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ORIGINAL ARTICLE Table of Contents  
Ahead of print publication
Phenotypic and molecular spectrum of guanidinoacetate N-Methyltransferase deficiency: An analytical study of a case series and a scoping review of 53 cases of guanidinoacetate N-Methyltransferase

1 Undergraduate Student, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
2 Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
3 Undergraduate Student, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia

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Date of Submission24-Feb-2022
Date of Decision24-May-2022
Date of Acceptance02-Jun-2022
Date of Web Publication05-Jan-2023


Background: Guanidinoacetate methyltransferase deficiency (GAMT) is an autosomal recessive inborn error of metabolism. A condition that results from a pathogenic variant in the GAMT gene that maps to 19p13.3. The prevalence can be estimated to be up to 1:2,640,000 cases; countries such as Saudi Arabia could have a higher prevalence due to high consanguinity rates. The clinical manifestations that a patient could obtain are broad and start to manifest in the patients' early childhood years. Materials and Methods: A thorough review of case reports in January 2022 was conducted. The retrieved literature was screened for demographic data. Patients of all ages were included. Qualitative variables were described as number and percentage (%), and quantitative data were described by the mean and standard deviation. In bivariate data, Chi-square test (χ2) was used and t-test for nonparametric variables. Results: Gender distribution was 53% of males and 47% females. Reported age ranged from 8 to 31 months. At the age of onset, 50% of the cases were infants, 28% were toddlers, and 15% were children, concluding that 79% of the reported cases developed symptoms before 5 years old. 68% of the cases developed generalized seizures throughout their life. 84% of the cases expressed a form of developmental delay. 43% of the cases had intellectual disabilities and mental retardation that affected their learning process; most cases required special care. 23% of the affected cases were of consanguineous marriages, and 7% had affected relatives. Conclusion: We described four novel case reports, the first to be reported in Saudi Arabia. Seizure was a leading finding in the majority of the cases. Developmental delay was broadly observed. Intellectual delay and language impairments are primary hallmarks. Further understanding and early diagnosis are recommended. Premarital testing of neurogenetic diseases using whole-exome sequencing is probably a future direction, especially in populations with high consanguinity rates.

Keywords: Autism, chromosomal abnormality, congenital anomaly, epilepsy, pediatrics, seizures

How to cite this URL:
Alyazidi AS, Muthaffar OY, Shawli MK, Ahmed RA, Aljefri YF, Baaishrah LS, Jambi AT, Alotibi FA. Phenotypic and molecular spectrum of guanidinoacetate N-Methyltransferase deficiency: An analytical study of a case series and a scoping review of 53 cases of guanidinoacetate N-Methyltransferase. J Microsc Ultrastruct [Epub ahead of print] [cited 2023 Feb 8]. Available from: https://www.jmau.org/preprintarticle.asp?id=362485

  Introduction Top

Guanidinoacetate methyltransferase deficiency (GAMT) is an inherited condition that is classified under cerebral creatine deficiency syndromes (CCDS) first described in 1994.[1] These conditions are classified as inborn errors of metabolism with an autosomal recessive pattern that interrupts the biosynthesis or transportation of creatine. It is characterized by the accumulation of guanidinoacetic acid and depletion of creatine,[2] consequently leading to an inadequacy in the usage and storage of energy.[3] The deficiency results from a pathogenic variant or biallelic mutations in the GAMT gene.[4] This gene maps to 19p13.3 and is involved in the biosynthesis of creatine. The incidence of GAMT was estimated by a pilot study in the Netherlands, in which it included 500 anonymized neonates from the Dutch's National Newborn Screening Program, and the pilot study concluded that GAMT deficiency had an incidence of 1:250,000 newborns.[5] Nonetheless, the prevalence of GAMT varied according to different studies. According to the U. S. National Organization for Rare Disorders' report, the prevalence had been estimated to be from 1:2,640,000 to 1:550,000 diagnosed patients to a conflicting report of 1:115,000 diagnosed patients.[6] In countries like Saudi Arabia, consanguinity rate is high reaching up to 57%.[7] Autosomal recessive conditions' prevalence is expected to be higher than international numbers.[8] Despite this, symptoms and signs in patients can vary in presentation and age of onset. The clinical presentation's age of onset ranges from the child's first few months of life and up to 10 years of age.[9] In an Indian CCDS patients' group, mental disability, disproportionate delay in speech, autism, and epilepsy were commonly detected.[10] Seizures, delay of intellectual abilities, autistic features, speech delay, and movement disorders are additionally common presentations.[11] However, GAMT precisely could present with progressive intellectual and neurological deterioration.[12] Other clinical manifestations could include severe delay in the development of comprehensible speech, as well as intellectual disabilities, autistic behavior, involuntary movements, and seizure disorders which may be resistance to drug therapy. It is speculated that the accumulation of guanidinoacetate significantly contributed to the pathological manifestations of this condition.[13],[14] Diagnostic tools can include confirmatory findings such as increased guanidinoacetate in the urine, low plasma creatine, and low brain creatine on magnetic resonance spectroscopy. Administering oral creatine supplements has shown promising results in improving the clinical conditions of children with creatine deficiency.[6] In detail, oral creatine monohydrate treatment (dosage of 400–800 mg/kg in 3 doses) along with ornithine (dosage of 400–800 mg/kg in 3 doses) and an arginine-restricted diet can result in improvements in seizures and intellectual abilities.[11] Moreover, treatment effectiveness could be assessed by measuring creatine levels in the brain. Creatine supplementation reported neurodevelopmental improvement and satisfactory seizure control in GAMT-deficient patients.[10] The majority of GAMT cases are identified and treated in early childhood.[12] New technologies, such as mass spectrometry, offer a strong possibility to describe particular biochemical abnormalities in the blood of the affected patients, allowing for a more accurate diagnosis of the condition in the future.[15] Despite the fact that the deficiency is curable, no GAMT-deficient patients have been documented to return to full developmental status following treatment.[13] The natural history of GAMT deficiency is not completely understood, and there are gaps in our knowledge of how the disease develops and progresses. Since most cases described are in their “early” childhood age group, knowledge of the adult phenotype is limited. Questions remain about the disorder's long-term consequences, the age at which different symptoms appear, and how the disease evolves over time. Determining the natural history and treatment outcomes (or lack thereof) is particularly important now that GAMT deficiency is being considered for newborn screening panels all over the world.[5],[16],[17],[18] The purpose of the present study is to identify and analyze cases diagnosed with GAMT deficiency. We further present detailed clinical characteristics and genetic diagnoses of four novel case reports in Saudi Arabia [Table 1]. To the best of our knowledge, these four cases are the first to be reported in Saudi Arabia. Ergo, by adding to the catalog of GAMT deficiency cases reported in the literature, we aim to expand the knowledge base and aid in the understanding of this condition.
Table 1: Clinical phenotype of our four guanidinoacetate methyltransferase deficiency deficiency cases +/- reflects the presence/absence of the symptom

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  Materials and Methods Top

Ethical approval

Ethical approval for the study content, protocol, and consent was obtained by the Unit of Biomedical Ethics Research Committee at Faculty of Medicine, King Abdulaziz University, Jeddah, KSA (Reference: 356-22). The guidelines outlined in the Declaration of Helsinki were followed.

Search strategy

A thorough review of available literature was conducted among GAMT-deficiency case reports in January 2022. From 53 studies yielded by our search, only 45 eligible studies met the inclusion criteria in the present scoping review. The study design included case reports as well as other designs (review articles and case series) that included case reports. We searched available publications from 1996 to January 2022 using the following terms: GAMT, Guanidinoacetate Methyltransferase, and Deficiency. The literature was obtained from MEDLINE/PubMed databases. The retrieved literature was screened for demographic data, which included age, gender, age of onset, reporting country, and family history. The clinical profile, as well as genetic mutations, management plans, available tests, and other significant findings, were also retrieved. Patients of all ages were included in the search strategy. Otherwise, articles written in languages other than English with no translated and verified copies were excluded from the present study. Moreover, literature findings were compared to four novel cases. The study was strengthened according to the Narrative Review Checklist. To the best of our knowledge, this is the first study on GAMT published by authors in Saudi Arabia. The four cases present novel case reports of GAMT patients in Saudi Arabia.

Statistical analysis

Microsoft Excel 2014 was used to conduct data entry, and statistical analysis was made using the Statistical Package for the Social Sciences (SPSS) version 21 (IBM Corp., Armonk, NY, USA). According to the type of variables, the descriptive data were analyzed: qualitative variables were described as number and percentage (%) and quantitative data were described by the mean and standard deviation. In bivariate data, the

Chi-square test (χ2) was utilized to compare categorical variables, and for the nonparametric variables, t-test test was used. Clinical symptoms were stratified according to gender (male and female), age groups (0–1 years: infants; 2–4 years: toddlers; and 5–12 years: children), and reporting region (Europe, Asia, or North America). The prevalence of symptoms was compared using the MannWhitney U-test, where the occurrence of the symptom was given 1 point and nonoccurrence was given 0. Furthermore, a 5% margin of error was deemed significant with a confidence level of 95%, and P < 0.05 was considered statistically significant.

  Results Top

Scoping review

After constructing the search methodology, our review which included every reported case in the literature yielded 53 cases. However, 45 of them met our inclusion criteria and were candidates for the present study [Table 2]. Demographic characterization was analyzed [Table 3]. The reported cases included multiple countries across the globe with a heterozygous population of different ethnicities [Figure 1]. Gender distribution in the cases was as follows: 53% of the cases were male and 47% were female [Figure 2]. The reported age ranged from 8 months to 31 years [Figure 3]. At the age of onset, 50% of the cases were infants (0–1 year), 28% were toddlers (2–4 years), and 15% were children (5–12 years) [Figure 4], concluding that 79% of the reported cases developed symptoms before the onset of 5 years old. Reported symptoms included delayed walking or speech, developmental retardation, and behavioral abnormalities. Moreover, 68% of the cases developed generalized seizures throughout their life varied from atonic to myoclonic, a few of which were reported to be drug resistant. In addition, 84% of the cases expressed a form of developmental delay ranging in severity, with the majority (64%) exhibiting global delay (both motor and speech). Nonetheless, 18% of the cases had isolated speech delay and 4.5% had isolated motor delay. In addition, 43% of the cases had intellectual disabilities and mental retardation that affected their learning process; most cases required special care. 52% of the cases had movement and tone disorders. 25% of the cases had hypotonia which ranged between generalized, truncal, or peripheral, with the remaining cases experiencing varying symptoms including tremors, rigidity, asthenia, dystonia, dyskinesia, gait abnormalities, muscular atrophy, and ataxia. Consequently, we noticed that 29.5% manifested with variable behavioral abnormalities including episodes of crying, restlessness, screaming modes changes, anxiety, social withdrawal, and self-injurious behaviors. However, 23% of the cases had autistic behaviors, 7% of which were clinically diagnosed with autism and 18% had atypical symptoms made up of hepatomegaly, mild-to-moderate hearing loss, constipation, poor swallowing, sialorrhea, and abnormal head size [Figure 5]. Finally, of the 45 cases, 34 reported their genetic testing results. The results revealed that 48% of the cases had a homozygous mutation, while only 29.5% had a heterozygous mutation. Moreover, 23% of the cases were children of consanguineous marriages, and 7% had affected relatives. In [Table 4], the results are expressed and a comparison of the appearance of clinical symptoms according to their gender characteristics is included. Independent t-test was conducted and yielded no statistical significance according to the input variable.
Figure 1: World map according to the reported origin. Map projection was set according to Van der Grinten I projection

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Figure 2: Demographic characterization graph of the included patient's gender from the literature review

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Figure 3: Individual reporting ages according to the current age and age of onset

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Figure 4: Age of onset for the reported literature

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Figure 5: A summary of remarkable clinical findings from the literature review

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Table 2: Clinical phenotype of the literature cases for patients with guanidinoacetate methyltransferase deficiency. +/- reflects the presence/absence of the symptom

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Table 3: The distribution of participants according to their characteristics

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Table 4: Significance was made using independent T-test

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Case presentation

Case 1

After obtaining patients consent, we reported the first case of a 6-year-old male with a homozygous pathogenic variant in the GAMT gene (exon4:c.403G>C: p.D135 h). The patient's age of disease onset was 2 years. His milestones were initially normal. He presented with speech delay, intellectual disability, learning disability, seizures, and epilepsy. His physical findings included unsteady gait, normal power, tone, and reflexes in the four limbs. The patient's investigations included testing for the Fragile X gene and a magnetic resonance imaging (MRI) of the brain, both of which were normal. His seizures were intractable. He failed five antiseizure medications (ASMs) and currently he is on a combination of valproic acid, topiramate, and clobazam. His seizures were polymorphic, tonic spasms, generalized tonic–clonic seizures, and myoclonic seizures. Electroencephalogram (EEG) showed a slow background for age and slow spike and waves suggestive for Lennox–Gastaut syndrome. The frequency of seizures improved and now occurring on monthly basis. The patient's parents are consanguineous and the other two siblings are healthy. No similar family history was reported. After starting creatine and ornithine supplements at the age of 5 years, the family reported more than 50% improvement in his seizures and attention.

Case 2

We reported the second case of a 4-year-old male with a homozygous pathogenic variant in the GAMT gene (c.160G>Cp.[Ala54Pro]) found on whole-exome sequencing (WES). The patient's age at disease onset was 2 years and first presented with delayed speech, restricted language development, developmental regression, attention-deficit hyperactivity disorder (ADHD), generalized-onset seizure, and intellectual disability. His seizures were intractable to multiple ASMs. He, furthermore, underwent a vagal nerve stimulator implant. He was also labeled as Lennox–Gastaut type of epilepsy. He became unable to walk due to frequent head drops and tonic seizures. Upon clinical examination, he was not dysmorphic, and his power, tone, and reflexes were symmetric. EEGs showed slow spikes and waves and generalized paroxysmal fast activities. The patient's MRI was normal. The patient's parents are consanguineous and he has a cousin with epilepsy. After starting him on creatine and ornithine, a dramatic clinical improvement was observed. No more seizures were observed. He was weaned off his current 4 ASMs and even started to walk again independently and joined kindergarten. His interaction and speech also greatly improved.

Case 3

The third reported case was an 8-year-old female with a homozygous pathogenic variant in the GAMT gene (exon6:x. 577c>T: pQ193X) found on WES. Similar to other patients, she was noticed to have speech delay at the age of 2 years. Furthermore, intellectual delay and seizures were observed in the first 4 years. Her epilepsy was also intractable. She had a nonfocal neurological examination. Her MRI brain showed no structural etiology. Her parents are first-degree cousins. Her seizures frequency decreased from almost daily myoclonic and at times tonic seizures into occasional brief monthly seizures. She was on 3 ASMs and decreased to one ASM along with creatine and ornithine supplement.

Case 4

The fourth reported case was a patient who presented at the age of 4 years old and now he is 12 years old. The patient is homozygous in the GAMT gene for a sequence variant designated c.406C>T, which is predicted to result in an amino acid substitution (p.Thr136Met). In the clinic, the patient presented with speech delay, ADHD, and epilepsy. He had episodes of seizures despite being on 3 ASMs. He had some modest improvement in seizure frequency from a weekly basis to a monthly basis after adding creatine and ornithine.

  Discussion Top

GAMT deficiency is a disorder with an autosomal recessive pattern classified as an inborn error of metabolism. This is caused by a genetic mutation in the GAMT gene located on 19p13.3 chromosome, encoding the catalytic enzyme guanidinoacetate N-methyltransferase. This enzyme produces creatine, making it essential to consistently regulate energy storage utilization. Once the genetic mutation occurs, it will result in a defect in generating adequate creatine. Consequently, symptoms will arise in different organ systems around the human body that require sufficient energy to function appropriately, mainly the brain and muscles. In the present study, infants contributed the most to the cases of the retrieved literature with a percent reaching up to 50%. This could be explained by the genetic inheritance of the disease in which clinical manifestations starts to appear early in life. According to Mercimek-Andrews et al.[46], the age of onset for the majority of the clinical manifestation ranged from 3 months to 2 years.[46] However, a novel finding in this study concluded that 79% of the reported cases developed symptoms before the onset of 5 years old. The results further yielded that developmental delay was manifested in 84% of the cases. This finding was consistent with other literature which demonstrated that mental retardation and language disorder are a form of developmental delay and constitute a primary hallmark of creatine metabolism disorders.[47] Furthermore, seizure was a leading finding characterized in 68% of the cases. In some literature cases, seizure was a primary finding in the visiting patients.[21] The common clinical findings in our case series were intractable epilepsy, speech delay, intellectual delay and, ADHD features. In addition, Ayanoğlu et al. in 2020[19] reported a case, describing a 12-year-old male patient with intellectual disability, movement, and tone disorders. The patient presented with mild and generalized tremor, dystonia, rigidity, increased deep tendon reflexes, and lead pipe-like rigidity. However, his atypical symptoms included lethargy, sialorrhea, altered consciousness, and autonomic instability. Two siblings from Turkey were reported by Aydın and Sönmez in 2019:[20] a male aged 10 years and a female aged 9 years. They both carried the same genetic mutation and clinical features, which are intellectual disability, autism, behavioral abnormalities described as problematic, and seizures. Upon presentation, they showed signs of intellectual delay. The only difference between the two siblings was the type of seizures. The male was witnessed to have generalized seizures, whereas the female was witnessed during an attack of atonic seizures. An intriguing report by Rostami et al. in 2020[21] from Iran reported two cases. The first was a 6-year-old male patient with truncal hypotonia, repeated seizures, developmental delay described as cognitive, speech, and motor delay, failure to thrive, and neurologic regression. His atypical features were abnormal facies including large and low set ears and high arch palate, poor swallowing, and constipation. Most of his clinical features represented a severe neurological disorder that may have been caused by repeated seizures. The second reported case was a male aged 2½ years with developmental delay and hypotonia. Although most cases reported seizures, this patient did not have seizures. Sun et al. in 2017[22] reported the case of a 4-year-old Chinese female who presented with seizures that were later confirmed that she suffered from intractable epilepsy. She had a global developmental delay, specifically motor and speech delay. She also experienced autistic behavior, hyperkinetic movement disorder, and asthenia. Stern et al. in 2017[23] further reported the case of a 26-year-old male from the UK; he was noted to have seizures, autism, intellectual disability, and developmental delay. Seizures were described as drop attacks and milder atypical absence episodes despite being on multiple ASMs. A reported case in Italy by Leuzzi et al. in 2006[25] was a 13-year-old female with seizures, intellectual disability, behavioral abnormalities, developmental delay, and hypotonia. Seizures were polymorphic and she was severely delayed (Leiter International Performance Scale IQ <20). In addition, she suffered from restlessness, temper tantrum, some vocal and motor stereotypies, speech delay, lack of expressive language, mild generalized muscle hypotrophy and hypotonia. From Portugal, Caldeira et al. in 2005[27] reported a female patient presented at 5 months old for the first time with seizures. She was diagnosed at the age of 19 years old. She had seizures, intellectual disability, and global developmental delay. In the same report by Caldeira et al.[27], another case was presented for an 8-year-old male patient with intellectual disability, autism, developmental delay, hypotonia but no history of seizures. Furthermore, Hinnell et al.[30] presented a case for a Turkish female with behavioral abnormalities, speech delay, and movement and tone disorders. In her first presentation at the age of 25 years old, she suffered from epileptic seizures that were eventually controlled. It was described that she had behavioral difficulties, late onset of speech, focal dystonia, abnormal gait with flexion at the hips and knees, and echolalia. When she turned 31 years old, her seizures resolved, and she learned to speak in proper sentences. Also, O'Rourke et al.[32] reported a case of an 18-year-old female patient from Ireland with an age of onset of 1-year-old. She had seizures classified as emerging myoclonus along with movement and tone disorder described as slowing of mobility and twisting movements of the head. Her intellectual disability was severely affecting her learning, and the behavioral abnormalities were impulsive with mood changes in the form of bouts of anxiety and agitation. She had speech delay as well as autistic features. Furthermore, multiple studies reported various findings such as afebrile seizures, decreased muscle bulk, walking difficulties, history of hypothyroidism, microcephaly, and repetitive choreiform movements.[9],[26],[33],[34],[35] Moreover, Morris et al. in 2007[36] reported the case of a 21-month-old patient with an age of onset of 10 months. The patient presented with seizures, hypotonia, and choreoathetosis. Abnormal cerebellar findings were also found in the literature[38] in parallel to neurologic deterioration, intellectual delay, learning difficulties, abnormal language developments, autistic-like behavior, and epilepsy.

  Conclusion Top

The aim of the present study was to explore, analyze, and elaborate on reported literature cases with GAMT deficiency. We elaborated on their genetic and clinical aspects. We described the clinical characteristics and genetic identification of four novel case reports, the first to be nationally reported in Saudi Arabia. All four cases showed clinical improvement once creatine and ornithine were commenced. This study revealed that most of the reported cases had developed symptoms before the age of five. Seizure was a leading finding described in the majority of the cases. Furthermore, we revealed that developmental delay was observed in another vast majority of cases. The study also showed that intellectual delay and language impairments are primary hallmark symptoms of creatine metabolism disorders and illustrated various presentations and outcomes for the disorder. Further understanding and early diagnosis of this condition are recommended. Premarital testing of neurogenetic diseases using WES is probably a future direction, especially in populations with high consanguinity rates.

Limitations of the study

This study presented limitations to some extent which was related to the literature availability of data and how efficient and accurate the reported cases. However, overall, the findings came consistent with the general knowledge of the condition alongside minor atypical findings. The research was conducted at an early stage with preliminary understanding of the condition, which is subjected to further investigations that could provide new and novel data.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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Correspondence Address:
Anas S Alyazidi,
College of Medicine, King Abdulaziz University, Jeddah 23446
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmau.jmau_16_22


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

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