Creatine Deficiency Syndromes

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2021-01-18

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Summary

Clinical characteristics.

The cerebral creatine deficiency syndromes (CCDS), inborn errors of creatine metabolism, include the two creatine biosynthesis disorders, guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency, and the creatine transporter (CRTR) deficiency. Intellectual disability and seizures are common to all three CCDS. The majority of individuals with GAMT deficiency have a behavior disorder that can include autistic behaviors and self-mutilation; about 40% have movement disorder. Onset is between ages three months and three years. Only 14 individuals with AGAT deficiency have been reported. The phenotype of CRTR deficiency in affected males ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, movement disorder and behavior disorder; age at diagnosis ranges from two to 66 years. Clinical phenotype of females heterozygous for CRTR deficiency ranges from asymptomatic to severe phenotype resembling male phenotype.

Diagnosis/testing.

Cerebral creatine deficiency in brain MR spectroscopy (¹H-MRS) is the characteristic hallmark of all CCDS. Diagnosis of CCDS relies on: measurement of guanidinoacetate (GAA), creatine, and creatinine in urine and plasma; and molecular genetic testing of the three genes involved, GAMT, GATM, and SLC6A8. If molecular genetic test results are inconclusive, GAMT enzyme activity (in cultured fibroblast or lymphoblasts), GATM enzyme activity (in lymphoblasts), or creatine uptake in cultured fibroblasts can be assessed.

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. In males with CRTR deficiency creatine supplementation alone does not improve clinical outcome and does not result in replenished cerebral creatine levels; likewise, high-dose L-arginine and L-glycine supplementation so far has not consistently improve clinical or biochemical outcome in males although some have been reported to have increased muscle mass and improved motor and personal social IQ skills. One female with intractable epilepsy responded to high-dose L-arginine and L-glycine supplementation with cessation of seizures.

Prevention of primary manifestations: Early treatment at the asymptomatic stage of the disease in individuals with GAMT and AGAT deficiencies appears to be beneficial: treatment in newborn sibs of individuals with AGAT or GAMT deficiency prevented disease manifestations.

Surveillance: In those treated with creatine monohydrate, routine measurement of renal function to detect possible creatine-associated nephropathy is warranted.

Evaluation of relatives at risk: Early diagnosis of neonates at risk for GAMT deficiency, AGAT deficiency, and CRTR deficiency by biochemical or molecular genetic testing allows for early diagnosis and treatment of the defects in creatine metabolism.

Genetic counseling.

GAMT deficiency and AGAT deficiency are inherited in an autosomal recessive manner. At conception, each sib of an individual with GAMT deficiency 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. CRTR deficiency is inherited in an X-linked manner. Mothers who are carriers 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 heterozygous and may have learning and behavior problems. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible for all three defects in creatine metabolism if the pathogenic variants in the family are known.

Diagnosis

The cerebral creatine deficiency syndromes (CCDS) are inborn errors of creatine metabolism that include [Stockler-Ipsiroglu et al 2012]:

Two creatine biosynthesis defects (both inherited in an autosomal recessive manner):
- Guanidinoacetate methyltransferase (GAMT) deficiency
- L-arginine:glycine amidinotransferase (AGAT) deficiency
One creatine transporter defect (inherited in an X-linked manner): creatine transporter (CRTR) deficiency

Suggestive Findings

Cerebral creatine deficiency syndromes (CCDS) should be suspected in:

A young child with developmental delay, hypotonia, seizures, and movement disorder;
An older child with intellectual disability, epilepsy, movement disorder, and behavior problems.

See Table 1.

Table 1.

Clinical Features of GAMT, AGAT, and CRTR Deficiency

Deficiency	# of Affected Persons	ID	Epilepsy		Movement Disorder ¹		Behavior Problems
Deficiency	# of Affected Persons	ID	Frequency	Drug Resistance	Frequency	Severity	Behavior Problems
GAMT	110	Mild to severe	69/80 (86%) ²	46% ²	30/80 (37.5%) ²	Mild to severe ²	Hyperactivity, autism spectrum disorder, aggressive behavior, self-injurious behavior
AGAT	14	Mild to moderate	2/14 (14%)	None	None		None
CRTR	>160 ³	Mild to severe	59/101 (60%) males ³	3/59 (5%) ³	41/101 (40%) ³	Mild to severe ⁴	86/101 (85%) attention deficit hyperactivity, autism spectrum disorder ³

: ID = intellectual disability
1.: Dystonia, chorea, choreoathetosis, ataxia
2.: Based on the 80 patients reported by Mercimek-Mahmutoglu et al [2006], Stockler-Ipsiroglu et al [2014], and Mercimek-Mahmutoglu et al [2014a]
3.: The authors are aware of more than 160 patients; however, the clinical characteristics have only been described for ~101 males from 85 families. The most recent international registry paper to review these data is van de Kamp et al [2013a].
4.: 101 males reported by van de Kamp et al [2013b] had movement disorder including ataxia (29%) and dystonia or athetosis (11%).

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, van de Kamp et al 2014, Mørkrid et al 2015].

Table 2.

Urinary Metabolites by CCDS Disorder

Deficiency		GAA ¹ Concentration	Creatine Concentration	Creatine/Creatinine Ratio
GAMT		Elevated ²	Low to low normal ³	Low normal
AGAT		Low to low normal ⁴	Low normal ³	Low normal
CRTR	Males	Normal ⁵	Normal to elevated	Elevated ⁶
CRTR	Females	Normal	Normal to elevated	Normal to mildly elevated

1.: Guanidinoacetate
2.: Pathognomonic finding
3.: Battini et al [2002], Stockler-Ipsiroglu et al [2012]
4.: Almeida et al [2004], Cognat et al [2004]
5.: If GAA is presented as guanidinoacetate mmol/mol creatinine, the values may appear slightly increased because of the generally lower creatinine values in males with CRTR deficiency.
6.: Diagnostic finding [van de Kamp et al 2013a, van de Kamp et al 2014]

Table 3.

Plasma Concentration of Metabolites by CCDS Disorder

Deficiency		GAA ¹	Creatine	Creatinine
GAMT		Elevated ²	Low	Low to normal ⁴
AGAT		Low to low normal ³	Low ³
CRTR	Males	Normal	Normal ³
CRTR	Females	Normal	Normal
Normal		See age-related reference range ³	Normal	Normal

1.: Guanidinoacetate
2.: Mercimek-Mahmutoglu et al [2006]
3.: Almeida et al [2004], van de Kamp et al [2015]
4.: Determination of plasma creatinine concentration alone cannot identify a CCDS.

Table 4.

CSF Concentration of Metabolites by CCDS Disorder

Deficiency		GAA ¹	Creatine	Creatinine
GAMT		Elevated ²	Low	Low
AGAT		No data	No data	No data
CRTR	Males	Normal to mildly elevated ³	Normal to mildly elevated ³	Low
CRTR	Females	No data	No data	No data
Normal		See age-related reference range ⁴	Normal	Normal

1.: Guanidinoacetate
2.: Mercimek-Mahmutoglu et al [2006]
3.: van de Kamp et al [2013b]
4.: Almeida et al [2004], Cognat et al [2004]

Brain imaging for in vivo assessment of brain creatine levels. Proton magnetic resonance spectroscopy (¹H-MRS) reveals almost complete depletion of the cerebral creatine pool in all individuals with GAMT deficiency and AGAT deficiency and in males with CRTR deficiency. Partial depletion or even normal levels of the cerebral creatine pool are observed in female carriers with X-linked CRTR deficiency [van de Kamp et al 2011].

Note: Complete lack of creatine in the presence of a normal choline and N-acetyl aspartate (NAA) levels in ¹H-MRS is unique to CCDS [Stöckler et al 1996].

Establishing the Diagnosis

The diagnosis of CCDS is established in a proband with identification of biallelic pathogenic variants in GAMT or GATM or a hemizygous pathogenic variant (in males) of SLC6A8 on molecular genetic testing (see Table 5) using the following algorithm for guidance.

The diagnostic testing algorithm for an individual with the listed clinical features and/or reduced creatine levels on brain ¹H-MRS (see Figure 1):

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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 genetic (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 brain ¹H-MRS [van de Kamp et al 2011].
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 [Item et al 2001, Verhoeven et al 2003, Verhoeven et al 2004].
Note: Methods for testing GAMT enzyme activity (in cultured fibroblast or lymphoblasts), AGAT enzyme activity (in lymphoblasts), or creatine uptake in cultured fibroblasts have been reported and may be helpful in the interpretation of variants of unknown significance [Rosenberg et al 2007, Betsalel et al 2012, Mercimek-Mahmutoglu et al 2012b, Mercimek-Mahmutoglu et al 2014a, Desroches et al 2015]. See Molecular Genetics for details.

Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

GAMT, GATM, and SLC6A8 testing is advised if biochemical features (e.g. creatine deficiency in brain ¹H-MRS) are suggestive of GAMT, AGAT, or CRTR deficiency.
Serial single gene testing is advised in the case of specific abnormalities in metabolites of creatine metabolism in body fluids (Tables 2-4). Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis and/or mRNA analysis if only one or no pathogenic variant is found.
A multigene panel that includes GAMT, GATM, SLC6A8, and other genes of interest (see Differential Diagnosis) may also be considered in patients with developmental delay, intellectual disability, and/or epilepsy and/or movement disorder who did not undergo biochemical investigations for CCDS. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of CCDS.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 5.

Molecular Genetic Testing Used in CCDS

Gene ¹	Proportion of CCDS Attributed to Pathogenic Variants in Gene	Proportion of Pathogenic Variants ² Detected by Method ³
Gene ¹		Sequence analysis ⁴	Gene-targeted deletion/duplication analysis ⁵
GAMT	39% ⁶	~100% ⁶	Unknown ⁷
GATM	5% ⁸	~100% ⁸	Unknown ⁷
SLC6A8	56% ⁹	~95% ^9, 10	~5% ¹¹

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: In individuals with biochemical and/or enzymatic diagnosis of a specific CCDS
4.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6.: Mercimek-Mahmutoglu et al [2006], Mercimek-Mahmutoglu et al [2014a], Stockler-Ipsiroglu et al [2014]
7.: No data on detection rate of gene-targeted deletion/duplication analysis are available.
8.: Item et al [2001], Battini et l [2002], Battini et al [2006], Edvardson et al [2010], Verma [2010], Ndika et al [2012], Comeaux et al [2013], Nouioua et al [2013]
9.: van de Kamp et al [2013a]
10.: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
11.: Anselm et al [2006], van de Kamp et al [2015], Leiden Open Variation Database

Clinical Characteristics

Clinical Description

Intellectual disability and seizures are common to all three creatine deficiency syndromes. Intellectual disability is associated with expressive speech delay and behavior disorder [Stockler-Ipsiroglu et al 2012].

GAMT Deficiency

Approximately 110 affected individuals have been published either as single case reports or small groups of cases [Mercimek-Mahmutoglu et al 2006, Verbruggen et al 2007, Vodopiutz et al 2007, Dhar et al 2009, Engelke et al 2009, O'Rourke et al 2009, Sempere et al 2009a, Mercimek-Mahmutoglu et al 2010b, Cheillan et al 2012, Nasrallah et al 2012, Comeaux et al 2013, El-Gharbawy et al 2013, Viau et al 2013, Akiyama et al 2014, Mercimek-Mahmutoglu et al 2014a, Mercimek-Mahmutoglu et al 2014b, Stockler-Ipsiroglu et al 2014].

A review of 80 individuals with GAMT deficiency revealed that intellectual disability and epilepsy are the most consistent clinical features [Mercimek-Mahmutoglu et al 2006, Mercimek-Mahmutoglu et al 2014a, Stockler-Ipsiroglu et al 2014]. About 60% of individuals with GAMT deficiency have a severe phenotype characterized by severe intellectual disability, intractable epilepsy, and movement disorder [Mercimek-Mahmutoglu et al 2006, Mercimek-Mahmutoglu et al 2014a, Stockler-Ipsiroglu et al 2014].

Onset of the first clinical manifestations ranges from early infancy (age 3-6 months) to age three years.

Intellectual disability, the most consistent clinical manifestation, is present in all affected individuals. The severity of intellectual disability ranges from mild to severe. About 60% of individuals with GAMT deficiency have severe developmental delay or intellectual disability [Mercimek-Mahmutoglu et al 2006, Mercimek-Mahmutoglu et al 2014a, Stockler-Ipsiroglu et al 2014].

Language. Variable expressive language deficits were reported in two sibs with GAMT deficiency: the index case spoke fewer than ten words whereas her younger sister spoke in short sentences at age 13 years [O'Rourke et al 2009].

Seizures, the second most consistent manifestation in GAMT deficiency, are observed in about 78% of affected individuals. Seizure types include myoclonic, generalized tonic-clonic, partial complex, head nodding, and atonic seizures. Seizure severity ranges from occasional seizures to seizures that are non-responsive to various antiepileptic drugs [Mercimek-Mahmutoglu et al 2006, Mercimek-Mahmutoglu et al 2014a, Stockler-Ipsiroglu et al 2014].

Movement disorders, observed in about 30% of individuals, are mainly chorea, athetosis, dystonia, or ataxia [Mercimek-Mahmutoglu et al 2006, Mercimek-Mahmutoglu et al 2014a, Stockler-Ipsiroglu et al 2014]. Pathologic signal intensities in the basal ganglia in brain MRI are observed in individuals with or without a movement disorder [Mercimek-Mahmutoglu et al 2006, Mercimek-Mahmutoglu et al 2014a, Stockler-Ipsiroglu et al 2014]. The onset is usually before age 12 years; however, recently a young woman with GAMT deficiency was reported to have onset of movement disorder (including ballistic and dystonic movements) at age 17 years [O'Rourke et al 2009].

A behavior disorder (e.g., hyperactivity, autism, or self-injurious behavior) is reported in about 77% of affected individuals [Mercimek-Mahmutoglu et al 2006, Mercimek-Mahmutoglu et al 2014a].

AGAT Deficiency

Fourteen individuals from seven families have been diagnosed with AGAT deficiency [Item et al 2001, Battini et al 2002, Battini et al 2006, Edvardson et al 2010, Verma 2010, Ndika et al 2012, Comeaux et al 2013, Nouioua et al 2013].

Intellectual disability, the most consistent clinical manifestation, is present in all affected individuals. The severity of intellectual disability ranges from mild to moderate.

Seizures, observed in only 9% of affected individuals, were occasional and associated with fever.

Muscle weakness or hypotonia was observed in 67% of affected individuals [Edvardson et al 2010, Verma 2010, Ndika et al 2012, Nouioua et al 2013].

Failure to thrive was reported in two sibs [Edvardson et al 2010].

A behavior disorder was present in 27% of affected individuals.

Movement disorders were not reported in any affected individuals.

CRTR Deficiency

Affected Males

Since the first description of SLC6A8 deficiency by Salomons et al [2001], 85 families comprising a total of 101 male individuals with an SLC6A8 pathogenic variant have been reported in a single international registry study [van de Kamp et al 2013a]. The phenotype ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, and behavior disorder that may become more marked during the course of the disease.

The age at diagnosis ranges from one to 66 years indicating that life expectancy can be normal. Now that the disorder is reasonably well described and diagnostic testing is more widely available, it is anticipated that diagnosis will mainly occur within the first three years of life.

Intellectual disability was present in all affected male individuals ranging from mild to severe: 85% of affected males had mild to moderate intellectual disability up to age four years; 75% of affected males older than age 18 years had severe intellectual disability [van de Kamp et al 2013a]. One adult had progressive cognitive dysfunction [Kleefstra et al 2005].

Speech-language disorder. Speech development was delayed in all affected males. First words were at a mean age of 3.1 years (age range: 9 months to 10 years). In affected males older than age ten years, 14% had no speech development, 55% were able to speak single words, and 31% were able to speak in sentences [van de Kamp et al 2013a].

A neuropsychological profile in four affected boys from two unrelated families from the Netherlands revealed a semantic-pragmatic language disorder (difficulty in understanding the meaning of words) with oral dyspraxia [Mancini et al 2005].

Seizures were present in 59% of affected male individuals. The most common seizure type was generalized tonic-clonic and simple or complex partial seizures with or without secondary generalization. Absence and myoclonic seizures were rare. Age of seizure onset was between one and 21 years [van de Kamp et al 2013b]. Fewer than ten patients with intractable epilepsy have been reported [Mancardi et al 2007, Fons et al 2009, Mercimek-Mahmutoglu et al 2010a, van de Kamp et al 2013a].

Movement disorder. Wide-based gait or ataxia and dystonia or athetosis were reported in 29% and 11% of affected males respectively [van de Kamp et al 2013a].

Behavior disorder. Behavior disorder was reported in 85% of affected males. The most common behavior disorders were attention deficit and/or hyperactivity (55%) and autistic features (41%). Other behavior disorders reported in affected males include social anxiety or shyness (20%), stereotypic behavior (20%), impulsive behavior (27%), aggressive behavior (19%), self-injurious behavior (10%), and obsessive-compulsive behavior (8%) [van de Kamp et al 2013a].

Other neurologic clinical features. Hypotonia was present in 40% of affected males. Spasticity was reported in 26% of affected males. Four individuals had mild (sensorial-neural) hearing loss. Nine affected males were reported with strabismus or bilateral abducens nerve palsy. Myopathic face, ptosis, joint laxity (likely secondary to the hypotonia), and decreased muscle bulk were also reported [van de Kamp et al 2013a].

Other non-neurologic clinical features

Dysmorphic features including microcephaly, broad forehead, midface retrusion, high palate, short nose, prominent nasal bridge, ear differences (underfolded helices, large ears, and/or cupped ears), deeply set eyes, fifth finger clinodactyly, and slender body build were reported in 45% of affected males [Anselm et al 2006, van de Kamp et al 2013a, van de Kamp et al 2013b].
Gastrointestinal findings including failure to thrive, vomiting, constipation, ileus likely secondary to constipation, hepatitis, gastric and duodenal ulcers, and hiatal hernia (which may or may not be related to CRTR deficiency) were reported in 35% of affected males [van de Kamp et al 2013a].
Cardiac features. One boy with CRTR deficiency developed multiple premature ventricular contractions in his second year [Anselm et al 2008]. Two affected males with mild cardiomyopathy were reported [Puusepp et al 2010]. One affected male had long QT syndrome [van de Kamp et al 2013a].
Medical concerns in adulthood. Twenty-one of 101 affected males were adults (age >18 years). Adults affected with CRTR deficiency had intellectual disability ranging from moderate to severe [van de Kamp et al 2013b]. They presented with myopathic face, ptosis, external ophthalmoplegia, or parkinsonism. Chronic constipation leading to megacolon, ileus or bowel perforation, and/or gastric or duodenal ulcer disease have been reported in some adults [Hahn et al 2002, Kleefstra et al 2005, Sempere et al 2009b, van de Kamp et al 2013a].

Heterozygous Females

Females heterozygous for their family-specific SLC6A8 pathogenic variant are either asymptomatic or have mild intellectual disability [van de Kamp et al 2011]. There was no clinical correlation between skewed X-inactivation in favor of the pathogenic