Clinical Characteristics, Developmental Trajectory, and Caregiver Burden of Patients With Creatine Transporter Deficiency (SLC6A8).

Practice Parameter for the Assessment and Treatment of Children and Adolescents With Autism Spectrum Disorder

Creatine transporter deficiency (CTD) is an X-linked, neurometabolic disorder associated with intellectual disability that is characterized by brain creatine (Cr) deficiency and caused by mutations in SLC6A8, the Cr transporter 1 protein gene. CTD is identified by elevated urine creatine/creatinine (Cr/Crn) ratio or reduced Cr peak on brain magnetic resonance spectroscopy; the diagnosis is confirmed by decreased Cr uptake in cultured fibroblasts, and/or identification of a mutation in the SLC6A8 gene. Prevalence studies suggest this disorder may be underdiagnosed. We sought to identify cases from a well-characterized cohort of children diagnosed with neurodevelopmental disorders. Urine screening for CTD was performed on a cohort of 46 males with autism spectrum disorder (ASD) and 9 males with a history of non-ASD developmental delay (DD) classified with intellectual disability. We identified 1 patient with CTD in the cohort based on abnormal urine Cr/Crn, and confirmed the diagnosis by the identification of a novel frameshift mutation in the SLC6A8 gene. This patient presented without ASD but with intellectual disability, and was characterized by a nonspecific phenotype of early language delay and DD that persisted into moderate-to-severe intellectual disability, consistent with previous descriptions of CTD. Identification of patients with CTD is possible by measuring urine Cr and Crn levels and the current case adds to the growing literature of neurocognitive deficits associated with the disorder that affect cognition, language and behavior in childhood.

Cerebral creatine deficiency syndromes (CCDS) are a rare group of inherited metabolic disorders (IMDs) that often present with nonspecific findings including global developmental delay (GDD), intellectual disability (ID), seizures, hypotonia, and behavioral differences. Creatine transporter (CRTR) deficiency is the most common CCDS, exhibiting X-linked inheritance and an estimated prevalence as high as 2.6% in individuals with neurodevelopmental disorders. Here, we present a 20-month-old boy with worsening failure to thrive (FTT) and GDD admitted for evaluation. He was found to have persistently low serum creatinine levels and a family history notable for a mother with learning disabilities and a maternal male cousin with GDD. Urine analyses revealed a marked elevation of creatine and elevated creatine:creatinine ratio suggestive of CRTR deficiency. Molecular genetic testing of SLC6A8 identified a maternally inherited hemizygous variant and brain magnetic resonance spectroscopy (MRS) showed diffusely diminished creatine peaks, further supporting the diagnosis of CRTR deficiency. The proband was started on creatine, arginine, and glycine supplementation and has demonstrated improved development. This case highlights that CRTR deficiency should be considered in all patients presenting with FTT and abnormal neurodevelopmental features, particularly if creatinine levels are low on serum chemistry studies. The nonspecific presentation of this condition in males and females likely has resulted in CRTR deficiency being underdiagnosed. There are existing therapies for individuals affected with CRTR deficiency and other CCDS, highlighting the importance of early diagnosis and intervention for affected individuals.

Two inborn errors of metabolism of creatine synthesis as well as the X-linked creatine transporter (SLC6A8) deficiency have been recognized. This report describes the features of five identified male patients and their female relatives who are carriers of the X-linked creatine transporter deficiency syndrome. Proton MR spectroscopy was used to recognize creatine deficiency in the patients. Molecular analysis of the SLC6A8 gene was performed, confirming the diagnosis of homozygous males and heterozygous females. We describe four families from a metropolitan area in the U. S. with X-linked creatine transporter deficiency. All affected males present with developmental delay and severe developmental language impairment. Proton MR spectroscopy shows significantly depressed to essentially absent creatine and phosphocreatine in the male patients. Nonsense mutations and amino acid deletions were found in the SLC6A8 gene in the affected families. Creatine transporter deficiency may be a more common X-linked genetic disorder than originally presumed. The affected males exhibit mental retardation with severe expressive language impairment.

Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, is the second most common cause of X-linked intellectual disability. Symptoms include intellectual disability, epilepsy, and behavioral disorders and are caused by reduced cerebral creatine levels. Targeted treatment with oral supplementation is available, however the treatment efficacy is still being investigated. There are clinical and theoretical indications that heterozygous females with CTD respond better to supplementation treatment than hemizygous males. Unfortunately, heterozygous females with CTD often have more subtle and uncharacteristic clinical and biochemical phenotypes, rendering diagnosis more difficult.We report a new female case who presented with learning disabilities and seizures. After determining the diagnosis with molecular genetic testing confirmed by proton magnetic resonance spectroscopy (1H-MRS), the patient was treated with supplementation treatment including creatine, arginine, and glycine. After 28 months of treatment, the patient showed prominent clinical improvement and increased creatine levels in the brain. Furthermore, we provide a review of the 32 female cases reported in the current literature including a description of phenotypes, genotypes, diagnostic approaches, and effects of supplementation treatment.Based on this, we find that supplementation treatment should be tested in heterozygous female patients with CTD, and a prospective treatment underlines the importance of diagnosing these patients. The diagnosis should be suspected in a broad clinical spectrum of female patients and can only be made by molecular genetic testing. 1H-MRS of cerebral creatine levels is essential for establishing the diagnosis in females, and especially valuable when assessing variants of unknown significance.

Objectives Investigation of inherited metabolic disorders in autism spectrum disorder (ASD) is a matter of debate. X-linked creatine transporter deficiency is among the metabolic disorders which may present predominantly with features of ASD and intellectual disability. Here, we aimed to screen for creatine transporter deficiency in boys with ASD at a university hospital in Turkey. Methods Random urine samples were collected from males with ASD (age 3–18 years); urine creatinine, creatine and guanidinoacetate levels were determined by liquid chromatography – tandem mass spectrometry. Demographic and clinical data were obtained via history and physical examination. The primary outcome was the diagnosis of creatine transporter deficiency (elevated urinary creatine:creatinine ratio). The diagnosis of guanidinoacetate methyltransferase deficiency and the parameters associated with the creatine metabolites were secondary outcomes. Results Forty seven boys were enrolled, 21.3 and 19.1 % of whom had gross motor delay or paroxysmal abnormalities. 55.3 and 51.1 % patients had low urine creatine and guanidinoacetate levels, respectively, and no cases of creatine transporter deficiency or guanidinoacetate methyltransferase deficiency were identified. Age at ASD diagnosis, age at speech onset, otic or ocular dysmorphic features and psychotropic medications were weakly associated with creatine metabolites. Conclusions We found no evidence to support routine screening of boys with ASD for creatine transporter deficiency, but the small number of participants is a limitation. Associates of urinary creatine metabolites were not considered to be clinically significant. High proportion of patients with low creatine and guanidinoacetate levels may be due to nutritional issues, and requires further study.

Early Signs

Variable White Matter Atrophy and Intellectual Development in a Family With X-linked Creatine Transporter Deficiency Despite Genotypic Homogeneity

Creatine transporter (CrT) deficiency (CTD) is an X-linked disorder characterized by intellectual disability and speech delay. There have been reports that show female carriers have clinical symptoms. We have created CrT knockout (CrT(-/y)) mice in which males show severe cognitive deficits as a model of this disorder. The purpose of this study was to examine if the female carrier mice show cognitive deficits. Reductions in Cr levels as well as CrT transcript were observed in the brains of the female CrT(+/-) mice. CrT(+/-) mice show hyperactivity and increased latency to find the cued platform in the Morris water maze (MWM). CrT(+/-) female mice showed deficits in MWM hidden platform acquisition but not during reversal testing. Memory deficits on probe trials were observed during both phases. Novel object recognition memory and contextual fear memory were not affected in female CrT(+/-) mice. Female CrT(+/-) mice show moderate cognitive deficits, which is consistent with some of the human data. Female CrT(+/-) mice could prove to be beneficial in further understanding CTD and testing therapeutic approaches.

Creatine (Cr) Transporter Deficiency (CTD) is an X-linked metabolic disorder, mostly caused by missense mutations in the SLC6A8 gene and presenting with intellectual disability, autistic behavior, and epilepsy. There is no effective treatment for CTD and patients need lifelong assistance. Thus, the research of novel intervention strategies is a major scientific challenge. Animal models are an excellent tool to dissect the disease pathogenetic mechanisms and drive the preclinical development of therapeutics. This review illustrates the current knowledge about Cr metabolism and CTD clinical aspects, with a focus on mainstay diagnostic and therapeutic options. Then, we discuss the rodent models of CTD characterized in the last decade, comparing the phenotypes expressed within clinically relevant domains and the timeline of symptom development. This analysis highlights that animals with the ubiquitous deletion/mutation of SLC6A8 genes well recapitulate the early onset and the complex pathological phenotype of the human condition. Thus, they should represent the preferred model for preclinical efficacy studies. On the other hand, brain- and cell-specific conditional mutants are ideal for understanding the basis of CTD at a cellular and molecular level. Finally, we explain how CTD models might provide novel insight about the pathogenesis of other disorders, including cancer.

X-linked creatine transport (CRTR) deficiency, caused by mutations in the SLC6A8 gene, leads to intellectual disability, speech delay, epilepsy, and autistic behavior in hemizygous males. Additional diagnostic features are depleted brain creatine levels and increased creatine/creatinine ratio (cr/crn) in urine. In heterozygous females the phenotype is highly variable and diagnostic hallmarks might be inconclusive. This survey aims to explore the intrafamilial variability of clinical and brain proton Magnetic Resonance Spectroscopy (MRS) findings in males and females with CRTR deficiency. X-chromosome exome sequencing identified a novel missense mutation in the SLC6A8 gene (p.G351R) in a large family with X-linked intellectual disability. Detailed clinical investigations including neuropsychological assessment, measurement of in vivo brain creatine concentrations using quantitative MRS, and analyses of creatine metabolites in urine were performed in five clinically affected family members including three heterozygous females and one hemizygous male confirming the diagnosis of CRTR deficiency. The severe phenotype of the hemizygous male was accompanied by most distinct aberrations of brain creatine concentrations (-83% in gray and -79% in white matter of age-matched normal controls) and urinary creatine/creatinine ratio. In contrast, the heterozygous females showed varying albeit generally milder phenotypes with less severe brain creatine (-50% to -33% in gray and -45% to none in white matter) and biochemical urine abnormalities. An intrafamilial correlation between female phenotype, brain creatine depletion, and urinary creatine abnormalities was observed. The combination of powerful new technologies like exome-next-generation sequencing with thorough systematic evaluation of patients will further expand the clinical spectrum of neurometabolic diseases.

The Impact of COVID-19 on Individuals With Intellectual and Developmental Disabilities: Clinical and Scientific Priorities.

Developmental trajectories of 31 French Creatine Transporter Deficiency (SLC6A8) patients: New insights into outcome measures selection

Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the SLC6A8 gene. The impaired creatine uptake in the brain results in intellectual disability, behavioral disorders, language delay, and seizures. In this work, we generated human brain organoids from induced pluripotent stem cells of healthy subjects and CTD patients. Brain organoids from CTD donors had reduced creatine uptake compared with those from healthy donors. The expression of neural progenitor cell markers SOX2 and PAX6 was reduced in CTD-derived organoids, while GSK3β, a key regulator of neurogenesis, was up-regulated. Shotgun proteomics combined with integrative bioinformatic and statistical analysis identified changes in the abundance of proteins associated with intellectual disability, epilepsy, and autism. Re-establishment of the expression of a functional SLC6A8 in CTD-derived organoids restored creatine uptake and normalized the expression of SOX2, GSK3β, and other key proteins associated with clinical features of CTD patients. Our brain organoid model opens new avenues for further characterizing the CTD pathophysiology and supports the concept that reinstating creatine levels in patients with CTD could result in therapeutic efficacy.

Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the SLC6A8 gene. The impaired creatine uptake in the brain results in intellectual disability, behavioral disorders, language delay, and seizures. In this work, we generated human brain organoids from induced pluripotent stem cells of healthy subjects and CTD patients. Brain organoids from CTD donors had reduced creatine uptake compared with those from healthy donors. The expression of neural progenitor cell markers SOX2 and PAX6 was reduced in CTD-derived organoids, while GSK3β, a key regulator of neurogenesis, was up-regulated. Shotgun proteomics combined with integrative bioinformatic and statistical analysis identified changes in the abundance of proteins associated with intellectual disability, epilepsy, and autism. Re-establishment of the expression of a functional SLC6A8 in CTD-derived organoids restored creatine uptake and normalized the expression of SOX2, GSK3β, and other key proteins associated with clinical features of CTD patients. Our brain organoid model opens new avenues for further characterizing the CTD pathophysiology and supports the concept that reinstating creatine levels in patients with CTD could result in therapeutic efficacy.