Cerebral Creatine Deficiency Syndromes Research Articles

Cerebral creatine deficiency syndrome

Cerebral creatine deficiency syndrome

ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes

Cerebral creatine deficiency syndromes (CCDS) are inherited metabolic phenotypes of creatine synthesis and transport. There are two enzyme deficiencies, guanidinoacetate methyltransferase (GAMT), encoded by GAMT and arginine-glycine amidinotransferase (AGAT), encoded by GATM, which are involved in the synthesis of creatine. After synthesis, creatine is taken up by a sodium-dependent membrane bound creatine transporter (CRTR), encoded by SLC6A8, into all organs. Creatine uptake is very important especially in high energy demanding organs such as the brain, and muscle. To classify the pathogenicity of variants in GAMT, GATM, and SLC6A8, we developed the CCDS Variant Curation Expert Panel (VCEP) in 2018, supported by The Clinical Genome Resource (ClinGen), a National Institutes of Health (NIH)-funded resource. We developed disease-specific variant classification guidelines for GAMT-, GATM-, and SLC6A8-related CCDS, adapted from the American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant interpretation guidelines. We applied specific variant classification guidelines to 30 pilot variants in each of the three genes that have variants associated with CCDS. Our CCDS VCEP was approved by the ClinGen Sequence Variant Interpretation Working Group (SVI WG) and Clinical Domain Oversight Committee in July 2022. We curated 181 variants including 72 variants in GAMT, 45 variants in GATM, and 64 variants in SLC6A8 and submitted these classifications to ClinVar, a public variant database supported by the National Center for Biotechnology Information. Missense variants were the most common variant type in all three genes. We submitted 32 new variants and reclassified 34 variants with conflicting interpretations. We report specific phenotype (PP4) using a points system based on the urine and plasma guanidinoacetate and creatine levels, brain magnetic resonance spectroscopy (MRS) creatine level, and enzyme activity or creatine uptake in fibroblasts ranging from PP4, PP4_Moderate and PP4_Strong. Our CCDS VCEP is one of the first panels applying disease specific variant classification algorithms for an X-linked disease. The availability of these guidelines and classifications can guide molecular genetics and genomic laboratories and health care providers to assess the molecular diagnosis of individuals with a CCDS phenotype.

Electro-clinical features and long-term outcomes in guanidinoacetate methyltransferase (GAMT) deficiency

ObjectiveTo evaluate clinical characteristics and long-term outcomes in patients with guanidinoacetate methyltransferase (GAMT) deficiency with a special emphasis on seizures and electroencephalography (EEG) findings. MethodsWe retrospectively analyzed the clinical and molecular characteristics, seizure types, EEG findings, neuroimaging features, clinical severity scores, and treatment outcomes in six patients diagnosed with GAMT deficiency. ResultsMedian age at presentation and diagnosis were 11.5 months (8–12 months) and 63 months (18 months −11 years), respectively. Median duration of follow-up was 14 years. Global developmental delay (6/6) and seizures (5/6) were the most common symptoms. Four patients presented with febrile seizures. The age at seizure-onset ranged between 8 months and 4 years. Most common seizure types were generalized tonic seizures (n = 4) and motor seizures resulting in drop attacks (n = 3). Slow background activity (n = 5) and generalized irregular sharp and slow waves (n = 3) were the most common EEG findings. Burst-suppression and electrical status epilepticus during slow-wave sleep (ESES) pattern was present in one patient. Three of six patients had drug-resistant epilepsy. Post-treatment clinical severity scores showed improvement regarding movement disorders and epilepsy. All patients were seizure-free in the follow-up. ConclusionsEpilepsy is one of the main symptoms in GAMT deficiency with various seizure types and non-specific EEG findings. Early diagnosis and initiation of treatment are crucial for better seizure and cognitive outcomes. This long-term follow up study highlights to include cerebral creatine deficiency syndromes in the differential diagnosis of patients with global developmental delay and epilepsy and describes the course under treatment.

Molecular Mechanism of SLC6A8 Dysfunction with c.1699T > C (p.S567P) Mutation in Cerebral Creatine Deficiency Syndromes.

Cerebral creatine deficiency syndromes (CCDS) are neurodevelopmental disorders caused by a decrease in creatine levels in the central nervous system (CNS) due to functional mutations in creatine synthetic enzymes or creatine transporter (CRT/SLC6A8). Although SLC6A8 mutations have been reported to be the most frequent cause of CCDS, sufficient treatment for patients with CCDS harboring SLC6A8 mutations has not yet been achieved. This study aimed to elucidate the molecular mechanism of SLC6A8 dysfunction caused by the c. 1699T > C missense mutation, which is thought to induce dysfunction through an unidentified mechanism. A study on SLC6A8-expressing oocytes showed that the c.1699T > C mutation decreased creatine uptake compared to that in wild-type (WT) oocytes. In addition, a kinetics study of creatine uptake revealed that the c.1699T > C mutation reduced the maximum uptake rate but not Michaelis-Menten constant. In contrast, the c.1699T > C mutation did not attenuate SLC6A8 protein levels or alter its cellular localization. Based on the SLC6A8 structure in the AlphaFold protein structure database, it is possible that the c.1699T > C mutation alters the interaction between the S567 and Y143 residues of SLC6A8, leading to decreased creatine transport function. These findings contribute to the understanding of the pathology of CCDS and to the development of strategies for CCDS treatment.

Clinical and genetic analysis of a child with Cerebral creatine deficiency syndrome due to variant of SLC6A8 gene

To explore the clinical features and genetic variant in a child with Cerebral creatine deficiency syndrome (CCDS). A child who had presented at the Affiliated Children's Hospital of Fudan University on March 5, 2021 was selected as the study subject. Whole exome sequencing (WES) was carried out for the child, and candidate variant was verified by Sanger sequencing. The level of creatine in the brain was determined by magnetic resonance spectroscopy. The patient, a 1-year-and-10-month male, had presented with developmental delay and epilepsy. Both his mother and grandmother had a history of convulsions. MRS showed reduced cerebral creatine in bilateral basal ganglia and thalamus. The child was found to harbor a hemizygous splicing variant of the SLC6A8 gene, namely c.1767+1_1767+2insA, which may lead to protein truncation. The variant was not found in the public databases. Both his mother and grandmother were heterozygous carriers for the same variant. The hemizygous c.1767+1_1767+2insA variant of the SLC6A8 gene probably underlay the CCDS in this child. Discovery of the novel variant has also expanded the mutational spectrum of the SLC6A8 gene.

Cerebral creatine deficiency syndrome with a novel missense variant in SLC6A8 gene

AbstractCerebral creatine deficiency syndromes (CCDS) are three metabolic diseases characterized by loss of function in three proteins (GATM, GAMT, and SLC6A8) that required in creatine (Cr) synthesis pathway and transport. In this study, we aimed to identify the causal variant in a male who was 12‐year‐old manifesting intellectual disability (ID), seizures, expressive dysphasia and autism‐like behavior. Urinary Cr metabolite measurements and MRI‐spectroscopy (MRS) findings were consistent with CCDS. Molecular analysis revealed de novo hemizygous SLC6A8 (NM_005629.4): c.1400 T > G (p.Met467Arg) variant. The variant was not found in ClinVar, (the date of access: April 23th, 2023) and population databases (ExAC, gnomAD, 1000 Genomes, ESP 6500, Turkish Variome, GenomeAsia, Iranome, GME Variome, TOPMed Bravo and 4.7KJPN), it alters the physicochemical properties of the amino acid, the region is moderately conserved across species and in‐silico prediction tools (REVEL, CADD, SIFT, PolyPhen2, Mutation Taster, MetaLR, MCAP, MetaRNN and MutPred) unanimously emphasize pathogenicity. Based on this evidence, the variant was interpreted as “likely pathogenic” according to the ACMG criteria (PS2, PM2,PP3, and PP4‐S). This report may further elucidate the nature and phenotypic consequences of SLC6A8 variants.

Fourteen cases of cerebral creatine deficiency syndrome in children: a cohort study in China.

This study sought to analyze the clinical characteristics, biochemical metabolic indications, treatment results, and genetic spectrum of cerebral creatine deficiency syndrome (CCDS), estimate the prevalence of CCDS in Chinese children and provide a reference to guide clinical practice. We performed a retrospective cohort study of 3,568 children with developmental delay at Children's Hospital of Fudan University over a 6-year period (January 2017-December 2022). Metabolites in the blood/urine were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and genetic testing was performed by next-generation sequencing (NGS). The patients with suspected CCDS were ultimately diagnosed by magnetic resonance spectroscopy (MRS). The patients were then treated and followed up. All the reported cases of CCDS, their gene mutations, and treatment results in China were summarized. Ultimately, 14 patients were diagnosed with CCDS. The age of onset was between 1-2 years. All the patients had developmental delay, 9 had epilepsy, and 8 had movement or behavioral disorders. A total of 17 genetic variants were identified, including 6 novel variants. c.403G>A, c.491dupG of the guanidinoacetate methyltransferase (GAMT) gene had a relatively high frequency. After treatment, patients with GAMT deficiency showed obvious improvements, and brain creatine (Cr) levels recovered to 50-80% of normal, 1 patient achieved normal neurodevelopment, and 3 patients became epilepsy free; however, 6 male patients with X-linked creatine transporter gene (SLC6A8) variants received Cr for 3-6 months with no effect, and 2 patients received combined therapy with few improvements. The prevalence of CCDS is ~0.39% in Chinese children with developmental delay. Alow-protein diet, Cr and, ornithine were useful for patients with GAMT deficiency. Male patients with SLC6A8 deficiency showed only limited improvement on combined therapy.

Novel guanidinoacetate methyltransferase (GAMT) mutation associated with cerebral creatine deficiency syndrome in a Syrian child: a case report.

A 2.5-year-old boy presented to the paediatric neurology clinic with evidence of neurodevelopmental delays and intellectual disabilities. Recurrent eye blinking, generalized non-motor (absence) seizures, hyperactivity, and poor eye contact were revealed in the neurological examination. Some athetoid and dystonic movements were noticed. His electroencephalography (EEG) was very disturbed because of generalized spike-wave and slow-wave discharges. Based on these findings antiepileptic drugs were administered. His seizures slightly improved, but then relapsed with myoclonic and drop attacks. After 6 years of unbeneficial treatment, a genetic test was required. Whole-exome sequencing was conducted and identified a novel homozygous GAMT variant (NM_138924.2:c.391+5G>C). Treatment with oral creatine supplementation, ornithine, and sodium benzoate was administered. After 1.7 years of follow-up, the child was almost seizure-free with a remarkable reduction of epileptic activity on EEG. He demonstrated good-but not complete-behavioural and motor improvement due to delayed diagnosis and treatment. GAMT deficiency should be considered in differential diagnoses in children with neurodevelopmental regression along with drug-refractory epilepsy. A special concern is needed in Syria for such genetic disorders; regarding the high prevalence of consanguinity. Whole-exome sequencing and genetic analysis can be used to diagnose this disorder. We reported a novel GAMT variant to extend its mutation spectrum and provide an additional molecular marker for the definitive diagnosis of GAMT deficiency patients and prenatal diagnosis in the affected families.

Cerebral Creatine Deficiency Affects the Timing of Oligodendrocyte Myelination.

Cerebral creatine deficiency syndrome (CCDS) is an inborn error of metabolism characterized by intellectual delays, seizures, and autistic-like behavior. However, the role of endogenously synthesized creatine on CNS development and function remains poorly understood. Here, magnetic resonance spectroscopy of adult mouse brains from both sexes revealed creatine synthesis is dependent on the expression of the enzyme, guanidinoacetate methyltransferase (GAMT). To identify Gamt-expressed cells, and how Gamt affects postnatal CNS development, we generated a mouse line by knocking-in a GFP, which is expressed on excision of Gamt We found that Gamt is expressed in mature oligodendrocytes during active myelination in the developing postnatal CNS. Homozygous deletion of Gamt resulted in significantly reduced mature oligodendrocytes and delayed myelination in the corpus callosum. Moreover, the absence of endogenous creatine resulted in altered AMPK signaling in the brain, reduced brain creatine kinase expression in cortical neurons, and signs of axonal damage. Experimental demyelination in mice after tamoxifen-induced conditional deletion of Gamt in oligodendrocyte lineage cells resulted in delayed maturation of oligodendrocytes and myelin coverage in lesions. Moreover, creatine and cyclocreatine supplementation can enhance remyelination after demyelination. Our results suggest endogenously synthesized creatine controls the bioenergetic demand required for the timely maturation of oligodendrocytes during postnatal CNS development, and that delayed myelination and altered CNS energetics through the disruption of creatine synthesis might contribute to conditions, such as CCDS.SIGNIFICANCE STATEMENT Cerebral creatine deficiency syndrome is a rare disease of inborn errors in metabolism, which is characterized by intellectual delays, seizures, and autism-like behavior. We found that oligodendrocytes are the main source of endogenously synthesized creatine in the adult CNS, and the loss of endogenous creatine synthesis led to delayed myelination. Our study suggests impaired cerebral creatine synthesis affects the timing of myelination and may impact brain bioenergetics.

Guanidinoacetate Methyltransferase Deficiency, a Treatable Neurodevelopmental Disorder

AbstractGuanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive inborn error of creatine synthesis that results in intellectual disability, epilepsy, expressive language delay, and dystonia. We report data from two siblings with an uncommon GAMT deficiency phenotype and their clinical, biochemical, imaging, and treatment findings. The older sibling had intellectual disability, epilepsy, and generalized dystonia. The younger sibling had intellectual disability and generalized dystonia. After treatment with creatine, verbal fluency improved, as well as dystonia and aggression. This study confirms that in patients with unexplained intellectual disability, epilepsy, and/or movement disorders, GAMT deficiency should be considered. GAMT-associated cerebral creatine deficiency syndrome is a potentially treatable condition and can be identified by elevated levels of guanidinoacetate in plasma or urine or by a significantly decreased creatine peak on magnetic resonance spectroscopy.

A novel variation of gamt in cerebral creatine deficiency syndrome, first complete homozygous deletion of GAMT

Cerebral Creatine Deficiency Syndromes (CCDS) are congenital metabolic disorders in the creatine metabolism pathway. In this study, we evaluated the clinical, phenotypic, radiological and genetic features of patients with CCDS. We tried to identify early diagnosis clues in patients. Especially, we reviewed the causes of delay in patients with late diagnosis. In line with these findings, the diagnosis is confirmed by enzyme tests and next generation sequencing based whole genome sequencing. In this study, 6 patients whose diagnosis was genetically confirmed were presented (5 GAMT mutations (someone is complete homozygous deletion in GAMT gene), 1 SLC6A8 mutation). 5 of these patients were from the same family, and 4 patients were patients with a late diagnosis. Two of the 4 patients who were diagnosed late were moderate and two had severe phenotype. The neurological findings consisted of patients with different clinical findings such as speech disorder, cognitive retardation, autism and epilepsy. Patients received appropriate treatment for the type of cerebral creatine deficiency. While response to treatment was good in early diagnosed cases, a partial clinical improvement was detected in cases diagnosed late. The patient, who was started treatment before neurological symptoms appeared, was neurodevelopmentally normal. It was observed that there was a strong relationship between age at diagnosis and phenotype and prognosis. We compared the clinical findings, phenotype and genotype characteristics of patients with CCDS. We reviewed the causes of delay in patients with late diagnosis. Thus, we wanted to raise awareness about early diagnosis and treatment of CCDS, one of the rare metabolic diseases.

Identification of novel variations in SLC6A8 and GAMT genes causing cerebral creatine deficiency syndrome

Cerebral creatine deficiency syndromes (CCDSs) are a group of rare mendelian disorders mainly characterized by intellectual disability, movement anomaly, behavior disorder and seizures. SLC6A8, GAMT, and GATM are known genes responsible for CCDS. In this study, seven pediatric patients with developmental delay were recruited and submitted to a series of clinical evaluation, laboratory testing, and genetic analysis. The clinical manifestations and core biochemical indications of each child were basically consistent with the diagnosis of CCDS. Genetic diagnosis determined that all patients were positive for SLC6A8 or GAMT variation. A total of 12 variants were identified in this cohort, including six novel ones. The frequency of these variants, the Revel scores and the conservatism of the affected amino acids support their pathogenicity. Our findings expanded the mutation spectrum of CCDS disorders, and provided solid evidence for the counseling to affected families.

Clinical diagnosis of metabolic disorders using untargeted metabolomic profiling and disease-specific networks learned from profiling data

Untargeted metabolomics is a global molecular profiling technology that can be used to screen for inborn errors of metabolism (IEMs). Metabolite perturbations are evaluated based on current knowledge of specific metabolic pathway deficiencies, a manual diagnostic process that is qualitative, has limited scalability, and is not equipped to learn from accumulating clinical data. Our purpose was to improve upon manual diagnosis of IEMs in the clinic by developing novel computational methods for analyzing untargeted metabolomics data. We employed CTD, an automated computational diagnostic method that “connects the dots” between metabolite perturbations observed in individual metabolomics profiling data and modules identified in disease­specific metabolite co-perturbation networks learned from prior profiling data. We also extended CTD to calculate distances between any two individuals (CTDncd) and between an individual and a disease state (CTDdm), to provide additional network-quantified predictors for use in diagnosis. We show that across 539 plasma samples, CTD-based network-quantified measures can reproduce accurate diagnosis of 16 different IEMs, including adenylosuccinase deficiency, argininemia, argininosuccinic aciduria, aromatic l-amino acid decarboxylase deficiency, cerebral creatine deficiency syndrome type 2, citrullinemia, cobalamin biosynthesis defect, GABA-transaminase deficiency, glutaric acidemia type 1, maple syrup urine disease, methylmalonic aciduria, ornithine transcarbamylase deficiency, phenylketonuria, propionic acidemia, rhizomelic chondrodysplasia punctata, and the Zellweger spectrum disorders. Our approach can be used to supplement information from biochemical pathways and has the potential to significantly enhance the interpretation of variants of uncertain significance uncovered by exome sequencing. CTD, CTDdm, and CTDncd can serve as an essential toolset for biological interpretation of untargeted metabolomics data that overcomes limitations associated with manual diagnosis to assist diagnosticians in clinical decision-making. By automating and quantifying the interpretation of perturbation patterns, CTD can improve the speed and confidence by which clinical laboratory directors make diagnostic and treatment decisions, while automatically improving performance with new case data.

EP194: Three generations of females with a heterozygous likely pathogenic variant in SLC6A8 causative of X-linked creatine transporter defect

SLC6A8-Related Disorders falls under the umbrella of cerebral creatine deficiency syndromes (CCDS). CCDS are inborn errors of creatine metabolism. SLC6A8-Related Disorders is specifically a creatine transporter deficiency. The SLC6A8 is located at Xq28 and encodes for the sodium- and chloride-dependent creatine transporter 1 that assists in transporting creatine into cells. Pathogenic variants in SLC6A8 impair the ability of the transporter protein to bring creatine into cells, resulting in a creatine shortage.

Clinical characterization and genetic testing for a patient with creatine deficiency syndrome 1

To explore the genetic basis for a child affected with cerebral creatine deficiency syndrome 1 (CCDS1). High-throughput sequencing was carried out to screen pathogenic variant associated with the clinical phenotype of the proband. The candidate variant was verified by Sanger sequencing. High-throughput sequencing revealed that the proband has carried heterozygous c.327delG variant of the SLC6A8 gene, which was verified by Sanger sequencing.Neither parent was found to carry the same variant. The de novo heterozygous c.327delG variant of the SLC6A8 gene probably underlay the CCDS1 in this child.

Laboratory Diagnosis of Cerebral Creatine Deficiency Syndromes by Determining Creatine and Guanidinoacetate in Plasma and Urine.

Cerebral creatine deficiency syndromes are caused by the dysfunctional creatine biosynthesis or transport and comprise three hereditary neurodevelopmental defects including arginine-glycine amidinotransferase (AGAT), guanidinoacetate methyltransferase (GAMT), and creatine transporter deficiencies. All conditions are characterized by seizures, intellectual disability, and behavioral abnormalities. Laboratory diagnosis of these disorders relies on the determination of creatine and guanidinoacetate concentrations in both plasma and urine. Here we describe a rapid quantitative UPLC/MS/MS method for the simultaneous determination of these analytes using a normal-phase HILIC column after analyte derivatization. The approach is suitable for neonatal screening follow-ups and monitoring of the treatment for creatine deficiency syndromes.

GATM and GAMT synthesize creatine locally throughout the mammalian body and within oligodendrocytes of the brain

The enzymes glycine amidinotransferase, mitochondrial (GATM also known as AGAT) and guanidinoacetate N-methyltransferase (GAMT) function together to synthesize creatine from arginine, glycine, and S-Adenosyl methionine. Deficiency in either enzyme or the creatine transporter, CT1, results in a devastating neurological disorder, Cerebral Creatine Deficiency Syndrome (CCDS). To better understand the pathophysiology of CCDS, we mapped the distribution of GATM and GAMT at single cell resolution, leveraging RNA sequencing analysis combined with in vivo immunofluorescence (IF). Using the mouse as a model system, we find that GATM and GAMT are coexpressed in several tissues with distinct and overlapping cellular sources, implicating local synthesis as an important mechanism of creatine metabolism in numerous organs. Extending previous findings at the RNA level, our analysis demonstrates that oligodendrocytes express the highest level of Gatm and Gamt of any cell type in the body. We confirm this finding in the mouse brain by IF, where GATM localizes to the mitochondria of oligodendrocytes, whereas both oligodendrocytes and cerebral cortical neurons express GAMT. Interestingly, the latter is devoid of GATM. Single nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) analysis of 4 brain regions highlights a similar primacy of oligodendrocytes in the expression of GATM and GAMT in the human central nervous system. Importantly, an active putative regulatory element within intron 2 of human GATM is detected in oligodendrocytes but not neurons.

Intellectual Disability and Brain Creatine Deficit: Phenotyping of the Genetic Mouse Model for GAMT Deficiency.

Guanidinoacetate methyltransferase deficiency (GAMT-D) is one of three cerebral creatine (Cr) deficiency syndromes due to pathogenic variants in the GAMT gene (19p13.3). GAMT-D is characterized by the accumulation of guanidinoacetic acid (GAA) and the depletion of Cr, which result in severe global developmental delay (and intellectual disability), movement disorder, and epilepsy. The GAMT knockout (KO) mouse model presents biochemical alterations in bodily fluids, the brain, and muscles, including increased GAA and decreased Cr and creatinine (Crn) levels, which are similar to those observed in humans. At the behavioral level, only limited and mild alterations have been reported, with a large part of analyzed behaviors being unaffected in GAMT KO as compared with wild-type mice. At the cerebral level, decreased Cr and Crn and increased GAA and other guanidine compound levels have been observed. Nevertheless, the effects of Cr deficiency and GAA accumulation on many neurochemical, morphological, and molecular processes have not yet been explored. In this review, we summarize data regarding behavioral and cerebral GAMT KO phenotypes, and focus on uncharted behavioral alterations that are comparable with the clinical symptoms reported in GAMT-D patients, including intellectual disability, poor speech, and autistic-like behaviors, as well as unexplored Cr-induced cerebral alterations.

Prospective identification by neonatal screening of patients with guanidinoacetate methyltransferase deficiency

IntroductionGuanidinoacetate methyltransferase (GAMT) deficiency is an inherited metabolic disorder that impairs the synthesis of creatine (CRE). Lack of CRE in the brain can cause intellectual disability, autistic-like behavior, seizures, and movement disorders. Identification at birth and immediate therapy can prevent intellectual disability and seizures. Here we report the first two cases of GAMT deficiency identified at birth by newborn screening (NBS) in Utah and New York. MethodsNBS dried blood spots were analyzed by tandem mass spectrometry (MS/MS) using either derivatized or non-derivatized assays to detect guanidinoacetate (GUAC) and CRE. For any positive samples, a second-tier test using a more selective method, ultra-performance liquid chromatography (UPLC) combined with MS/MS, was performed to separate GUAC from potential isobaric interferences. ResultsNBS for GAMT deficiency began in Utah on June 1, 2015 using a derivatized method for the detection of GUAC and CRE. In May 2019, the laboratory and method transitioned to a non-derivatized method. GAMT screening was added to the New York State NBS panel on October 1, 2018 using a derivatized method. In New York, a total of 537,408 babies were screened, 23 infants were referred and one newborn was identified with GAMT deficiency. In Utah, a total of 273,902 infants were screened (195,425 with the derivatized method, 78,477 with the non-derivatized method), three infants referred and one was identified with GAMT deficiency. Mean levels of GUAC and CRE were similar between methods (Utah derivatized: GUAC = 1.20 ± 0.43 μmol/L, CRE = 238 ± 96 μmol/L; Utah non-derivatized: GUAC = 1.23 ± 0.61 μmol/L, CRE = 344 ± 150 μmol/L, New York derivatized: GUAC = 1.34 ± 0.57 μmol/L, CRE = 569 ± 155 μmol/L). With either Utah method, similar concentrations of GUAC are observed in first (collected around 1 day of age) and the second NBS specimens (routinely collected at 7–16 days of age), while CRE concentrations decreased in the second NBS specimens. Both infants identified with GAMT deficiency started therapy by 2 weeks of age and are growing and developing normally at 7 (Utah) and 4 (New York) months of age. ConclusionsNewborn screening allows for the prospective identification of GAMT deficiency utilizing elevated GUAC concentration as a marker. First-tier screening may be incorporated into existing methods for amino acids and acylcarnitines without the need for new equipment or staff. Newborn screening performed by either derivatized or non-derivatized methods and coupled with second-tier testing, has a very low false positive rate and can prospectively identify affected children.SummaryCerebral creatine deficiency syndromes caused by defects in creatine synthesis can result in intellectual disability, and are preventable if therapy is initiated early in life. This manuscript reports the identification of two infants with GAMT deficiency (one of the cerebral creatine deficiency syndromes) by newborn screening and demonstrates NBS feasibility using a variety of methods.

Case report of cerebral creatine deficiency syndrome with novel mutation of SLC6A8 gene in a male child in Bangladesh

Case report of cerebral creatine deficiency syndrome with novel mutation of <i>SLC6A8</i> gene in a male child in Bangladesh