Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.0
• Status (Adult): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: SLC6A8, GAMT, GATM
• Condition: Cerebral creatine deficiency syndromes
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• SLC6A8 ⇔ 0000456 (cerebral creatine deficiency syndrome): Limited Actionability
• GAMT ⇔ 0000456 (cerebral creatine deficiency syndrome): Moderate Actionability
• GATM ⇔ 0000456 (cerebral creatine deficiency syndrome): Moderate Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric for GAMT and GATM. For SLC6A8 all experts rated as limited instead because of concerns of effectiveness.

Final Consensus Scores

Gene Condition Pairs: GAMT ⇔ 0000456 (OMIM:612736)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity due to creatine biosynthesis deficiency (GAMT deficiency) / Referral to specialist to guide creatine supplementation and dietary management	2	3C	2C	2	9CC
Morbidity due to creatine biosynthesis deficiency (AGAT deficiency) / Referral to specialist to guide creatine supplementation	2	2C	2C	2	8CC
Morbidity due to creatine transporter deficiency (males only) (CRTR deficiency) / Referral to specialist to guide creatine, arginine, and glycine supplementation	2	3C	1C	2	8CC

Gene Condition Pairs: GATM ⇔ 0000456 (OMIM:612718)

Gene Condition Pairs: SLC6A8 ⇔ 0000456 (OMIM:300352)

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Creatine transporter (CRTR) deficiency is the most common cerebral creatine deficiency syndrome (CCDS), with over 150 individuals reported. In males, the estimated prevalence of CRTR deficiency ranges from 0.8-5.4% of those with intellectual disability (ID). Despite reports of high prevalence of CRTR deficiency in males with ID, there are no true prevalence studies in the general population. Guanidinoacetate methyltransferase (GAMT) deficiency is the second most common CCDS, with approximately 130 individuals reported worldwide. The estimated incidence of GAMT deficiency in the general population ranges from 1 in 2.6 million to 1 in 250,000. L-arginine:glycine amidinotransferase (AGAT) deficiency appears to be much rarer, with fewer than 20 reported individuals. [1, 2, 3, 4, 5]

Clinical Features

Cerebral creatine deficiency syndromes consist of three neurometabolic disorders: GAMT deficiency, AGAT deficiency, and CRTR deficiency. All three conditions are characterized by muscle hypotonia, developmental and speech delays, seizures, ID, and behavioral abnormalities (hyperactivity, autism spectrum, impulsivity, social anxiety, and self-injurious behaviors). Seizure types vary and can be intractable. Individuals with AGAT deficiency may also have a prominent myopathy. Individuals with GAMT deficiency and CRTR deficiency may also develop movement disorders (chorea, athetosis, dystonia, hypotonia, ataxia). GAMT deficiency often shows a more complex phenotype (intractable seizures, extrapyramidal movement abnormalities, and dysfunction of the basal ganglia). Non-neurologic features have been described in CRTR deficiency including dysmorphic features, gastrointestinal findings (poor weight gain and constipation), cardiac features (prolonged QTc on EKG). [1, 2, 3, 6, 7]

Natural History

Symptoms typically appear during infancy to early childhood and after development of significant impairment, treatment has limited utility.
GAMT deficiency
Onset of clinical manifestations of GAMT deficiency is between ages three months and three years. The onset of movement disorders is usually before age 12 years. The age of diagnosis ranges from neonatal to 34 years. Life expectancy is limited, particularly in those who have multiple disabilities and severe seizures.
AGAT deficiency
In a series of 16 individuals with AGAT deficiency from eight families individuals were diagnosed between 3 weeks and 25 years (median 8 years). Myopathy was found predominantly in older individuals diagnosed in adolescence and young adulthood.
CRTR deficiency
Onset of clinical manifestations ranges from four to 54 months, but usually occurs before the age of 2 years. The age of diagnosis ranges from one to 66 years, indicating that life expectancy can be normal. In affected males older than age 10 years, 14% had no speech development, 55% were able to speak single words, and 31% were able to speak in sentences. Seizure onset was between ages one and 21 years. Females heterozygous for SLC6A8 pathogenic variants can have various combinations and severities of manifestations but are typically either asymptomatic or have mild ID. Life expectancy is limited, particularly in those who have severe seizures and associated comorbidities. [1, 3, 5, 6, 7]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening: https://www.acmg.net/PDFLibrary/GAMT.pdf.

To establish the extent of disease and needs in an individual diagnosed with a CCDS, the following evaluations are recommended:
•Brain proton magnetic resonance spectroscopy (1H-MRS)
•EEG if any clinical seizures or suspicion of seizures
•Developmental/neuropsychologic assessments
•Orthopedics, physical medicine & rehab, PT, OT evaluations
•Neurobehavioral evaluation
•Baseline kidney function studies (blood urea, blood creatinine, urinalysis)
•EKG & echocardiography (for those with CRTR deficiency)
•Assessment by nutritionist for feeding and growth (Tier 4) [2]

In general, GAMT deficiency and AGAT deficiency can be treated with oral supplementation of creatine monohydrate and dietary manipulations, which seem more effective when started early in life. GAMT deficiency requires arginine restriction through a low-protein diet and additional treatment with ornithine and sodium benzoate. (Tier 3) [1, 2]

GAMT deficiency
Oral creatine supplementation with the aim of correcting cerebral creatine deficiency as well as strategies to reduce accumulation of guanidinoacetate (GAA), such as high dose L-ornithine and an arginine/protein restricted diet, are the mainstay of treatment. Treatment must be supervised by a metabolic dietician. An arginine restricted diet together with an arginine-free essential amino acid supplement effectively reduces GAA levels. L-ornithine supplementation (at least low dose) should be considered in individuals who receive an arginine-restricted diet. (Tier 2) [8]

In a study of 48 individuals with GAMT deficiency from 38 families the median age at treatment initiation was 25.5 and 39 months in individuals with mild and moderate DD/ID, respectively. Treatment regimens included various combinations/dosages of creatine monohydrate and L-ornithine, sodium benzoate, and/or protein/arginine restricted diets. Median age at treatment initiation was 11 years in individuals with severe DD/ID. Treatment duration was between 11 and 192 months (median 48, mean 64.1). A decrease, but not normalization of elevated GAA levels was evident in all 35 individuals who had at least 1 measurement upon treatment. Clinical improvement was achieved in the majority of individuals. Improvements were noted in several domains of DD/ID (behavior, language, and self-supportive skills/activities of daily life), as well as in epilepsy and movement disorders, based on clinical judgement and third-party informants. Improvements were achieved in individuals with severe, moderate, and mild DD/ID, irrespective of the treatment modality. The 10 individuals who received creatine as monotherapy showed mainly improvements in epilepsy and movement disorder. Another study included 22 individuals with GAMT deficiency from 20 families (average age 14 years, range 5-31 years). Prior to initiation of treatment, 5 individuals had severe, 14 had moderate and 3 had mild phenotype based on the clinical severity score. All individuals were on creatine, 18 were also on ornithine and 15 on arginine- or protein-restricted diet, with an average treatment duration of 6 years, 8 months (range 26 months to 11 years). Clinical severity score (composite score including DD/ID, seizures, and movement disorder) improved in 13 individuals on treatment. DD/ID improved in 5 individuals. Eleven individuals became seizure free. Movement disorder resolved in 4 individuals. Between the two studies, seizure freedom was achieved in approximately 50% and movement disorder resolved in 50% of symptomatic persons. (Tier 3) [2]

Age appropriate neurodevelopmental and behavioral assessments should be considered to objectively document any delayed skills and behavioral problems. Individuals may also benefit from ancillary services such as speech, occupational and physiotherapy. (Tier 2) [8]

AGAT deficiency
AGAT deficiency is treated with oral creatine monohydrate. (Tier 4) [2]

In a series of 16 individuals with AGAT deficiency from eight families treatment with oral creatine monohydrate was started at age 4 months to 25 years. Fifteen individuals had ID/DD and eight also had myopathy/proximal muscle weakness. Treatment duration ranged from 5 to 14 years and resulted in significant improvement of myopathy in almost all affected persons. Early treatment (n=2) seemed to prevent adverse developmental outcomes. In late treated patients the cognitive improvement was modest compared to results achieved by early treatment (< 2 years). (Tier 3) [2]

CRTR deficiency
CRTR deficiency is treated with oral creatine monohydrate and arginine and glycine supplementation. All three supplements should be started together in newly diagnosed persons to slow disease progression. (Tier 4) [2]

The clinical effectiveness of treatment with three supplements is not confirmed, but improvements have been noted. (Tier 3) [2]

A review included 58 individuals (ages 9 months-16 years) with CRTR deficiency from 15 studies. Treatment regimens varied with different combinations of creatine monohydrate, L-arginine and/or glycine. The treatment duration ranged from 2 - 72 months. A total of 19 individuals (32%) demonstrated response to treatment, manifested by either an increase in cerebral creatine or improved clinical parameters, including cognitive abilities, gross motor function, and epilepsy. No clinical improvements were reported in the 10 individuals on creatine monotherapy. (Tier 5) [9]

Surveillance

Surveillance recommendations for individuals with a CCDS include:
•Monitor developmental progress and educational needs at each visit
•Monitor those with seizures as clinically indicated at each visit
•Assess for new manifestations such as seizures, movement disorders and behavioral problems at each visit (Tier 4) [2]

Circumstances to Avoid

Individuals with GAMT deficiency should avoid protein rich food such as meat and dairy products. (Tier 2) [8]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive
GAMT deficiency (GAMT gene) [2]

Autosomal Recessive
AGAT deficiency (GATM gene) [2]

X-linked
CRTR deficiency (SLC6A8 gene) [2]

Prevalence of Genetic Variants

Pathogenic variants in SLC6A8, GAMT, and GATM account for 64%, 33% and 3% of individuals with CCDS, respectively. The estimated carrier frequency of AGAT deficiency was 1 in 1,292 in a general population database. Pathogenic variants in SLC6A8 occurred de novo in 30% of individuals with CRTR deficiency. (Tier 3) [2]

The estimated carrier frequency of CRTR deficiency in females in the general population was 1 in 4,060 (0.024%) in the EVS database. (Tier 5) [4]

Penetrance

GAMT deficiency
(Based on two studies totaling 130 symptomatic individuals.)
Developmental delay (DD) or ID 100%
Severe DD or ID 50-75%
Behavior disorder >75%
Seizures >70%
Movement disorders 30% (Tier 3) [2]

AGAT deficiency
(Based on one study of 16 individuals from 8 families.)
DD or ID 100%
Mild to moderate ID >80%
Behavior disorder 25%
Seizure 10%
Movement disorder 0
Muscle weakness/myopathy 50% (Tier 3) [2]

CRTR deficiency – males
(Based on one study of 101 males from 85 families [median age of diagnosis was 10 years, range 1 to 66 years]).
DD or ID 100%
Mild to moderate ID 85%
Behavior disorder 85%
Seizures 59%
Motor dysfunction 58%
Hypotonia 40%
Gastrointestinal findings 35% (Tier 3) [2]

One study of 18 males with CRTR deficiency reported that seven (39%) had prolonged QTc on EKG and left ventricular anomalies on echocardiography. (Tier 3) [2]

Relative Risk

No information on relative risk was found.

Expressivity

GAMT deficiency
The severity of DD/ID ranges from mild to severe. Seizure severity ranges from occasional seizures to seizures that are non-responsive to various anti-seizure medications. (Tier 3) [2]

AGAT deficiency
The severity of ID ranges from mild to severe. (Tier 4) [2]

CRTR deficiency
The severity of ID ranges from mild to severe; 75% of males older than age 18 years had severe ID. Females heterozygous for SLC6A8 pathogenic variants may be asymptomatic or present with signs and symptoms of variable severity, ranging from learning disabilities to seizures. (Tier 3) [1, 2]

4. What is the Nature of the Intervention?

Nature of Intervention

Creatine is given as creatine-monohydrate orally, administered in 3-6 divided doses. Ingestion of high amounts of creatine may result in the formation of urinary crystals and subsequent urinary tract infections, warranting regular assessments of kidney function and urinalysis, respectively. Crystals may be reversible upon dose reduction. L-Ornithine supplementation is also given orally. L-Ornithine has a bitter taste, and this might have a negative influence on compliance. High dose L-Ornithine supplementation has been associated with tremors and loose stools/frequent bowel movements in a few individuals. L-Ornithine-HCl given in high dosages can cause metabolic acidosis. Protein- and arginine-restricted diets are difficult in application, including unpleasant taste of medical food, requirement of close monitoring for growth and nutritional status by a metabolic dietician and compliance problems in older individuals. Dietary restriction of arginine could result in hyperammonemia, warranting regular monitoring of plasma ammonia levels. [5, 8, 10]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

CCDSs produce a relatively nonspecific phenotype and are likely underdiagnosed. Historically, newborns have not been identified by newborn screening though GAMT deficiency was added to the Recommended Uniform Screening Panel (RUSP) in January 2023. Individuals with GAMT deficiency in the newborn period may have normal guanidinoacetate-to-creatinine ratios in urine. CRTR deficiency can be challenging to diagnose. Plasma creatine levels are generally unreliable indicators of CRTR status, as they may be elevated or normal in individuals with CRTR deficiency. Other conditions such as arginase deficiency may cause altered concentrations of creatine and guanidinoacetate in plasma and urine. Individuals with AGAT deficiency may be missed by the study of urine creatine and guanidinoacetate alone because of inherently low concentrations of these compounds in some unaffected individuals. (Tier 4) [1, 3]

Reasons for late diagnosis include limited awareness among developmental pediatricians and neurologists. Conventional MRI shows no or mild structural and signal abnormalities, which are often not specific enough to suggest a definite diagnosis. (Tier 5) [8, 9]

Date of Search: 09.19.2022 (updated 11.28.2023)

Reference List

1. Sharer JD, Bodamer O, Longo N, Tortorelli S, Wamelink MM, Young S. Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics. Genet Med. (2017) 19(1530-0366):256-263.

2. S. Mercimek-Andrews and G. S. Salomons. Creatine Deficiency Disorders. Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews((R)). Seattle (WA). (1993) Website: https://www.ncbi.nlm.nih.gov/pubmed/20301745

3. Ream MA, Lam WKK, Grosse SD, Ojodu J, Jones E, Prosser LA, Rose AM, Comeau AM, Tanksley S, Powell CM, Kemper AR. Evidence and Recommendation for Guanidinoacetate Methyltransferase Deficiency Newborn Screening. Pediatrics. (2023) 152(1098-4275).

4. DesRoches CL, Patel J, Wang P, Minassian B, Salomons GS, Marshall CR, Mercimek-Mahmutoglu S. Estimated carrier frequency of creatine transporter deficiency in females in the general population using functional characterization of novel missense variants in the SLC6A8 gene. Gene. (2015) 565(1879-0038):187-91.

5. Stockler-Ipsiroglu S, Apatean D, Battini R, DeBrosse S, Dessoffy K, Edvardson S, Eichler F, Johnston K, Koeller DM, Nouioua S, Tazir M, Verma A, Dowling MD, Wierenga KJ, Wierenga AM, Zhang V, Wong LJ. Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide. Mol Genet Metab. (2015) 116(1096-7206):252-9.

6. Guanidinoacetate methyltransferase deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=382

7. X-linked creatine transporter deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=52503

8. Stockler-Ipsiroglu S, van Karnebeek C, Longo N, Korenke GC, Mercimek-Mahmutoglu S, Marquart I, Barshop B, Grolik C, Schlune A, Angle B, Araújo HC, Coskun T, Diogo L, Geraghty M, Haliloglu G, Konstantopoulou V, Leuzzi V, Levtova A, Mackenzie J, Maranda B, Mhanni AA, Mitchell G, Morris A, Newlove T, Renaud D, Scaglia F, Valayannopoulos V, van Spronsen FJ, Verbruggen KT, Yuskiv N, Nyhan W, Schulze A. Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab. (2014) 111(1096-7206):16-25.

9. Li J, Xu S. Diagnosis and Treatment of X-Linked Creatine Transporter Deficiency: Case Report and Literature Review. Brain Sci. (2023) 13(2076-3425).

10. Khaikin Y, Sidky S, Abdenur J, Anastasi A, Ballhausen D, Buoni S, Chan A, Cheillan D, Dorison N, Goldenberg A, Goldstein J, Hofstede FC, Jacquemont ML, Koeberl DD, Lion-Francois L, Lund AM, Mention K, Mundy H, O'Rourke D, Pitelet G, Raspall-Chaure M, Tassini M, Billette de Villemeur T, Williams M, Salomons GS, Mercimek-Andrews S. Treatment outcome of twenty-two patients with guanidinoacetate methyltransferase deficiency: An international retrospective cohort study. Eur J Paediatr Neurol. (2018) 22(1532-2130):369-379.