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LETTERS TO THE EDITOR
Year : 2022  |  Volume : 25  |  Issue : 6  |  Page : 1196-1198
 

Guanidinoacetate methyltransferase deficiency: A treatable cause of developmental delay diagnosed by magnetic resonance spectroscopy


Department of Paediatrics, Mahatma Gandhi Medical College Hospital and Research Institute, Pillaiyarkuppam, Pondicherry, India

Date of Submission08-Jul-2022
Date of Decision26-Aug-2022
Date of Acceptance01-Sep-2022
Date of Web Publication04-Nov-2022

Correspondence Address:
L Caroline Silvia
Department of Paediatrics, Mahatma Gandhi Medical College Hospital and Research Institute, Pillaiyarkuppam, Pondicherry
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.aian_597_22

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How to cite this article:
Silvia L C, Chandramohan A, Palanisamy S. Guanidinoacetate methyltransferase deficiency: A treatable cause of developmental delay diagnosed by magnetic resonance spectroscopy. Ann Indian Acad Neurol 2022;25:1196-8

How to cite this URL:
Silvia L C, Chandramohan A, Palanisamy S. Guanidinoacetate methyltransferase deficiency: A treatable cause of developmental delay diagnosed by magnetic resonance spectroscopy. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Jan 29];25:1196-8. Available from: https://www.annalsofian.org/text.asp?2022/25/6/1196/360469




Dear Editor,

The cerebral creatine deficiency syndromes (CCDS) are a group of inborn errors of creatine metabolism that present as global developmental delay, impairment of expressive speech, intellectual disability, autistic features, and epilepsy.[1] CCDS include autosomal recessive guanidinoacetate methyltransferase deficiency, L-Arginine: glycine amidinotransferase deficiency, and X-linked Creatine transporter deficiency.[2] The biochemical hallmark of these disorders is cerebral creatine deficiency which can be detected in vivo by magnetic resonance spectroscopy (MRS) of the brain. A distinct lack of combined creatine and phosphocreatine peak on proton MRS is a hallmark of all three CCDS.[3] Guanidinoacetate methyltransferase deficiency (GAMT-D) is potentially a treatable disorder, necessitating an early diagnosis. Herewith we report a child who presented with global developmental delay and seizures diagnosed as creatine deficiency syndrome by absence of creatine peak in MRS, then confirmed as GAMT-D by genetic testing.

A four-year-old female child, firstborn of third-degree consanguineous parents presented with two episodes of afebrile generalized seizures in the past month. She had a global developmental delay in which language and social domains were markedly involved. Her neonatal period was uneventful. There was no prior or family history of seizures. No H/O abnormal odor of urine or abnormal startle either.

On examination, she was conscious with poor attention span and minimal eye-to-eye contact. She could recognize her parents but was not obeying commands and was making irrelevant sounds. Cranial nerves were intact. There was mild hypotonia with preserved reflexes and flexor plantars. She had poor coordination in the upper limbs and a wide-based gait. There were no involuntary movements. Her head circumference was 46 cm (<3 SD) indicating microcephaly. There were neither dysmorphic features nor neurocutaneous markers. Fundi were normal. Her weight for age, height for age, and weight for height corresponded to <3 SD indicating severe wasting and stunting.

Thyroid profile, liver, renal function tests, vitamin B12 levels, serum ammonia, and lactate were normal. An ophthalmological examination did not reveal any abnormality. MRI brain showed symmetrical involvement of globus pallidus [Figure 1]a. Tandem mass spectrometry and urine gas chromatography or mass spectrometry for organic acids were negative. Because of developmental delay, seizures, microcephaly, and bilateral basal ganglia lesions, mitochondrial disorder such as Leigh syndrome was considered. Mitochondrial cocktail (carnitine, thiamine, riboflavin, biotin, Co Q and vitamin C) was added to anticonvulsants. She underwent occupational and speech therapy as well. There were no further seizures, but the child did not show improvement in acquiring milestones.
Figure 1: (a) MRI brain axial view T2W image showing hyperintensities in both globus pallidi. (b) Magnetic resonance spectroscopy showing absent creatine peak. (c) Normal MRS showing creatine peak for comparison

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Six months later, she was admitted with acute onset of choreoathetosis, truncal and gait ataxia following two days of fever. Repeat MRI brain with MRS acquired by a single-voxel point-resolved spectroscopy sequence (1.5 Tesla, TE, 35 milliseconds; TR, 2000 milliseconds; 128 averages on a volume of interest [VOI] of 3.4 mL) positioned in the basal ganglia revealed an absent creatine peak which gave us a clue to consider creatine deficiency syndromes in this child [Figure 1]b.

Clinical exome sequencing identified a pathogenic homozygous missense variant c.432G>A in exon 4 of the GAMT gene (Chr19:1399154C>T; depth: 46x) that resulted in a stop codon and premature truncation of the protein at codon 144 (p. Trp144Ter; ENST00000447102.3). The phenotype was matching with the genotype, thus confirming the diagnosis of GAMT-D.

Mitochondrial cocktail was withheld. She was started on creatine monohydrate 400 mg/kg/day in three divided doses, a low protein diet (0.5 gm/kg/day), and sodium benzoate 250 mg/kg/day in three divided doses. There were no further seizures. Mild improvement in socio-cognitive skills was noted over the next one year. She started showing interest in her surroundings and began playing with her peers. She began comprehending spoken language and started obeying simple commands. Her attention span had improved. She could identify common objects and body parts and indicate bladder and bowel needs. However, speech impairment persisted in that she could speak only two words. The child was under regular follow-up for the past two years with periodic developmental assessment, occupational therapy, and speech therapy.

GAMT-D is due to a mutation in the guanidinoacetate methyltransferase (GAMT) gene on chromosome 19p13.3, with an estimated incidence of 1:250,000.[4] Our child had a classical clinical picture of GAMT-D, namely, global delay, intellectual disability, speech delay, autistic features, seizures, and movement disorder. Speech delay is considered a hallmark of this disease.[3] Seizures tend to occur in 75%–90% of patients with GAMT-D.[2] About 40% of the patients develop movement disorders.[2],[5] Intellectual disability may range from mild to severe.[5] Behavioral problems such as hyperactivity, and autistic features are common. However, there was no self-mutilation in our child.[6]

MRI brain may show bilateral hyperintensities in globus pallidus but may be normal as well.[7] The clinical and radiological features may resemble mitochondrial encephalopathy.[8] We did consider mitochondrial disorder a possibility and initiated mitochondrial cocktail in our patient. CCDS was diagnosed when the child developed choreoathetosis and underwent a repeat imaging along with MRS.

A distinct lack or profound diminution of the combined creatine and phosphocreatine peak on proton MRS is a hallmark of cerebral creatine deficiency syndromes.[3] Biochemically, GAMT-D is identified by elevated levels of guanidino acetic acid (GAA) in body fluids such as urine, serum, and cerebrospinal fluid.[8] In contrast, GAA levels are low in AGAT-D and normal in CRTR defects. We suspected creatine deficiency disorder in our patient based on the absence of creatine peak in MRS. Due to the non-availability of biochemical investigations at our center, we proceeded with genetic studies that confirmed the diagnosis of GAMT-D.

The pathophysiology of GAMT-D involves a combination of cerebral energy deficiency due to a depletion of brain creatine/phosphocreatine and neurotoxic action of GAA, a partial agonist at GABA-A receptors.[9]

Management of GAMT-D aims to replenish cerebral creatine levels by supplementation with creatine monohydrate and to decrease the accumulation of neurotoxic GAA in the central nervous system by ornithine supplementation and protein- or arginine-restricted diet. Creatine monohydrate and ornithine supplementation decrease GAA accumulation by competitive inhibition of AGAT enzyme activity. Creatine monohydrate of 400–800 mg/kg/day should be given in three to six divided doses. Ornithine supplementation of 400–800 mg/kg/day in divided doses is useful.[10] Sodium benzoate conjugates glycine and inhibits GAA production via substrate deprivation. Occupational, speech, and physical therapies to treat developmental disabilities and behavior therapy to address behavior problems are important. Treatment results in improvement of epilepsy and movement disorder, whereas intellectual disability and speech impairment persists[2] which is true in our patient as well.

Early detection is possible in the neonatal period by detection of GAA in dried blood spots. Pre-symptomatic treatment is effective in achieving good neurodevelopmental outcome.[4],[11]

Since biochemical investigations such as estimation of GAA levels in urine or blood are not available in all settings and most MRI scanners have the software capabilities to perform spectroscopy, we propose that any child with unexplained developmental delay should undergo MRS along with MRI brain to identify cerebral creatine deficiency and receive further confirmation by biochemical or genetic studies.

In conclusion, any child with unexplained developmental delay, intellectual disability, autistic behavior, and seizures should undergo MRS to diagnose guanidinoacetate methyltransferase deficiency (GAMT-D)—a creatine deficiency syndrome.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Stockler S, Holzbach U, Hanefeld F, Marquardt I, Helms G, Requart M, et al. Creatine deficiency in the brain: A new, treatable inborn error of metabolism. Pediatr Res 1994;36:409-13.  Back to cited text no. 1
    
2.
Mercimek-Mahmutoglu S, Stoeckler-Ipsiroglu S, Adami A, Appleton R, Caldeira Araujo H, Duran M, et al. GAMT deficiency: Features, treatment, and outcome in an inborn error of creatine synthesis. Neurology 2006;67:480-4.  Back to cited text no. 2
    
3.
Clark JF, Cecil KM. Diagnostic methods and recommendations for the cerebral creatine deficiency syndromes. Pediatr Res 2015;77:398-405.  Back to cited text no. 3
    
4.
Mercimek-Mahmutoglu S, Pop A, Kanhai W, Fernandez Ojeda M, Holwerda U, Smith D, et al. A pilot study to estimate the incidence of guanidinoacetate methyltransferase deficiency in newborns by direct sequencing of the GAMT gene. Gene 2016;575:127-31.  Back to cited text no. 4
    
5.
Lion-François L, Cheillan D, Pitelet G, Acquaviva-Bourdain C, Bussy G, Cotton F, et al. High frequency of creatine deficiency syndromes in patients with unexplained mental retardation. Neurology 2006;67:1713-4.  Back to cited text no. 5
    
6.
Stockler-Ipsiroglu S, van Karnebeek C, Longo N, Kroenke GC, Mercimek-Mahmutoglu S, Marquart I, et al. Guanidinoacetate methyltransferase (GAMT) deficiency: Outcomes in 48 individuals and recommendations for diagnosis, treatment, and monitoring. Mol Genet Metab 2014;111:16-25.  Back to cited text no. 6
    
7.
Pacheva I, Ivanov I, Penkov M, Kancheva D, Jordanova A, Ivanova M. Creatine deficiency syndrome could be missed easily: A case report of guanidinoacetate methyltransferase deficiency presented with neurodevelopmental delay, seizures, and behavioral changes, but normal structural MRI. Ann Clin Lab Sci 2016;46:557-61.  Back to cited text no. 7
    
8.
Morris AA, Appleton RE, Power B, Isherwood DM, Abernethy LJ, Taylor RW, et al. Guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy. J Inherit Metab Dis 2007;30:100. doi: 10.1007/s10545-006-0478-2.  Back to cited text no. 8
    
9.
Neu A, Neuhoff H, Trube G, Fehr S, Ullrich K, Roeper J, et al. Activation of GABA (A) receptors by guanidinoacetate: A novel pathophysiological mechanism. Neurobiol Dis 2002;11:298-307.  Back to cited text no. 9
    
10.
Stockler-Ipsiroglu S, van Karnebeek C, Longo N, Kroenke GC, Mercimek-Mahmutoglu S, Marquart I, et al. Guanidinoacetate methyltransferase (GAMT) deficiency: Outcomes in 48 individuals and recommendations for diagnosis, treatment, and monitoring. Mol Genet Metab 2014;111:16-25.  Back to cited text no. 10
    
11.
Schulze A, Hoffmann GF, Bachert P, Kirsch S, Salomons GS, Verhoeven NM, et al. Pre symptomatic treatment of neonatal guanidinoacetate methyltransferase deficiency. Neurology 2006;67:719-21.  Back to cited text no. 11
    


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