Clinical characteristics.

The creatine deficiency disorders (CDDs), inborn errors of creatine metabolism and transport, comprise three disorders: the creatine biosynthesis disorders guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency; and creatine transporter (CRTR) deficiency. Developmental delay and cognitive dysfunction or intellectual disability and speech-language disorder are common to all three CDDs.

• Onset of clinical manifestations of GAMT deficiency (reported in ~130 individuals) is between ages three months and two years; in addition to developmental delays, the majority of individuals have epilepsy and develop a behavior disorder (e.g., hyperactivity, autism, or self-injurious behavior), and about 30% have movement disorder.
• AGAT deficiency has been reported in 16 individuals; none have had epilepsy or movement disorders.
• Clinical findings of CRTR deficiency in affected males (reported in ~130 individuals) in addition to developmental delays include epilepsy (variable seizure types and may be intractable) and behavior disorders (e.g., attention deficit and/or hyperactivity, autistic features, impulsivity, social anxiety), hypotonia, and (less commonly) a movement disorder. Poor weight gain with constipation and prolonged QTc on EKG have been reported. While mild-to-moderate intellectual disability is commonly observed up to age four years, the majority of adult males with CRTR deficiency have been reported to have severe intellectual disability. Females heterozygous for CRTR deficiency are typically either asymptomatic or have mild intellectual disability, although a more severe phenotype resembling the male phenotype has been reported.

Diagnosis/testing.

The diagnosis of a CDD is established in a proband with suggestive findings and biallelic pathogenic variants in GAMT or GATM or a hemizygous or heterozygous pathogenic variant in SLC6A8 identified by molecular genetic testing.

Management.

Treatment of manifestations: GAMT deficiency and AGAT deficiency are treated with oral creatine monohydrate to replenish cerebral creatine levels. Treatment of GAMT deficiency requires supplementation of ornithine and dietary restriction of arginine or protein. CRTR deficiency is treated with oral creatine monohydrate and arginine and glycine supplementation. The developmental delay, intellectual disability, and behavior problems are managed with an individualized education and therapy program; epilepsy and movement disorder are treated by the appropriate specialist in a standard manner.

Surveillance: In those treated with creatine monohydrate, periodic determination of cerebral creatine level by in vivo ¹H-MRS and annual measurement of renal function to detect possible creatine-associated nephropathy is warranted. Developmental and neurologic assessments are recommended at each clinic visit.

Evaluation of relatives at risk: Early diagnosis of neonates at risk for a CDD by biochemical or molecular genetic testing allows for early diagnosis and treatment.

Genetic counseling.

GAMT deficiency (caused by pathogenic variants in GAMT) and AGAT deficiency (caused by pathogenic variants in GATM) are inherited in an autosomal recessive manner. CRTR deficiency (caused by pathogenic variants in SLC6A8) is inherited in an X-linked manner.

• Autosomal recessive inheritance. If both parents are known to be heterozygous for a GAMT or GATM pathogenic variant, each sib of an affected individual has at conception 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 the GAMT or GATM pathogenic variants have been identified in an affected family member, molecular genetic carrier testing and prenatal and preimplantation genetic testing are possible.
• X-linked inheritance. Mothers who are heterozygous for an SLC6A8 pathogenic variant have a 50% chance of transmitting the pathogenic variant in each pregnancy; sons who inherit the pathogenic variant will be affected; daughters who inherit the pathogenic variant will be heterozygotes and may develop clinical findings related to the disorder. Once the SLC6A8 pathogenic variant has been identified in an affected family member, molecular genetic testing to identify female heterozygotes and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

A CDD should be suspected in probands with the following clinical, biochemical, and imaging findings and family history.

Clinical findings

• Developmental delay
• Cognitive dysfunction or intellectual disability
• Hypotonia
• Seizures or refractory epilepsy
• Movement disorders (e.g., chorea-athetosis, dystonia)
• Behavior problems (e.g., attention-deficit/hyperactivity disorder, autism spectrum disorder, aggressive behavior)

Biochemical findings [van de Kamp et al 2014, Mørkrid et al 2015]

• GAMT deficiency. Elevated guanidinoacetate (GAA) levels in urine, plasma, or cerebrospinal fluid (CSF) and low or low-normal creatine and creatinine levels in urine, plasma, or CSF
• AGAT deficiency. Low GAA levels in urine, plasma, or CSF and low or low-normal creatine and creatinine levels in urine, plasma, or CSF
• CRTR deficiency. Elevated creatine-to-creatinine ratio in urine in males. Females can have normal or mildly elevated creatine-to-creatinine ratio in urine.

Imaging findings

• Proton magnetic resonance spectroscopy (¹H-MRS) reveals absent or significantly decreased creatine peak in the brain in all individuals with GAMT deficiency and AGAT deficiency and in males with CRTR deficiency [van de Kamp et al 2014].
• ¹H-MRS reveals partial depletion or normal levels of creatine peak in the brain in heterozygous females with X-linked CRTR deficiency [van de Kamp et al 2011].

Family history

• GAMT and AGAT deficiencies. Consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
• CRTR deficiency. Consistent with X-linked inheritance (e.g., no male-to-male transmission, affected maternal uncle or male sibs, normal to mildly affected female sibs or mother). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of a CDD is established in a proband with suggestive clinical findings by identification of biallelic pathogenic (or likely pathogenic) variants in GAMT or GATM or of a hemizygous or heterozygous pathogenic (or likely pathogenic) variant in SLC6A8 on molecular genetic testing.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic GAMT or GATM variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) does not establish or rule out the diagnosis of GAMT or AGAT deficiency. In these individuals, typical brain ¹H-MRS and abnormal urine, plasma, or CSF GAA and creatine levels and GAMT and AGAT activity measurements in fibroblasts or in lymphocytes will be required to confirm biochemical diagnosis of GAMT or AGAT deficiency. (3) Identification of a hemizygous or heterozygous SLC6A8 variant of uncertain significance does not establish or rule out a diagnosis of CTR deficiency. In these individuals, abnormal brain ¹H-MRS and abnormal levels of urine creatine-to-creatinine ratio in males will be required to confirm biochemical diagnosis. Creatine uptake in the individual's cultured skin fibroblasts will be required to confirm biochemical diagnosis of CRTR deficiency in males.

A diagnostic testing algorithm is useful for guiding molecular genetic testing in an individual suspected of having suggestive clinical, biochemical, and/or imaging findings and/or reduced creatine levels on brain ¹H-MRS (see Figure 1).

Figure 1.

Algorithm for diagnosis of the creatine deficiency disorders. Note: Urinary creatine-to-creatinine ratio and creatine uptake studies in cultured skin fibroblasts are often not informative in females with SLC6A8 deficiency; hence, molecular genetic testing (more...)

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel for epilepsy, intellectual disability, or autism spectrum disorder) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved based on the biochemical and imaging findings, whereas genomic testing does not. Individuals with the distinctive biochemical or imaging findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with intellectual disability and/or epilepsy are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Developmental delay, cognitive dysfunction, and intellectual disability are common to all three creatine deficiency disorders (CDDs). See Table 2 for comparison of the three deficiencies; further details follow the table.

Genotype-Phenotype Correlations

No genotype-phenotype correlations for any of the CDDs have been identified.

Prevalence

GAMT deficiency. About 130 individuals with GAMT deficiency have been diagnosed worldwide.

The estimated incidence of GAMT deficiency in the general population ranges from 1:2,640,000 to 1:250,000 [Desroches et al 2015, Mercimek-Mahmutoglu et al 2016]. This is in agreement with information from pilot newborn screening programs for GAMT deficiency, which screened more than 1,500,000 newborns; to date two of the newborns have a confirmed diagnosis of GAMT deficiency [Mercimek-Mahmutoglu et al 2012, Pasquali et al 2014, Pitt et al 2014, Stockler-Ipsiroglu et al 2014, Sinclair et al 2016, Hart et al 2021].

The estimated incidence of GAMT deficiency in the Utah and New York newborn population was 1:405,655 [Hart et al 2021].

Smaller studies of individuals with neurologic disease or severe intellectual disability found GAMT deficiency present in 1.1% [Cheillan et al 2012].

AGAT deficiency. The estimated carrier frequency of AGAT deficiency was one in 1,292 (0.077%; CI=0.06%-0.10%) in the general population using the ExAC Browser Beta database [DesRoches et al 2016].

CRTR deficiency. CRTR deficiency has been studied in many cohorts ranging from 49 to 4,426 individuals with familial or nonfamilial ID. These studies were summarized by van de Kamp et al [2014]; the prevalence in males with ID was estimated between 0.4% and 1.4%. In a recent study, the prevalence of creatine transporter deficiency was 2.64% in individuals with neurodevelopmental disorders [Bahl et al 2020].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a CDD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The general treatment of CDDs of any cause is presented in Table 5.

Medical treatment specific to the type of CDD follows in Table 6 (GAMT deficiency), Table 7 (AGAT deficiency), and Table 8 (CRTR deficiency).

Prevention of Primary Manifestations

See Treatment of Manifestations.

Surveillance

Surveillance recommendations for CDDs are summarized in Table 9.

Evaluation of Relatives at Risk

It is appropriate to evaluate neonates at risk for a creatine deficiency disorder to allow for early diagnosis and treatment. (Note: It is not proven that early treatment of CRTR deficiency would change the outcome.)

Evaluations can include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Biochemical genetic testing if the pathogenic variants in the family are not known.

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

Pregnancy Management

Pregnancy management has been reported in a single individual with AGAT deficiency. The fetal growth and head circumference declined by 20 weeks of pregnancy during monitoring. Creatine levels were low in the pregnant woman. Daily creatine dose was increased in the pregnant woman, and the baby was normal at delivery and was not affected with AGAT deficiency [Alessandrì et al 2020].

Therapies Under Investigation

There are no current clinical trials for any of the CDDs. Some pharmacotherapies are being investigated in cell lines or animal models of CRTR deficiency:

• Swiss mice brain hippocampal slices were treated with diacetyl creatine ethyl ester (DAC) after creatine transporter was blocked using guanidinopropionic acid. The study showed an increase in intracellular creatine, and DAC was metabolized to creatine. Authors concluded that further research is needed to fully elucidate their hypotheses [Adriano et al 2018].
• Dodecyl creatine ester was administered intranasally and intracerebroventricularly in Slc6a8^-/y mice and a novel object recognition (NOR) test was applied. There was restoration of NOR learning and 50% increase in creatine [Ullio-Gamboa et al 2019].
• 4-phenylbutyrate (4-PBA) was shown to increase creatine uptake in transfected HEK293 cells expressing pathogenic variants in SLC6A8 [El-Kasaby et al 2019]. 4-PBA was considered to be a pharmaco-chaperone to rescue CTRT activity.
• Cyclocreatine was used in a CRTR deficiency mouse model and was effective in treating cognitive functions, epilepsy, and behavioral features [Cacciante et al 2020].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency are inherited in an autosomal recessive manner.

Creatine transporter (CRTR) deficiency is inherited in an X-linked manner.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with GAMT or AGAT deficiency are presumed to be heterozygous for a GAMT or GATM pathogenic variant.
• Molecular genetic testing recommended for the parents of a proband to confirm that both parents are heterozygous for a GAMT or GATM pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same 2 pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a GAMT or GATM pathogenic variant, each sib of an affected individual has at conception 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with GAMT or AGAT deficiency are not known to reproduce.

Other family members. Each sib of the proband's parents is at 50% risk of being a carrier of a GAMT or GATM pathogenic variant.

Carrier detection. Molecular genetic carrier testing for at-risk relatives requires prior identification of the GAMT or GATM pathogenic variants in the family.

Note: Because biochemical testing is normal in carriers for GAMT and AGAT deficiencies, identification of carriers requires molecular genetic testing for the familial GAMT or GATM pathogenic variants.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of a male with CRTR deficiency will not have the disorder nor will he be hemizygous for the SLC6A8 pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected child, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the SLC6A8 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member, the mother may be a heterozygote, the affected male may have a de novo SLC6A8 pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/germline mosaicism [van de Kamp et al 2013a, van de Kamp et al 2014].
  • SLC6A8 pathogenic variants occurred de novo in 30% of the individuals with CRTR deficiency in a retrospective study of 85 families [van de Kamp et al 2013a].
  • 7% of mothers in a retrospective study of 85 families had somatic/germline mosaicism [van de Kamp et al 2013a].
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• Heterozygous mothers may have a history of learning disability or mild intellectual disability or seizures [Mercimek-Mahmutoglu et al 2010, van de Kamp et al 2011] (see Clinical Description, CRTR Deficiency ‒ Heterozygous Females).

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has an SLC6A8 pathogenic variant, the chance of transmitting it in each pregnancy is 50%:
  • Males who inherit the pathogenic variant will be affected;
  • Females who inherit the pathogenic variant will be heterozygous and may develop clinical findings related to the disorder (see Clinical Description, CRTR Deficiency ‒ Heterozygous Females).
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the SLC6A8 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism [van de Kamp et al 2011, van de Kamp et al 2013a].

Offspring of a male proband. Affected males are not to known to reproduce.

Other family members. The proband's maternal aunts may be at risk of being heterozygous for the SLC6A8 pathogenic variant and the aunts' offspring, depending on their sex, may be at risk of being heterozygous or hemizygous for the pathogenic variant.

Heterozygote detection. Molecular genetic testing to identify female heterozygotes requires prior identification of the SLC6A8 pathogenic variant in the family. Note: Females who are heterozygous for an SLC6A8 pathogenic variant may develop clinical findings related to the disorder (see Clinical Description, CRTR Deficiency ‒ Heterozygous Females).

Note: Because heterozygous females may have a normal creatine-to-creatinine ratio in urine and normal creatine content on brain ¹H-MRS [van de Kamp et al 2011], identification of female heterozygotes requires SLC6A8 molecular genetic testing.

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 and discussion of the availability of prenatal/preimplantation genetic 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 heterozygous or are at risk of being heterozygous.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the GAMT, GATM, or SLC6A8 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Biochemical testing. Prenatal diagnosis for a pregnancy at increased risk for GAMT deficiency is possible by analysis of guanidinoacetate (GAA) and creatine in amniotic fluid. Amniocentesis for prenatal diagnosis was performed at 15 weeks' gestation in the mother of a child with GAMT deficiency. GAA was 11.43 μmol/L (normal range for 15 weeks of amenorrhea was 2.96±0.70 μmol/L) [Cheillan et al 2006]. As there is very limited information on the use of biochemical testing in the prenatal diagnosis of creatine deficiency disorders, molecular genetic testing is the preferred method for prenatal diagnosis.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Creatine is synthesized by two enzymatic reactions:

• Transfer of the amidino group from arginine to glycine, yielding guanidinoacetic acid (GAA) and catalyzed by L-arginine:glycine amidinotransferase (also known as glycine amidinotransferase, mitochondrial, AGAT, or GATM)
• Methylation of the amidino group in the GAA 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 the liver, which has high GAMT activity. Both genes and enzymes have been detected in the 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 2.

Schema illustrating (1) CREATINE SYNTHESIS that occurs mainly in liver, pancreas, and kidney; (2) CREATINE UPTAKE into cells (especially for high energy-requiring organs such as muscles and the brain by the creatine transporter (CRTR); and (3) non-enzymatic (more...)

Mechanism of disease causation

• Biallelic pathogenic variants in either GAMT or GATM result in a deficiency of the associated enzyme, resulting in deficient synthesis of creatine.
• A hemizygous (or heterozygous) pathogenic variant in SLC6A8 results in deficient synthesis of the creatine transporter protein, resulting in deficient transport of creatine to the brain and muscle.

Gene-specific laboratory considerations: SLCA8. A paralogous copy of this gene is localized at chromosome 16, which can interfere with the genetic tests.

Author Notes

Dr Mercimek-Andrews has long-standing experience in the diagnosis and treatment of creatine deficiency disorders (CDDs). She is a neurometabolic physician and clinician scientist. She treats patients with CRTR deficiency and provides consultations to physicians and parents for the treatment of CDDs. She is one of the Scientific Medical Advisory Board members for the Association for Creatine Deficiencies.

www.wchri.org/members-and-trainees/find-a-researcher/saadet-andrews/

www.ualberta.ca/medical-genetics/people/faculty/saadet-andrews.html

Dr Salomons has long-standing experience in the laboratory diagnosis of CDDs. She is a clinical laboratory genetic specialist and head of the Laboratory of Genetic Metabolic Diseases at the Amsterdam University Medical Centers, the Netherlands. She discovered CRTR deficiency with her team and that of Dr DeGrauw.

www.amc.nl/web/laboratory-genetic-metabolic-diseases-lgmd.htm

Acknowledgments

We would like to thank Dr Sylvia Stöckler (Stöckler-Ipsiroglu), who discovered the first two creatine biosynthesis defects, GAMT deficiency and AGAT deficiency.

We would like to thank Dr DeGrauw and Dr Salomons, who discovered CRTR deficiency.

We would like to thank Dr Schulze, who discovered the high-dose ornithine supplementation combined with an arginine- and protein-restricted diet for the treatment of GAMT deficiency.

Author History

Saadet Mercimek-Andrews, MD, PhD, FCCMG, FRCPC (2008-present)
Gaija S Salomons, PhD (2008-present)
Sylvia Stöckler-Ipsiroglu, MD, PhD, MBA, FRCPC; University of British Columbia (2008-2015)

Revision History

• 10 February 2022 (ha) Comprehensive update posted live
• 10 December 2015 (me) Comprehensive update posted live
• 18 August 2011 (me) Comprehensive update posted live
• 15 January 2009 (me) Review posted live
• 24 July 2008 (smm) Original submission

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