Epilepsia, 54(2):217227, 2013

doi: 10.1111/epi.12020

CRITICAL REVIEW AND INVITED COMMENTARY

Inborn errors of creatine metabolism and epilepsy

*Vincenzo Leuzzi, *Mario Mastrangelo, yRoberta Battini, and yzGiovanni Cioni
*Division of Child Neurology, Department of Paediatrics and Child Neurology and Psychiatry, Sapienza
University of Rome, Rome, Italy; yDepartment of Developmental Neuroscience, IRCCS Stella Maris, Pisa, Italy;
and zDivision of Child Neurology and Psychiatry, University of Pisa, Pisa, Italy

Creatine metabolism disorders include guanidinoacetate

methyltransferase (GAMT) deficiency, arginine:glycine
amidinotransferase (AGAT) deficiency, and the creatine
transporter (CT1-encoded by SLC6A8 gene) deficiency.
Epilepsy is one of the main symptoms in GAMT and CT1
deficiency, whereas the occurrence of febrile convulsions
in infancy is a relatively common presenting symptom in
all the three above-mentioned diseases. GAMT deficiency
results in a severe early onset epileptic encephalopathy
with development arrest, neurologic deterioration, drugresistant seizures, movement disorders, mental disability,
and autistic-like behavior. In this disorder, epilepsy and
associated abnormalities on electroencephalography
(EEG) are more responsive to substitutive treatment with
creatine monohydrate than to conventional antiepileptic
drugs. AGAT deficiency is mainly characterized by mental
retardation and severe language disorder without epilepsy. In CT1 deficiency epilepsy is generally less severe

than in GAMT deficiency. All creatine disorders can be

investigated through measurement of creatine metabolites in body fluids, brain proton magnetic resonance spectroscopy (1H-MRS), and molecular genetic techniques.
Blood guanidinoacetic acid (GAA) assessment and brain
H-MRS examination should be part of diagnostic workup
for all patients presenting with epileptic encephalopathy
of unknown origin. In girls with learning and/or intellectual
disabilities with or without epilepsy, SLC6A8 gene assessment should be part of the diagnostic procedures. The
aims of this review are the following: (1) to describe the
electroclinical features of epilepsy occurring in inborn
errors of creatine metabolism; and (2) to delineate the
metabolic alterations associated with GAMT, AGAT, and
CT1 deficiency and the role of a substitutive therapeutic
approach on their clinical and electroencephalographic
epileptic patterns.
KEY WORDS: Guanidinoacetate methyltransferase deficiency, Arginine:glycine amidinotransferase deficiency,
Creatine transporter deficiency, Creatine, Epilepsy.

Creatine metabolism disorders are a relatively young

group of diseases in which the intracellular transfer of
energy is impaired (Stckler et al., 2007). Figure 1 summarizes the three biochemical steps involved in the biosynthesis of creatine.
Guanidinoacetate methyltransferase (GAMT), arginine:glycine amidinotransferase (AGAT), and creatine transporter 1
(CT1) deficiency share a cluster of common symptoms reflecting the derangement of the higher cortical functions: intellectual disability, language delay, and behavioral disorders
(Fig. 2A,C). Brain creatine depletion can be detected noninvasively through measurement of creatine metabolites in body
fluids and brain proton magnetic resonance spectroscopy
(1H-MRS) (Stckler et al., 2007). Patients with biochemical

and/or spectroscopic abnormalities compatible with the diagnostic suspect of inborn errors of creatine metabolism must
undergo the specific molecular genetic tests (Almeida et al.,
2007). Epilepsy is one of the main symptoms in two of these
conditions, GAMT and CT1 deficiency, whereas the occurrence of febrile convulsions in infancy is a relatively common
presenting symptom in all (Fig. 2B,D).
The aims of this review are the following: (1) to describe
the electroclinical features of epilepsy occurring in inborn
errors of creatine metabolism; and (2) to delineate the metabolic alterations associated with GAMT, AGAT, and CT1
deficiency and the role of a substitutive therapeutic
approach on their clinical and electroencephalographic
epileptic patterns.

Accepted September 18, 2012; Early View publication November 13,

2012.
Address correspondence to Vincenzo Leuzzi, Department of Paediatrics
and Child Neurology and Psychiatry, Via dei Sabelli 108, 00185 Roma,
Italy. E-mail: vincenzo.leuzzi@uniroma1.it

GAMT Deficiency

SUMMARY

Wiley Periodicals, Inc.

2012 International League Against Epilepsy

Clinical features
Clinical presentation of GAMT deficiency is usually
characterized by normal developmental milestones in the
first months of life, which can be abruptly discontinued by

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V. Leuzzi et al.

Figure 1.
Creatine is synthesized mainly in kidney and liver by a two-step
reaction. The first step (production of guanidinoacetic acid and
ornithine, respectively, from arginine and glycine) is catalyzed in
the kidney by arginine:glycine amidinotransferase (AGAT, EC
2.1.4.1), the expression and transcription of which are inhibited
by creatine, whereas the second one (production of creatine
and S-adenosyl-L-homocysteine, respectively, from guanidinoacetic acid and S-adenosyl-L-methionine) is regulated by guanidinoacetate-methyltransferase (GAMT, EC 2.1.1.2) in the liver.
Creatine is not utilized in these organs but it is concentrated in
tissues with high creatine kinase activity, such as muscle and
brain, through an active sodiumand energydependent
creatine transporter (CT1). Arg, arginine; Orn, ornithine; AGAT,
arginine:glycine amidinotransferase; GAA, guanidoacetic acid; AdoMet, S-adenosyl-L-methionine; AdoHcys, S-adenosyl-L-homocysteine;
GAMT, guanidinoacetate-methyltransferase; Cr, creatine; CT1,
creatine transporter 1.
Epilepsia ILAE

arrest/regression of psychomotor development with or without seizures (Stckler et al., 2007).

Epilepsy is the second most frequent symptom in GAMT
deficiency after intellectual disability. Febrile seizures
have often been reported in the early phase of the disease
occurring during the first 24 months of life (mainly 3
6 months) (Patient 1 Caldeira Araujo et al., 2005; Schulze
et al., 1997; Patient 2 Van der Knaap et al., 2003;
Ensenauer et al., 2004). Only in a few subjects onset of
epilepsy was delayed (Leuzzi et al., 2006; Vodopiutz et al.,
2007; Dhar et al., 2009 case 1). A description of seizures
type is available for almost half of the cases described. The
pattern of seizures is not consistent, and more than one
type of seizures can occur in the same patient at different
ages. Life-threatening tonic seizures with apnea or myoclonic seizures can be observed in the first months of life,
whereas myoclonic astatic seizures, generalized tonicclonic seizures, partial seizures with secondary generalization,
drop attacks, absences, and staring episodes appear in early
infancy or in adolescence (Fig. 2B). Febrile seizures, generalized tonicclonic seizures, and myoclonic astatic seizures are the most commonly reported seizure types
(Fig. 2B and Table S1).
No typical electroencephalography (EEG) pattern can be
defined in GAMT deficiency. A description of EEG features has been provided for one third of the published cases
Epilepsia, 54(2):217227, 2013
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(Table S1). An early derangement of background organization and interictal multifocal spikes and slow wave discharges are frequently recorded (Caldeira Araujo et al.,
2005). Focal EEG abnormalities, with a prominent involvement of frontal regions, have also been reported (Leuzzi
et al., 2000; Schulze et al., 2003; Leuzzi et al., 2006).
Severe epilepsy has been reported in almost all cases. Epilepsy was partially responsive to conventional antiepileptic
drugs in 29 of 44 patients and completely refractory in 12 of
44. The occurrence of the seizures has always resulted in a further derangement of mental functions, and no improvements
in intellectual performances were observed when seizure control was obtained (Mercimek-Mahmutoglu et al., 2006).
Movement disorders, such as athetosis, chorea, choreoathetosis, ballismus, and dystonia have been reported in 22
of 44 patients; in a single case dystonia was associated with
ataxia, which was the only motor disorder in three subjects
(Dhar et al., 2009). Although usually precocious, movement
disorders can emerge as late as 17 years or later (ORourke
et al., 2009; Hinnell et al., 2011 , Patient 2).
The most typical neuroimaging alteration in GAMT deficiency is represented by bilateral pallidal lesions (hypointensity in T1-weighted and hyperintensity in T2-weighted
magnetic resonance imaging [MRI] images). These lesions
have been reported in 8 of 33 patients, and movement disorders were evident in 5 of them. These data confirm the
vulnerability of pallidum to neurotoxins resulting from several metabolic disorders other than GAMT deficiency such
as methylmalonic aciduria, Wilson disease, mitochondrial
encephalopathies, or succinic semialdehyde dehydrogenase
deficiency (Zimmerman, 2011).
In a few cases the lesion extended in the brainstem and
selectively involved the white matter of the floor of fourth
ventricle or the posterior pontine region (Leuzzi et al., 2000;
Mercimek-Mahmutoglu et al., 2012). A cytotoxic edema
was suggested by diffusion-weighted imaging (DWI)
sequences in one of these cases (Leuzzi et al., 2000).
Epilepsy, movement disorders, and pallidal alteration on
MRI may occur independently: Case 8 by Dhar et al., 2009
had, at the onset, a generalized dystonia and intellectual disability without epilepsy or MRI alterations (Dhar et al.,
2009).
It is unclear at the moment if GAMT deficiency has a stationary self-limiting or a rather progressive course. In some
patients a late neurologic deterioration is reported as progressive paraparesis with (cases 1 and 2 by Caldeira Araujo
et al., 2005) or without (case 3 by Caldeira Araujo et al.,
2005) rigidity or late-onset generalized dystonia (Hinnell
et al., 2011). Sudden unexpected death has also been
reported (case 3 by Caldeira Araujo et al., 2005).
Biochemical alterations and diagnostic work-up
Biochemical findings associated with GAMT deficiency
include the following: (1) reduced concentration of creatine
in plasma, urine, cerebrospinal fluid (CSF), muscle, and

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Epilepsy in Creatine Disorders
A

Figure 2.
(AD) Frequency and severity of symptoms and seizure-types in GAMT deficiency (A and B) and CT1 deficiency (C and D) that have
been reported in literature (see also Tables S1 and S2).
Epilepsia ILAE

brain; and (2) marked increase of guanidinoacetic acid

(GAA) in all the biologic fluids, mainly in the CSF (Stckler
et al., 2007). High values of GAA can be detected also
in dry blood spot since the first days of life (Carducci et al.,
2006). A mild increase of GAA over the normal range
has been detected in blood and/or urine of some carriers of
GAMT gene mutations (Carducci et al., 2002; Caldeira
Araujo et al., 2005). GAMT enzyme activity may be
tested in liver tissue, skin fibroblasts, and lymphoblasts
(Stckler et al., 1996; Ilas et al., 2000; Alessandr et al.,
2004).
Treatment and clinical follow-up
The aim of treatment is to correct both the depletion of
creatine/creatine-phosphate pools and the accumulation of
GAA. GAA shares the same transporter system as creatine;
therefore, a high GAA level in biologic fluids potentially
affects transport and restoration of cerebral creatine (Leuzzi
et al., 2000). In GAMT deficiency, a lifelong oral supple-

mentation with high doses of creatine monohydrate

(350 mg/kg/day to 2 g/kg/day) has been shown, by plasma
creatine assessment (muscle creatine pool) and brain
1
H-MRS (brain creatine pool), to replenish body creatine
pools (Caldeira Araujo et al., 2005; Bianchi et al., 2007).
The high dosage required to replenish brain creatine in
GAMT deficiency is probably due to the competitive effect
of blood GAA at level of CT1 (Wyss & Kaddurah-Daouk,
2000) as well as to the low efficiency of creatine transport
throughout the bloodbrain barrier (Braissant, 2012).
Although creatine supplementation should theoretically
lower GAA levels through the inhibition of AGAT transcription (Wyss & Kaddurah-Daouk, 2000), it results in
only a partial reduction of GAA in plasma and brain of
patients with GAMT deficiency (Schulze et al., 2001). A
further abating effect on AGAT activity can be obtained
through a dietary restriction of arginine (15 mg/kg/day)
coupled with ornithine supplementation (ornithine aspartate
350800 mg/kg/day) (Schulze et al., 2001; Schulze et al.,
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V. Leuzzi et al.
2003; Schulze et al., 2006; Dhar et al., 2009). Medicaments
such as sodium benzoate and phenylbutyrate, which remove
arginine and glycine, respectively, have also been proposed
according to a similar substrate inhibition approach (Schulze et al., 2006).
Normalization of GAA levels and complete restoration of
brain creatine or creatine-phosphate pool are not always
obtained through the abovementioned therapeutic
approaches. (Leuzzi et al., 2000; Van der Knaap et al.,
2003; Bianchi et al., 2007). When compared with pretreatment values, the reduction of GAA in biologic fluids was
relevant in plasma (5799%) and CSF (5084%), whereas it
was more variable in urine (083%) (Mercimek-Mahmutoglu et al., 2006). Figure 3A,B show the trend of blood GAA

in two GAMT-deficient patients treated along several years

according to different therapeutic approaches. The treatment is generally well tolerated. However, patient 1 experienced hyperammonemia after 11 years of treatment,
probably as a cumulative effect of dipropylacetate treatment
and arginine depletion (Fig. 3A).
Among the different clinical manifestations of GAMT
deficiency, epilepsy is by far the most responsive to treatment: according to the data reported by Mercimek-Mahmutoglu et al. (2006) and Dhar et al. (2009), 23 of 28 patients
experienced a reduction of seizures, and 13 of 28 became
seizure free. Similarly, movement disorders and pallidal
alterations, when present, vanished after treatment, whereas
minor improvement was observed for hypotonia, neuromotor

Epilepsia, 54(2):217227, 2013

doi: 10.1111/epi.12020

Figure 3.
(A, B) Relationship between blood
GAA levels and different
therapeutic approaches during a
prolonged follow-up (lasting
respectively 15 years in Patient 1
and 8 years in Patient 2) in two
patients of ours with GAMT
deficiency. Dosages of the drugs
are expressed in mg/kg/day. Cr,
creatine; HAD, hypoargininemic
diet; Orn HCl, ornithine
hypochloride; Orn Asp, ornithine
aspartate.
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Epilepsy in Creatine Disorders
development, and behavioral disturbances (MercimekMahmutoglu et al., 2006; Dhar et al., 2009). On the contrary, higher cognitive functions are much less influenced
by therapy (Mercimek-Mahmutoglu et al., 2006; Dhar
et al., 2009). IQ and language disorders remain substantially
unchanged, even after years of treatment (MercimekMahmutoglu et al., 2006; Dhar et al., 2009). These results
were observed in patients who had been diagnosed and treated several months/years after the beginning of the symptoms and the evolution of a severe epileptic encephalopathy
(Mercimek-Mahmutoglu et al., 2006; Dhar et al., 2009). A
different outcome has been reported in two very early treated newborns who were relatives of previously diagnosed
symptomatic patients (Schulze et al., 2006; Dhar et al.,
2009). Schulze et al. (2006) observed a patient with normal
development and no manifestations of GAMT deficiency
after 14 months of follow-up. Dhar et al. reported a
patient (Patient 7) with developmental delay with absence
of speech and no seizures at the age of 11 months (Dhar
et al., 2009). Dietary arginine restriction was adopted only
in the case studied by Schulze et al. (2006) resulting in a
more optimal control of GAA blood levels and in a subsequent better outcome (Schulze et al., 2006; Dhar et al., 2009).

AGAT Deficiency
Bianchi et al. (2000) reported the first cases of AGAT
deficiency in 2000: two sisters with mild-to-moderate
mental retardation and severe language delay. Other
than an isolated episode of febrile seizures at age
18 months in one of the sisters, neither epilepsy nor
movement disorders were present (Bianchi et al., 2000;
Battini et al., 2002). 1H-MRS demonstrated lack of the
creatine peak in both patients. Serum GAA levels were
low in one patient and within the low normal range in
the other (Carducci et al., 2002). Both patients were
homozygous for a point mutation, resulting in a stop
codon on exon 3 of the AGAT gene (9093A>G) (Item
et al., 2001). Creatine monohydrate therapy resulted in
remarkable clinical improvement and restoration of creatine peak on H-MRS (Bianchi et al., 2007).
To date, AGAT deficiency has been reported in seven
patients across four families, and its clinical presentation
seems rather nonspecific, being characterized by psychomotor delay during the first years of life, autistic-like behavior,
severe language delay, and mild to moderate mental disability. EEG recordings while awake and asleep were normal in
all patients (Bianchi et al., 2000; Battini et al., 2002; Battini
et al., 2006; Edvardson et al., 2010).
Under creatine supplementation, clinical outcome is
favorable, ranging from normal mental and neurologic
functioning to mild learning difficulties (Ndika et al., 2012;
Battini R, unpublished data).
A single patient, from the index family, was diagnosed
during the first weeks of life and treated with creatine

(100 mg/kg/day) before the emergence of the disease (Battini et al., 2006). Although the restoration of brain creatine
was partial, his psychomotor development under creatine
supplementation was normal. He presented an occasional
febrile convulsion at the age of 3. At present, at the age of 7,
he is a mentally normal boy with mild learning disabilities.
Creatine/N-acetyl-aspartate (NAA) ratio at brain 1H-MRS is
about 70% of that detected in age-matched controls (Battini
R, Cioni G, unpublished data).

CT1 Deficiency
Clinical features
CT1 deficiency is one of the main causes of X-linked
mental retardation in males, and it is caused by SLC6A8
gene mutations (Cecil et al., 2001; Rosenberg et al., 2004;
Clark et al., 2006). Mental retardation and specific language
derangement (oral-verbal dyspraxia of speech) are, in fact,
the core symptoms of the disease (Fig. 2C; Mancini et al.,
2005; Chilosi et al., 2008).
The index patient was a 6-year-old Caucasian boy who
was diagnosed at 7 months with developmental delay and
central hypotonia. At the age of 2 years, he had partial status
epilepticus, multifocal epileptiform discharges at interictal
EEG, and small T2 hyperintense focus in the right posterior
periventricular white matter on brain MRI. At the age of
6 years, his speech and language functions were severely
retarded, and he had short attention span and mild hypotonia. Blood creatinine and GAA in serum and urine were normal, whereas serum and urine creatine levels were higher
than normal. Oral creatine monohydrate supplementation
for 3 months resulted in a 10-fold increase in urinary creatine and an increase in CSF creatine, without concurrent
appearance of creatine/creatine-phosphate peak on H-MRS
or improvement of clinical conditions (Cecil et al., 2001;
Salomons et al., 2001).
Apart from a few severely affected cases presenting with
developmental delay and paroxysmal and/or persistent
movement disorders, clinical onset of CT1 deficiency seems
to be more delayed than GAMT deficiency (Anselm et al.,
2006).
Epilepsy is frequent, but is never the presenting symptom
in CT1 deficiency. It is rarely severe and it is usually responsive to conventional antiepileptic drugs (Schiaffino et al.,
2005; Mancardi et al., 2007). Its onset ranges between
16 months and 12 years. Febrile convulsions represent the
first seizure-type in a number of subjects (Battini et al.,
2007; Battini et al., 2011; Valayannopoulos et al., 2012),
and in a single case they led to subcontinuous generalized
tonicclonic seizures (Mancardi, 2007). Seizure pattern and
EEG alterations can be extremely variable (Schiaffino
et al., 2005; Mancardi et al., 2007). Seizure-types include
myoclonic
seizures, generalized tonicclonic seizures, convulsive
status epilepticus, and partial seizures with secondary genEpilepsia, 54(2):217227, 2013
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V. Leuzzi et al.
A

Figure 4.
(A, B) Electroencephalographic pattern before (A) and after (B) the beginning of the arginine treatment in a male patient with CT1
deficiency. His previously drug-responsive active epilepsy worsened when he stopped the clinical follow-up and discontinued antiepileptic drugs until 6.5 years old because of an absent compliance of his parents. (A) Video-polygraphy at awakening (20 s/page, I paper
speed: 15 mm/s, Sensitivity: 300 lVp-p; HF: 70 Hz; LF: 1.0 Hz; Pg1Pg2 = left deltoid; A1A2 = right deltoid; 3132 = neck surface
EMG recording from cervical muscles). Diffuse fast activity dominant over the parietal-occipitotemporal regions followed by diffuse
delta waves of high amplitude with clinical correspondence to asymmetrical spasms. On left deltoid a mild contraction is
not constantly observed. These episodes repeated in series with irritability for the entire length of the cluster. (B) Under arginine
supplementation associated with valproate the patient became seizure free. EEG recording shows burst of fast activity dominant
over the parietal-occipitotemporal regions followed by generalized spikes and slow spike and wave discharges with no clinical
correlation.
Epilepsia ILAE

eralization (Schiaffino et al., 2005; Mancardi et al., 2007;

Fig. 2D). EEG recordings include normal tracing, diffuse
slowing, aspecific sharp abnormalities, and focal/generalized paroxysmal or slow abnormalities, with or without
sleep activation (Table S2; see also Fig. 4A,B). However,
according to our experience, paroxysmal abnormalities are
generally less severe as the child grows older. SLC6A8
genotype is not associated with epilepsy, as exemplified by
personal observations and cases from the literature: for
example the c.1631C>T mutation resulted in severe epilepsy in one case (Mancardi et al., 2007), but it was not
associated with seizures in others (Mancini et al., 2005;
Fons et al., 2008).
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Neuroimaging and clinical features suggest in some

patients a possible perinatal ischemic insult (see for example Fig. 5A,B). This aspect may be confounding from the
diagnostic point of view because clinical history rarely justifies this suspect. However, these lesions are congruent
with the concept of creatine as a protective factor against
potentially ischemic damage. Their possible role in the
determinism of epilepsy needs to be elucidated.
Some adult cases suggest CT1 defect as a nonstationary
disorder, including corticobasal dementia associated with
signs of muscle and visceral involvement, such as chronic
constipation, megacolon, gastric and duodenal ulcer disease, ileus, and bowel perforation (Kleefstra et al., 2005). A

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Epilepsy in Creatine Disorders

Figure 5.
(A, B) Brain MRI features in a patient of ours with a CT1 deficiency: a slight periventricular white matter hyperintensity
(A, arrows) and a decrease of creatine peak at 1H-MRS (B,
arrow).
Epilepsia ILAE

progressive cerebral atrophy on brain MRI was also

described (DeGrauw et al., 2002).
There are a few clinical reports on females carrying
SLC8A6 gene mutations. When symptomatic, they express a
milder phenotype, including mild intellectual disability,
behavioral disorders, problems of language development,
learning difficulties, impairment of visual-constructional
and fine motor skills, mild cerebellar symptoms, and constipation (Salomons et al., 2001; Mancini et al., 2005;
Po-Argelles et al., 2006; Van de Kamp et al., 2011;
Valayannopoulos et al., 2012). Late occasional epileptic
seizures have been described but not systematically studied
(Ardon et al., 2010; Van de Kamp et al., 2011). An abrupt
onset of severe epilepsy was recently described in a 3 year
and 7-month-old girl with intellectual disability carrying
c.1067G>T (Gly356Val) mutation (Mercimek-Mahmutoglu
et al., 2010). She presented with extremely frequent
seizures with psychomotor arrest, humming, breath-holding, eye rolling, stiffening of arms and legs, head drops, and
falls. Interictal EEG at the age of 6 showed dysrhythmic
background (67 Hz posterior dominant rhythm), excessive generalized paroxysmal theta and delta, maximally
seen in the frontal areas, and frequent spikes and sharp
waves in the central areas. Cerebral white matter alterations were detected by MRI. Her seizures were resistant to
antiepileptic drugs and ketogenic diet but were controlled
by a combined therapy with creatine plus arginine and
glycine (see below) (Mercimek-Mahmutoglu et al.,
2010).
Biochemical alterations and diagnostic work-up
The main biochemical alteration of patients with CT1
defect is the lack of brain creatine on H-MRS (Cecil et al.,
2001). A mild increase of blood and urinary creatine was
noticed in the index case, and the urinary ratio creatine/cre-

atinine (Cr/Crn) was proposed and confirmed as diagnostic

marker of the disease (Cecil et al., 2001; DeGrauw et al.,
2002; Almeida et al., 2004). Diagnostic urinary Cr/Crn ratio
ranged from 1.45.5 (reference values 0.0061.2 in children
under 4 years, 0.0170.72 in patients between 4 and
12 years, 0.0110.24 after 12 years of age) (Almeida et al.,
2004). However, urinary Cr/Crn may be influenced by
various nutritional and individual factors (Arias et al.,
2007). Creatine has been so far assessed in CSF only in a
few subjects and was found to be normal in basal conditions,
slightly increased under creatine treatment (350 mg/kg/
day), and normal under arginine supplementation (Cecil
et al., 2001; DeGrauw et al., 2002; Almeida et al., 2004;
Chilosi et al., 2008). GAA was found high by H-MRS and
normal in CSF (Sijens et al., 2005; Chilosi et al., 2008).
Fibroblast and lymphoblast express SLC6A8 gene, and
creatine uptake can be tested in these cells in patient with
suspect CT1 defect (Salomons et al., 2001; Leuzzi et al.,
2008). In contrast, muscle creatine is normal on both biochemical and H-MRS examination (DeGrauw et al., 2003;
Pyne-Geithman et al., 2004).
No key clinical and/or neuropsychological cues have
been identified to suggest the diagnosis of CT1 deficiency
in girls with epilepsy and intellectual disability or learning
difficulties. Apart from a single exception (MercimekMahmutoglu et al., 2010), all the reported female patients
affected by SLC6A8 gene defects were relatives of symptomatic males. Creatine depletion in the brain, as assessed
by 1H-MRS, is found in symptomatic females. In a single
case it was detected as early as 9 days of life (Cecil et al.,
2003). However, 1H-MRS usually shows a variable reduction of creatine peak with a wide range between 13% and
50% (Van de Kamp et al., 2011; Valayannopoulos et al.,
2012). These values overlap with normal controls in some
affected females (Van de Kamp et al., 2011; Valayannopoulos et al., 2012). For these reasons gene sequencing seems
to be the best diagnostic tool for females with a clinical
suspect of CT1.
Treatment and clinical follow-up
No effective treatment is available for males with CT1
defect. The supplementation of creatine, also at high dosages, does not improve 1H-MRS detectable brain creatine
pool and/or clinical status (Cecil et al., 2001). In vitro
experiments showed that arginine and glycine supplementation can restore intracellular creatine in peripheral cells
lacking CT1 (Leuzzi et al., 2008). In vivo trials were less
encouraging, since they resulted in only mild or no clinical
improvement with scarce or absent variation of brain creatine 1H-MRS signal (Chilosi et al., 2008; Fons et al., 2008;
Valayannopoulos et al., 2012; Van de Kamp et al., 2012).
However some anecdotic experiences, such as those
reported in Fig. 4A,B, where a clinical improvement could
be observed under arginine supplementation, suggest that
this topic deserves further study.
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V. Leuzzi et al.
In contrast, creatine, as well as creatine precursor, supplementation is potentially effective in symptomatic females
where the defect of CT1 is partial. In a recently described
case, the administration of creatine-monohydrate, L-arginine, and L-glycine resulted in a persistent seizure control
and increase of 1H-MRS creatine peak after 12 months of
treatment (Mercimek-Mahmutoglu et al., 2010). In this
context, the availability of a potential effective therapy
makes it mandatory to test all females with intellectual disability for CT1 deficiency (Van de Kamp et al., 2011). A
recent study showed that cognitive deficits in SLC6A8)/y
mouse can be reversed through nine weeks of treatment with
cyclocreatine (Kurosawa et al., 2012).

Pathogenetic and
Physiopathologic Aspects
Animal models of inborn errors of creatine metabolism
Two animal models of primary disorders of creatine
metabolism have been published to date. The GAMT
knockout mouse has a biochemical phenotype overlapping
that of affected human beings, but clinical presentation is
characterized mainly by muscle involvement, increased
neonatal mortality, decreased male fertility, no epilepsy,
and other severe neurologic symptoms and minor cognitive
defects (Schmidt et al., 2004; Kan et al., 2005; Torremans
et al., 2005). In contrast, the recently generated CT1 knockout mouse fits with the mental phenotype found in the
affected subjects, but presents with a more generalized creatine depletion that involves striate muscles (included heart)
and serum creatine, probably as a consequence of the
derangement of intestinal transport of creatine. Some
alterations such as those of serotoninergic and dopaminergic
system remain to be explored in man (Skelton et al.,
2011).
The epileptogenic role of guanidinoacetic acid
Some neurologic symptoms, mainly occurring in patients
with GAMT deficiency (such as severe epilepsy, movement
disorders, pallidal lesions), strongly point to a pathogenic role
of GAA (or related guanidine compounds), which is increased
in all biologic fluids and tissues only in this disorder. The epileptogenic effect of GAA is well known. GAA induces convulsions when administered intracisternally to rabbits
(De Deyn & Macdonald, 1990). In the striatum of rats, GAA
probably interferes with energetic metabolism at the level of
complex II, ATPase and creatine kinase activities through
lipid peroxidation causing oxidative stress (Zugno et al.,
2006; Zugno et al., 2007). Creatine prevents the neurotoxicity
of GAA in rat striatum (Kolling & Wyse, 2010). Moreover,
GAA (but not creatine) has a specific mimetic effect on GABA
A receptors (Neu et al., 2002). This effect probably results in a
reduction of convulsive threshold through various possible detrimental adaptive mechanisms on these receptors (Neu et al.,
2002).
Epilepsia, 54(2):217227, 2013
doi: 10.1111/epi.12020

Homeostasis of brain creatine: physiologic and

physiopathologic mechanisms
Different models have been proposed to explain the complex homeostasis of brain creatine. Experiences in patients
with GAMT and AGAT defects underscore the importance
of the endogenous synthesis for the normal homeostasis of
creatine in brain (Ensenauer et al., 2004). The effectiveness
of creatine supplementation in AGAT deficiency suggests
that (1) in normal conditions both endogenous and exogenous fonts of creatine contribute to the maintaining of the
brain creatine pool, but also that (2) under normal creatine
intake, blood supply is not sufficient to balance the failure of
cerebral endogenous synthesis (Bianchi et al., 2007). On the
contrary, CT1 defect discloses the importance of blood supply for the brain. In fact, lacking CT1, the endogenous synthesis of creatine proves to be an inadequate font of cerebral
creatine (also under the supplementation of creatine precursors) (Chilosi et al., 2008; Fons et al., 2008). According to a
recent model, the brain creatine pool would result from the
mutual vicariance of different nervous cells. GAMT, AGAT,
and CT1 expression in these cells is variable: 4% of cortex
cells express all three proteins; 8% of them AGAT and CT1;
7% of them GAMT and CT1; and 14%, 15%, and 14% of
them only CT1, AGAT, and GAMT, respectively. Twentyfive percent of neurons and 35% of astrocytes (including
those of bloodbrain barrier) do not express any of the three
proteins, whereas no more than 33% are equipped with CT1
(Braissant et al., 2010). This model does not completely fit
with the complete restoration of brain creatine pool after
9 months of creatine supplementation and (several months
later) the almost complete clinical normalization in patients
with AGAT deficiency (Bianchi et al., 2007; Battini et al.
unpublished data). The hypothesis that CT1 expression could
be induced by high levels of creatine has not been demonstrated so far (Braissant et al., 2011). It has also been suggested that neurons produce creatine from astrocitary GAA
(Braissant et al., 2010). If so, in the lack of CT1, GAA
(whose efflux from the CSF is also ascribed to CT1) (Tachikawa et al., 2008) should accumulate in extracellular fluids
and CSF. Although high GAA was detected by brain
1H-MRS in a CT1-deficient patient, CSF GAA was normal
in another subject (Chilosi et al., 2008).
Another dissociated model implies that glial cells express
GAMT activity and supply creatine to neurons with a high
creatine kinase activity (neuronal networks implied in high
energy demanding functions such as motor and sensory processing, learning, memory, and limbic functions) (Tachikawa et al., 2004; Mak et al., 2009). These data well explain
the pattern of intellectual disability found in all the three disorders of creatine metabolism. According to this model, in
CT1 deficiency, creatine should accumulate in extracellular
fluids and CSF. Clinical data did not confirm this accumulation in CSF of CT1-deficient patients (Cecil et al., 2001;
Almeida et al., 2004; Chilosi et al., 2008). This model also
contrasts with the lack of a clear regional differentiation in

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creatine depletion in the brains of patients with CT1 defect.
Waiting from more consistent data arising from the animal
model of SLC6A8 knockout mouse, recent in vitro experimental data suggest the prominence of uptake versus
de novo synthesis on the control of creatine homeostasis in
nervous tissue (Carducci et al., 2012).

Conclusions
Mental retardation, language derangement, and epilepsy
appear to be the specific hallmarks of the primary disorders
of creatine metabolism. Why mental functions are selectively affected by creatine deficiency remains to be clarified.
Febrile convulsions are a common presenting symptom that
anticipates epilepsy. Blood GAA assessment and brain
H-MRS examination should be part of diagnostic work-up
for all patients presenting with an epileptic encephalopathy of unknown origin. Waiting for a better phenotypic
characterization in girls suffering from learning and/or
intellectual disabilities with or without epilepsy SLC6A8
gene assessment remains the only reliable tool to diagnose
CT1 defect.

Acknowledgments
We are deeply grateful to all the colleagues of the Italian Group for
the Study of Creatine Disorders (Dr MC Bianchi, Dr. Ar. Ferrari, Dr. M.
Casarano, Dr M. Tosetti, and Dr MG Alessandr IRCSS Stella Maris,
Pisa; Prof. I. Antonozzi, Dr Cl. Carducci, Prof. Ca. Carducci Department of Experimental Medicine, Sapienza University of Rome) for
their stimulating support on the subject and Dr AM Ferrari, EEG
Lab IRCCS Stella Maris, for her help with the illustration and advice on
CT1 Fig. 4

Disclosure
None of the authors has any conflict of interest to disclose. We confirm
that we have read the Journals position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Table S1. Demographic, clinical, and epileptic features
of the patients with GAMT deficiency who have been
reported in the literature.
Table S2. Demographic, clinical, and epileptic features
of the patients with CT1 deficiency who have been reported
in the literature.

Epilepsia, 54(2):217227, 2013

doi: 10.1111/epi.12020