Clinical Diagnosis

The cerebral creatine deficiency syndromes (CCDS) are inborn errors of creatine metabolism that include [Stöckler-Ipsiroglu & Salomons 2006]:

• Two creatine biosynthesis defects
  • Guanidinoacetate methyltransferase (GAMT) deficiency
  • L-Arginine:glycine amidinotransferase (AGAT or GATM) deficiency
• One creatine transporter defect. Creatine transporter (SLC6A8) deficiency

A CCDS is suspected in a young child with global developmental delay and an older child with intellectual disability, epilepsy, pyramidal / extrapyramidal neurologic findings, and behavior problems (Table 1).

Testing

Screening Tests

Levels of guanidinoacetate (GAA), creatine, and creatinine are measured in urine (Table 2), plasma (Table 3), and cerebrospinal fluid (CSF) (Table 4) [Almeida et al 2004, Cognat et al 2004].

In vivo assessment of brain creatine levels. Proton magnetic resonance spectroscopy (MRS) reveals almost complete depletion of the cerebral creatine pool in all individuals with GAMT deficiency and AGAT deficiency and in males with SLC6A8 deficiency; partial depletion or even normal levels of the cerebral creatine pool are observed in females with SLC6A8 deficiency [van de Kamp et al 2011a].

Note: Complete lack of creatine in the presence of a normal choline and N-acetyl aspartate (NAA) levels in MRS is unique to CCDS [Stöckler et al 1996].

Confirmatory Tests

Assay of enzyme catalytic activity. Enzyme assays are performed in cultured skin fibroblasts (GAMT) and EBV-transformed lymphoblasts (GAMT and AGAT) [Item et al 2001, Verhoeven et al 2003, Verhoeven et al 2004].

• GAMT enzyme activity was less than 0.1 nmol/hr/mg protein in affected individuals (controls 0.61-0.84).
• AGAT enzyme activity was less than 0.3 nmol/hr/mg protein in affected individuals (controls 12.6-23.4).

Creatine uptake studies. In the presence of a strong suspicion of SLC6A8 deficiency in a male (e.g., elevated urine creatine-to-creatinine ratio or creatine deficiency in the cranial MR-spectroscopy) with no detected pathogenic mutation or with a novel mutation of uncertain pathogenicity, creatine uptake studies in cultured fibroblasts are important in the assessment of SLC6A8 deficiency. In males the creatine uptake is less than 10% of normal control fibroblasts (incubated with 25 µmol creatine) [Salomons et al 2001, Rosenberg et al 2007].

This testing may also be essential in a symptomatic heterozygous female with a novel mutation of uncertain pathogenicity.

Testing Strategy

Confirming/establishing the diagnosis in a proband. The diagnostic testing algorithm for an individual with the listed clinical features and/or reduced creatine levels on cranial MRS (see Figure 1) is:

Figure

Figure 1. Algorithm for diagnosis of the cerebral creatine deficiency syndromes. Note: Urinary creatine/creatinine ratio and creatine uptake studies in cultured skin fibroblasts are often not informative in females with SLC6A8 deficiency; hence, molecular (more...)

• Measurement of guanidinoacetate (GAA), creatine, and creatinine in urine (Table 2) and plasma (Table 3).
  • If GAA concentration in urine is high, molecular genetic testing of GAMT
  • If GAA concentration in urine is low and plasma concentration of GAA is low, molecular genetic testing of GATM
• If creatine/creatinine ratio in urine is high and GAA concentration in the urine is normal or slightly increased, molecular genetic testing of SLC6A8. Note: Diagnosis of heterozygous female probands requires molecular genetic testing of SLC6A8 because they may have a normal creatine-to-creatinine ratio in urine and normal creatine content on cranial MRS [van de Kamp et al 2011a].
• If molecular genetic test results are inconclusive (i.e., if sequence variants of unknown significance are identified), GAMT enzyme activity (in cultured fibroblast or lymphoblasts), AGAT enzyme activity (in lymphoblasts), or creatine uptake in cultured fibroblasts can be assessed.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation(s) in the family.

Note: (1) Carriers for the autosomal recessive disorders GAMT deficiency and AGAT deficiency are not at risk of developing the disorder. (2) Carriers for the X-linked disorder SLC6A8 deficiency may develop clinical findings related to the disorder. Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis and then by deletion/duplication analysis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in GAMT, GATM, and SLC6A8.

Natural History

Intellectual disability and seizures are common to all three creatine deficiency syndromes. Intellectual disability is associated with expressive speech delay and behavioral disorder [Stöckler-Ipsiroglu & Salomons 2006].

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known for any of the CCDS.

Of note, the phenotypes of individuals homozygous for the two most common GAMT mutations (c.59G>C and c.327G>A) range from mild to severe.

Prevalence

GAMT deficiency. Approximately 52 individuals with GAMT deficiency have been diagnosed worldwide.

Caldeira Araújo et al [2005] screened plasma and urinary uric acid and creatinine levels in 180 institutionalized individuals with severe intellectual disability. Urinary GAA was measured in individuals with high urinary uric acid to creatinine ratio and/or low plasma creatinine levels. The prevalence of GAMT deficiency was 1.1% (2/180) in this study. Of note, the high prevalence in this small Portuguese population in Madeira is likely the result of its relative isolation over a long period.

Eight carriers for the c.59G>C founder mutation were identified in 1002 newborn screening samples from a Portuguese population, suggesting a carrier rate of 0.8% [Almeida et al 2007].

AGAT deficiency. No prevalence studies have been performed to date. Seven individuals with AGAT deficiency have been reported worldwide: four from one Italian family [Item et al 2001, Battini et al 2002, Battini et al 2006]; one from the US [Johnston et al 2005]; and two sibs of Yemenite Jewish descent [Edvardson et al 2010].

SLC6A8 deficiency. SLC6A8 deficiency, studied in many cohorts ranging from 37 to 478 individuals with familial or non-familial intellectual disability, was found in:

• 2.1% of males with nonsyndromic X-linked intellectual disability [Rosenberg et al 2004, Mercimek-Mahmutoglu et al 2009];
• 2.2% of males with global developmental delay (defined as IQ<70) [Newmeyer et al 2005];
• 0.8% of males with intellectual disability of unknown cause who had normal testing for fragile X syndrome [Clark et al 2006];
• 5.4% of males with familial intellectual disability of unknown cause who had normal testing for fragile X syndrome;
• 3.5% of males with non-familial intellectual disability of unknown cause [Lion-François et al 2006];
• 66 individuals newly added to the European X-linked intellectual disability (EURO−MRX) consortium (prevalence of 1.5%) [Betsalel et al 2008];
• 2.3% of 157 males with global developmental delay, intellectual disability, and epilepsy [Mercimek-Mahmutoglu et al 2009];
• 2% of the X-linked intellectual disability in the Estonian population [Puusepp et al 2009].

Evaluations Following Initial Diagnosis

To assess the extent of disease and needs of an individual diagnosed with CCDS the following investigations should be performed:

• Detailed neurologic clinical evaluation. For individuals with GAMT deficiency use of a scoring system for cognitive ability, epilepsy, and movement disorder is recommended [Mercimek-Mahmutoglu et al 2006].
• Neuropsychological assessment of behavior and speech
• Video documentation of movement disorder
• EEG
• ECG and cardiac ECHO for cardiac involvement
• Prior to initiation of creatine monohydrate supplementation, glomerular filtration rate (GFR) for baseline assessment of kidney function
• Baseline determination of cerebral creatine level by in vivo MRS to document creatine deficiency [Stöckler et al 1996, Schulze et al 2001].

Treatment of Manifestations

GAMT deficiency. Treatment of GAMT deficiency aims to increase cerebral creatine levels by supplementation with creatine monohydrate in oral doses ranging from 300-400 mg to 2 g/kg BW/day in three to six divided doses. The dose of 350 mg/kg BW/day is about 20 times the daily creatine requirement and has not been associated with side effects in healthy volunteers [Greenhaff et al 1993].

The accumulation of GAA cannot be sufficiently corrected by creatine monohydrate supplementation alone and requires:

• Dietary restriction of arginine (the rate-limiting substrate for GAA synthesis) to 15-25 mg/kg/day that corresponds to 0.4-0.7 g/kg/day protein intake;
• Dietary supplementation of ornithine ranging from a low dose of 100 mg/kg/day (given in order to prevent shortage of arginine supply to the urea cycle) to a high dose of 800 mg/kg/day (which may have an additional effect on further decreasing GAA levels by competitive inhibition of AGAT activity). High-dose ornithine supplementation did not decrease plasma and urinary GAA concentrations in an individual with GAMT deficiency [Stöckler et al 1996]. Verbruggen et al [2007b] reported successful treatment and decrease in GAA levels in plasma and in urine after 29 months of oral ornithine substitution in 2007. Administration of ornithine is divided into three to six daily doses [Schulze et al 1998, Schulze et al 2001].

Oral creatine substitution has been effective in replenishing the cerebral creatine pool to approximately 70% of normal. Of the 23 individuals treated, 18 were treated with creatine monohydrate alone and five were treated with creatine monohydrate and dietary restriction of arginine [Mercimek-Mahmutoglu et al 2006]. Of the 18 treated with creatine monohydrate alone, clinical severity score improved from severe to moderate in four and from moderate to mild in five. Improvement was observed in epileptic seizures and movement disorder. Behavioral disorders improved in all. Neither intellectual ability nor speech improved; irreversible brain damage prior to treatment onset is the most probable explanation for these findings.

Determination of cerebral creatine level by in vivo MRS should be performed for individuals with GAMT deficiency to monitor cerebral creatine levels during creatine supplementation therapy.

Whether early treatment prevents disease manifestations totally is under investigation. Some examples of short-term outcomes following early diagnosis and treatment follow:

• A child, diagnosed at birth (due to a history of GAMT deficiency in an older sib) and treated with arginine-restricted diet and creatine monohydrate and ornithine supplementation at age three weeks prior to the onset of symptoms, had age appropriate development at age 14 months [Schulze et al 2006]. The index case in this family (Patient 9 in Mercimek-Mahmutoglu et al [2006]), who was diagnosed with GAMT deficiency at age 2.5 years, had a mild phenotype: developmental delay was noted about age six to nine months; the infant had speech delay and mild intellectual disability with occasional febrile seizures.
• In one individual with GAMT deficiency and epileptic seizures refractory to oral creatine substitution alone, additional measures to restrict dietary arginine and supplement dietary ornithine resulted in a significant decrease of urinary and plasma GAA concentrations and a significant improvement of epilepsy and EEG findings [Schulze et al 1998, Schulze et al 2001, Schulze et al 2003].
• In another individual treated with oral creatine substitution, dietary arginine restriction, and dietary ornithine supplementation, plasma GAA concentrations normalized and positive behavioral changes, increased alertness and attentiveness, and improved motor abilities were noted [Ensenauer et al 2004].

AGAT (GATM) deficiency. Treatment of AGAT deficiency aims to increase cerebral creatine levels by supplementation with creatine monohydrate in oral doses ranging from 300 to 400 mg to 2 g/kg BW/day in three to six divided doses. The dose of 350 mg/kg BW/day is about 20 times the daily creatine requirement and has not been associated with side effects in healthy volunteers [Greenhaff et al 1993].

Determination of cerebral creatine level by in vivo MRS should be performed for individuals with AGAT deficiency to monitor cerebral creatine levels during creatine supplementation therapy [Battini et al 2002, Battini et al 2006].

In the three individuals with AGAT deficiency treated with oral creatine supplementation, normalization of extremely low pretreatment cerebral creatine levels was accompanied by significant improvement of highly abnormal developmental scores [Bianchi et al 2000, Battini et al 2002]. Nonetheless, despite improvement and stabilization of their overall condition after six years of treatment, the two sisters, ages 13 and 11 years, continued to have moderate intellectual deficiency. In this same family, AGAT deficiency was diagnosed prenatally in a younger sib who was begun on creatine supplementation at age four months. Development in this child was normal at age 18 months, in contrast to his sisters who had already shown signs of developmental delay at this age [Battini et al 2006].

After nine to 17 months of treatment with 400-600 mg/kg/day creatine monohydrate, the child reported by Johnston et al [2005] showed acceleration of growth rate into the normal range, improved psychomotor development, and partial normalization of cerebral creatine levels.

These observations suggest that AGAT deficiency seems to respond better to creatine supplementation than does GAMT deficiency. As GAA concentration in the plasma is not elevated in AGAT deficiency, creatine substitution alone may effectively prevent neurologic sequelae in affected children who are treated early [Stöckler-Ipsiroglu et al 2005].

SLC6A8 deficiency does not appear to respond to the approaches that are effective in GAMT deficiency and AGAT deficiency. Treatment of both males and females with SLC6A8 deficiency with creatine-monohydrate was not successful [Stöckler-Ipsiroglu & Salomons 2006]. Only one heterozygous female with learning disability and mildly decreased creatine concentration on brain MRS showed mild improvement on neuropsychological testing after 18 weeks of treatment with creatine-monohydrate (250-750 mg/kg/day) [Cecil et al 2001].

Since the enzymes for creatine biosynthesis are present in the brain [Braissant & Henry 2008], individuals with SLC6A8 deficiency have been treated with L-arginine and L-glycine, precursors in the biosynthesis of creatine. Four individuals with SLC6A8 deficiency who were treated with oral L-arginine substitution for nine months had no improvement in neuropsychological outcome and cerebral creatine in MRS [Fons et al 2008]. However, in another report an individual with SLC6A8 deficiency showed improved neurologic, language, and behavioral status and an increase of brain creatine and phosphocreatine in MRS [Chilosi et al 2008].

Combined L-arginine and L-glycine supplementation therapy to enhance intra-cerebral creatine synthesis successfully treated intractable epilepsy in a female with SLC6A8 deficiency; however, intellectual disability had not improved after one year of treatment [Mercimek-Mahmutoglu et al 2010a].

Nine males with SLC6A8 deficiency and long-term treatment outcome on L-arginine and glycine along with creatine supplementation therapies initially showed improvement in locomotor and personal social IQ subscales; however, IQ declined after the initial improvement [van de Kamp et al 2011b].

Four males and two females with creatine deficiency treated for 42 months with creatine, L-arginine, and L-glycine did not show improvement in cognitive and psychiatric functions or cerebral creatine levels; however, increased muscle mass and improved gross motor skills were observed [Valayannopoulos et al 2011].

Determination of cerebral creatine level by in vivo MRS should be performed for individuals with SLC6A8 deficiency to monitor cerebral creatine levels for the assessment of treatment outcome during experimental therapies [Mercimek-Mahmutoglu et al 2010b, van de Kamp et al 2011b].

Prevention of Primary Manifestations

See Treatment of Manifestations.

Surveillance

GFR for baseline assessment of kidney function prior to initiation of creatine monohydrate supplementation is recommended. Repeat yearly while on creatine supplementation therapy to detect possible creatine-associated nephropathy [Barisic et al 2002].

Evaluation of Relatives at Risk

For GAMT deficiency and AGAT deficiency early diagnosis of at-risk neonates by biochemical or molecular genetic testing (if the family-specific mutations are known) allows early diagnosis and treatment.

See Genetic Counseling for issues related to evaluation of at-risk relatives for genetic counseling purposes.

Therapies under Investigation

In SLC6A8 deficiency, creatine is not delivered into the brain due to its deficient transporter.

• Dietary supplementation with high dose L-arginine and L-glycine, the primary substrates for creatine biosynthesis, combined with high doses of creatine-monohydrate are being investigated for treatment of SLC6A8 deficiency. The rationale behind this approach is that increased cerebral uptake of both amino acids may enhance intracerebral creatine synthesis [Mancini, van der Knaap, Salomons; unpublished].
• Creatine-derived compounds that cross the blood-brain barrier in a transporter-independent fashion would be useful in the therapy of SLC6A8 deficiency. In vitro, mouse hippocampal slices incubated with creatine benzyl ester or phosphocreatine-Mg-complex acetate, creatine-derived compounds, showed increased tissue creatine content despite functional blockage of creatine transporter with guanidinopropionic acid.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

GAMT deficiency and AGAT (GATM) deficiency are inherited in an autosomal recessive manner.

SLC6A8 deficiency is inherited in an X-linked manner.

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

• The parents of a child with GAMT or AGAT deficiency are obligate heterozygotes and therefore carry one mutant allele.
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an individual with GAMT or AGAT deficiency has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. To date, individuals with GAMT or AGAT deficiency have not reproduced.

Other family members of a proband. Each sib of the proband’s parents is at 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk family members is possible if the disease-causing mutations have been identified in a family member.

Risk to Family Members –X-linked Inheritance

Parents of a Proband

• The father of a male with SLC6A8 deficiency will not have the disease nor will he be a carrier of the mutation.
• In a family with more than one affected male, the mother of an affected male is either an obligate carrier or has germline mosaicism. However, low level somatic mosaicism cannot be excluded [Betsalel et al 2008]. No data are available on the possibility or frequency of germline mosaicism in the mothers.
• If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo mutation and, thus, the mother is not a carrier [Stöckler-Ipsiroglu & Salomons 2006].
• Heterozygous mothers may have a history of learning disability. Skewed X-chromosome inactivation may cause pronounced clinical manifestations in these cases similar to the male phenotype, whereas others remain completely asymptomatic [van de Kamp et al 2011a, Stöckler-Ipsiroglu & Salomons 2006]. One female with severe phenotype of SLC6A8 deficiency had no evidence of skewed X-chromosome inactivation in a peripheral blood sample [Mercimek-Mahmutoglu et al 2010a].
• When an affected male represents a simplex case, several possibilities regarding his mother's carrier status need to be considered:
  • He has a de novo disease-causing SLC6A8 mutation and his mother is not a carrier.
  • His mother has a de novo disease-causing SLC6A8 mutation, either (a) as a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body); or (b) as "germline mosaicism" (i.e., present in some of her germ cells only) [Betsalel et al 2008].
  • His mother has a disease-causing SLC6A8 mutation.

Sibs of a proband

• The risk to sibs depends on the carrier status of the mother.
• If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers. Some of the heterozygous females have learning and behavioral problems [van de Kamp et al 2011a]. Skewed X-chromosome inactivation may cause pronounced clinical manifestations in some females, whereas others remain completely asymptomatic [Stöckler-Ipsiroglu & Salomons 2006].
• If the disease-causing mutation cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of possible germline mosaicism [Betsalel et al 2008].

Offspring of a proband. Males will pass the disease-causing mutation to all of their daughters and none of their sons. To date, no individuals with SLC6A8 deficiency have reproduced.

Other family members of a proband

• The proband's maternal aunts may be at risk of being carriers. The aunts’ offspring, depending upon their gender, may be at risk of being carriers or of being affected.
• In one family, the maternal aunt was described with verbal memory deficit and a mild confrontational naming weakness [deGrauw et al 2003].

Carrier Detection

Molecular genetic testing. Carrier testing of at-risk female relatives is possible if the disease-causing mutation has been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing

• Prenatal diagnosis for pregnancies at risk for GAMT deficiency or AGAT deficiency is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.
• Prenatal testing is possible for pregnancies at increased risk for SLC6A8 deficiency if the SLC6A8 mutation has been identified in a family member. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15 to 18 weeks' gestation. If the karyotype is 46, XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Biochemical genetic testing. Prenatal diagnosis for pregnancies at increased risk for GAMT deficiency is possible by analysis of guanidinoacetate and creatine in amniotic fluid. Amniocentesis was performed in a mother with a ten-year-old child with GAMT deficiency at 15 weeks’ gestation for prenatal diagnosis. Guanidinoacetate was 11.43 μmol/L (normal range for 15 weeks of amenorrhea was 2.96 ± 0.70 μmol/L) [Cheillan et al 2006].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Molecular Genetic Pathogenesis

Creatine is synthesized by two enzymatic reactions: (1) transfer of the amidino group from arginine to glycine, yielding guanidinoacetic acid and catalyzed by L-arginine:glycine amidinotransferase (also known as glycine amidinotransferase, mitochondrial, AGAT, or GATM); or (2) methylation of the amidino group in the guanidinoacetic acid molecule by S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (also known as guanidinoacetate N-methyltransferase or GAMT). Creatine is synthesized primarily in the kidney and pancreas which have high AGAT activity and in liver which has high GAMT activity. Both genes and enzymes have been detected in brain as well [Braissant & Henry 2008]

Synthesized creatine is transported via the bloodstream to the organs of utilization (mainly muscle and brain), where it is taken up via sodium- and chloride-dependent creatine transporter 1 (SLC6A8 protein) (Figure 2) [Wyss & Kaddurah-Daouk 2000]. This protein is predominantly expressed in skeletal muscle and kidney, but also found in brain, heart, colon, testis, and prostate. The creatine-phosphocreatine shuttle has a key function in the maintenance of the energy supply to skeletal and cardiac muscle. Muscle cells do not synthesize creatine, but take it up via a special sodium-dependent transporter, the creatine transporter.

Figure

Figure 2. Schema illustrating (1) CREATINE SYNTHESIS that occurs mainly in liver, pancreas, and kidney; (2) CREATINE UPTAKE into muscle and brain by the creatine transporter (CRTR); and (3) non-enzymatic conversion of creatine to creatinine for CREATININE (more...)

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Suggested Reading

1. von Figura K, Hanefeld F, Isbrandt D, Stöckler-Ipsiroglu S. Guanidinoacetate methyltransferase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill; Chap 84. Available at online. Accessed 8-12-11.
2. Stockler S, Schutz PW, Salomons GS. Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology. Subcell Biochem. 2007;46:149–66. [PubMed: 18652076]
3. Stöckler-Ipsiroglu S, Mercimek-Mahmutoglu S, Salomons GS. Creatine deficiency syndromes. In: Saudubray JM, Van den Berghe G, Walter J, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 5 ed. Heidelberg, Germany: Springer; 2012:239-49.

Revision History

• 18 August 2011 (me) Comprehensive update posted live
• 15 January 2009 (me) Review posted live
• 24 July 2008 (smm) Original submission