Expanding the Neuroimaging Findings of Guanidinoacetate Methyltransferase Deficiency in an Iranian Girl with a Homozygous Frameshift Variant in the GAMT

Overview

Journal Neurogenetics

Specialty Neurology

Date 2023 Jan 12

PMID 36633690

Authors

Seyedeh Atiyeh Afjei

Mohammad Farid Mohammadi

Elham Pourbakhtyaran

Homa Ghabeli

Mahmoud Reza Ashrafi

Roya Haghighi

Maryam Rasulinezhad

Neda Pak

Ali Reza Tavasoli

Morteza Heidari

Affiliations

Soon will be listed here.

Abstract

Guanidinoacetate methyltransferase deficiency (GAMTD) is a treatable neurodevelopmental disorder with normal or nonspecific imaging findings. Here, we reported a 14-month-old girl with GAMTD and novel findings on brain magnetic resonance imaging (MRI).A 14-‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍month-old female patient was referred to Myelin Disorders Clinic due to onset of seizures and developmental regression following routine vaccination at 4 months of age. Brain MRI, prior to initiation of treatment, showed high signal intensity in T2-weighted imaging in bilateral thalami, globus pallidus, subthalamic nuclei, substantia nigra, dentate nuclei, central tegmental tracts in the brainstem, and posterior periventricular white matter which was masquerading for mitochondrial leukodystrophy. Basic metabolic tests were normal except for low urine creatinine; however, exome sequencing identified a homozygous frameshift deletion variant [NM_000156: c.491del; (p.Gly164AlafsTer14)] in the GAMT. Biallelic pathogenic or likely pathogenic variants cause GAMTD. We confirmed the homozygous state for this variant in the proband, as well as the heterozygote state in the parents by Sanger sequencing.MRI features in GAMTD can mimic mitochondrial leukodystrophy. Pediatric neurologists should be aware of variable MRI findings in GAMTD since they would be misleading to other diagnoses.

References

Schulze A . Creatine deficiency syndromes. Handb Clin Neurol. 2013; 113:1837-43. DOI: 10.1016/B978-0-444-59565-2.00053-8. View

Modi B, Khan H, van der Lee R, Wasim M, Haaxma C, Richmond P . Adult GAMT deficiency: A literature review and report of two siblings. Mol Genet Metab Rep. 2021; 27:100761. PMC: 8093930. DOI: 10.1016/j.ymgmr.2021.100761. View

Mercimek-Mahmutoglu S, Stoeckler-Ipsiroglu S, Adami A, Appleton R, Araujo H, Duran M . GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis. Neurology. 2006; 67(3):480-4. DOI: 10.1212/01.wnl.0000234852.43688.bf. View

Schulze A, Hess T, Wevers R, Mayatepek E, Bachert P, Marescau B . Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism. J Pediatr. 1997; 131(4):626-31. DOI: 10.1016/s0022-3476(97)70075-1. View

Verbruggen K, Knijff W, Soorani-Lunsing R, Sijens P, Verhoeven N, Salomons G . Global developmental delay in guanidionacetate methyltransferase deficiency: differences in formal testing and clinical observation. Eur J Pediatr. 2006; 166(9):921-5. DOI: 10.1007/s00431-006-0340-8. View

Stockler-Ipsiroglu S, Van Karnebeek C, Longo N, Korenke G, Mercimek-Mahmutoglu S, Marquart I . Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab. 2013; 111(1):16-25. DOI: 10.1016/j.ymgme.2013.10.018. View

Sinclair G, van Karnebeek C, Ester M, Boyd F, Nelson T, Stockler-Ipsiroglu S . A three-tier algorithm for guanidinoacetate methyltransferase (GAMT) deficiency newborn screening. Mol Genet Metab. 2016; 118(3):173-177. DOI: 10.1016/j.ymgme.2016.05.002. View

Pasquali M, Schwarz E, Jensen M, Yuzyuk T, DeBiase I, Randall H . Feasibility of newborn screening for guanidinoacetate methyltransferase (GAMT) deficiency. J Inherit Metab Dis. 2013; 37(2):231-6. DOI: 10.1007/s10545-013-9662-7. View

DesRoches C, Patel J, Wang P, Minassian B, Marshall C, Salomons G . Carrier frequency of guanidinoacetate methyltransferase deficiency in the general population by functional characterization of missense variants in the GAMT gene. Mol Genet Genomics. 2015; 290(6):2163-71. DOI: 10.1007/s00438-015-1067-x. View

10.

El-Gharbawy A, Goldstein J, Millington D, Vaisnins A, Schlune A, Barshop B . Elevation of guanidinoacetate in newborn dried blood spots and impact of early treatment in GAMT deficiency. Mol Genet Metab. 2013; 109(2):215-7. DOI: 10.1016/j.ymgme.2013.03.003. View

11.

Clark J, Cecil K . Diagnostic methods and recommendations for the cerebral creatine deficiency syndromes. Pediatr Res. 2014; 77(3):398-405. DOI: 10.1038/pr.2014.203. View

12.

Viau K, Ernst S, Pasquali M, Botto L, Hedlund G, Longo N . Evidence-based treatment of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab. 2013; 110(3):255-62. DOI: 10.1016/j.ymgme.2013.08.020. View

13.

Mohammadi P, Siavashani E, Mohammadi M, Bahramy A, Almadani N, Garshasbi M . Whole-exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3. Mol Genet Genomic Med. 2021; 9(11):e1834. PMC: 8606204. DOI: 10.1002/mgg3.1834. View

14.

Mohammadi P, Heidari M, Ashrafi M, Mahdieh N, Garshasbi M . A novel homozygous missense variant in the NAXE gene in an Iranian family with progressive encephalopathy with brain edema and leukoencephalopathy. Acta Neurol Belg. 2021; 122(5):1201-1210. DOI: 10.1007/s13760-021-01717-y. View

15.

Mohammadi P, Daneshmand M, Mahdieh N, Ashrafi M, Heidari M, Garshasbi M . Identification of a novel missense c.386G > A variant in a boy with the POMGNT1-related muscular dystrophy-dystroglycanopathy. Acta Neurol Belg. 2020; 121(1):143-151. DOI: 10.1007/s13760-020-01527-8. View

16.

Tavasoli A, Haji Esmaeil Memar E, Ashrafi M, Hosseini S, Haghighi R, Ghabeli H . Primary and Secondary Microcephaly, Global Developmental Delay, and Seizure in Two Siblings Caused by a Novel Missense Variant in the ZNF335 Gene. J Mol Neurosci. 2022; 72(4):719-729. DOI: 10.1007/s12031-021-01955-y. View

17.

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(5):557-61. View

18.

Stockler S, Isbrandt D, Hanefeld F, Schmidt B, von Figura K . Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. Am J Hum Genet. 1996; 58(5):914-22. PMC: 1914613. View

19.

Dhar S, Scaglia F, Li F, Smith L, Barshop B, Eng C . Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab. 2008; 96(1):38-43. DOI: 10.1016/j.ymgme.2008.10.008. View

20.

Mercimek-Mahmutoglu S, Ndika J, Kanhai W, de Villemeur T, Cheillan D, Christensen E . Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene. Hum Mutat. 2014; 35(4):462-9. DOI: 10.1002/humu.22511. View