ED, Reinders J, et al. Glycine amidinotransferase (GATM), renal fanconi syndrome, and kidney failure. J Am Soc Nephrol 2018;29(7):1849-58. PMID 29654216
34: Rosenberg EH, Almeida LS, Kleefstra T, et al. High prevalence of SLC6A8 deficiency in X-linked mental retardation. Am J Hum Genet 2004;75(1):97-105. PMID 15154114
35: Salomons GS, van Dooren SJ, Verhoeven NM, et al. X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet 2001;68(6):1497-500. PMID 11326334
36: Saltarelli MD, Bauman AL, Moore KR, Bradley CC, Blakely RD. Expression of the rat brain creatine transporter in situ and in transfected HeLa cells. Dev Neurosci 1996;18(5-6):524-34. PMID 8940628
37: Schjelderup J, Hope S, Vatshelle C, van Karnebeek CD. Treatment experience in two adults with creatinfe transporter deficiency. Mol Genet Metab Rep 2021;27:100731. PMID 33665121
38: Schloss P, Mayser W, Betz H. The putative rat choline transporter CHOT1 transports creatine and is highly expressed in neural and muscle-rich tissues. Biochem Biophys Res Commun 1994;198(2):637-45. PMID 8297374
39: Schulze A. Creatine deficiency syndromes. Mol Cell Biochem 2003;244(1-2):143-50. PMID 12701824
40: Schulze A. Strategies in the treatment of GAMT deficiency. In: Jakobs C, Stoeckler-Ipsiroglu S, (Co-Editors), Verhoeven NM, Salomons GS, editors. Clinical and molecular aspects of defects in creatine and polyol metabolism. APS Edition. 1st ed. Heilbronn: SPS Verlagsgesellschaft, 2005:19-33.
41: Schulze A. Creatine deficiency syndromes. Handb Clin Neurol 2013;113:1837-43. PMID 23622406
42: Schulze A, Bachert P, Schlemmer H, et al. Lack of creatine in muscle and brain in an adult with GAMT deficiency. Ann Neurol 2003;53(2):248-51. PMID 12557293
43: Schulze A, Chakraborty P. The Ontario Newborn Screening Program: a novel referral center model. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2023;66(11):1205-13. PMID 37792011
44: Schulze A, Ebinger F, Rating D, Mayatepek E. Improving treatment of guanidinoacetate methyltransferase deficiency: reduction of guanidinoacetic acid in body fluids by arginine restriction and ornithine supplementation. Mol Genet Metab 2001;74(4):413-9. PMID 11749046
45: Schulze A, Hess T, Wevers R, et al. Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism. J Pediatr 1997;131(4):626-31. PMID 9386672
46: Schulze A, Tran C, Levandovskiy V, Patel V, Cortez MA. Systemic availability of guanidinoacetate affects GABAA receptor function and seizure threshold in GAMT deficient mice. Amino Acids 2016;48(8):2041-7. PMID 26898547
47: Stockler S, Holzbach U, Hanefeld F, et al. Creatine deficiency in the brain: a new, treatable inborn error of metabolism. Pediatr Res 1994;36(3):409-13. PMID 7808840
48: Stockler-Ipsiroglu S, Apatean D, Battini R, et al. Arginine:glycine amidinotransferase (AGAT) deficiency: clinical features and long term outcomes in 16 patients diagnosed worldwide. Mol Genet Metab 2015;116(4):252-9. PMID 26490222
49: Stockler-Ipsiroglu S, van Karnebeek C, Longo N, et al. Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab 2014;111(1):16-25. PMID 24268530
50: Stoeckler-Ipsiroglu S, Braissant O, Schulze A. Disorders of creatine metabolism. In: Blau N, Dionisi-Vici C, Ferreira CR, Vianey-Saban C, vanKarnebeek CD, editors. Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. 2nd ed. Springer Nature: Switzerland AG, 2022:235-50.
51: Tkachyova I, Tropak MB, Lee A, Datti A, Ito S, Schulze A. Targeting AGAT gene expression - a drug screening approach for the treatment of GAMT deficiency. Expert Opin Drug Discov 2024;19(11):1383-97. PMID 39402976
52: van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, et al. Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet 2013;50(7):463-72. PMID 23644449
53: Verbruggen KT, Sijens PE, Schulze A, et al. Successful treatment of a guanidinoacetate methyltransferase deficient patient: findings with relevance to treatment strategy and pathophysiology. Mol Genet Metab 2007;91(3):294-6. PMID 17466557
54: Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM. Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis. Biochem J 1992;281(Pt 1)(Pt 1):21-40. PMID 1731757
55: Walzel B, Speer O, Zanolla E, Eriksson O, Bernardi P, Wallimann T. Novel mitochondrial creatine transport activity. Implications for intracellular creatine compartments and bioenergetics. J Biol Chem 2002;277(40):37503-11. PMID 12145274
56: Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev 2000;80(3):1107-213. PMID 10893433
57: Wyss M, Schulze A. Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease? Neuroscience 2002;112(2):243-60. PMID 12044443
58: References especially recommended by the author or editor for general reading.

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Andreas Schulze MD PhD

Dr. Schulze of the University of Toronto and Section Head, Metabolic Genetics, and Medical Director, Newborn Screening Program, The Hospital for Sick Children, has no relevant financial relationships to disclose.
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Editor

Deepa S Rajan MD

Dr. Rajan of UPMC Children's Hospital of Pittsburgh has no relevant financial relationships to disclose.
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Patient Profile

Age range of presentation: Typical:

GAMT deficiency: 3 months to 2 years

CTD: 6 months to 2 years

AGAT deficiency: 9 months to 2 years
Sex preponderance: GAMT deficiency: none

CTD: males affected, female carriers are most often asymptomatic

AGAT deficiency: none
Heredity: GAMT deficiency: autosomal recessive

CTD: X-linked inheritance

AGAT deficiency: autosomal recessive
Population groups selectively affected: No population group selectively affected
Occupation groups selectively affected: No occupation group selectively affected

ICD & OMIM codes

ICD-10: Disorder of amino-acid metabolism, unspecified: E72.9
ICD-11: Disorders of creatine metabolism: 5C53.4
OMIM: GAMT deficiency: OMIM # 612736

CTD: OMIM # 300352

AGAT deficiency: # 612718

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Creatine deficiency syndromes

Differential Diagnosis

Gyrate atrophy of choroid and retina
AGAT aggregation syndrome

Also Relevant

Argininosuccinic acidemia
HHH syndrome
Hyperornithinemia
Microcephaly
Movement disorders in childhood
- Screening of newborns for neurogenetic abnormalities

Clinical Categories

Neurogenetic Disorders

Creatine deficiency syndromes

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Biochemistry

Genetics

Pathology

Table 1. Comparison of Symptoms in Creatine Deficiency Syndromes

Pathophysiology

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

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