Expanding the neuroimaging findings of guanidinoacetate methyltransferase deficiency in an Iranian girl with a homozygous frameshift variant in the GAMT.

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.

Phenotypic subgrouping and multi-omics analyses reveal reduced diazepam-binding inhibitor (DBI) protein levels in autism spectrum disorder with severe language impairment.

BACKGROUND: The mechanisms underlying autism spectrum disorder (ASD) remain unclear, and clinical biomarkers are not yet available for ASD. Differences in dysregulated proteins in ASD have shown little reproducibility, which is partly due to ASD heterogeneity. Recent studies have demonstrated that subgrouping ASD cases based on clinical phenotypes is useful for identifying candidate genes that are dysregulated in ASD subgroups. However, this strategy has not been employed in proteome profiling analyses to identify ASD biomarker proteins for specific subgroups. METHODS: We therefore conducted a cluster analysis of the Autism Diagnostic Interview-Revised (ADI-R) scores from 85 individuals with ASD to predict subgroups and subsequently identified dysregulated genes by reanalyzing the transcriptome profiles of individuals with ASD and unaffected individuals. Proteome profiling of lymphoblastoid cell lines from these individuals was performed via 2D-gel electrophoresis, and then mass spectrometry. Disrupted proteins were identified and compared to the dysregulated transcripts and reported dysregulated proteins from previous proteome studies. Biological functions were predicted using the Ingenuity Pathway Analysis (IPA) program. Selected proteins were also analyzed by Western blotting. RESULTS: The cluster analysis of ADI-R data revealed four ASD subgroups, including ASD with severe language impairment, and transcriptome profiling identified dysregulated genes in each subgroup. Screening via proteome analysis revealed 82 altered proteins in the ASD subgroup with severe language impairment. Eighteen of these proteins were further identified by nano-LC-MS/MS. Among these proteins, fourteen were predicted by IPA to be associated with neurological functions and inflammation. Among these proteins, diazepam-binding inhibitor (DBI) protein was confirmed by Western blot analysis to be expressed at significantly decreased levels in the ASD subgroup with severe language impairment, and the DBI expression levels were correlated with the scores of several ADI-R items. CONCLUSIONS: By subgrouping individuals with ASD based on clinical phenotypes, and then performing an integrated transcriptome-proteome analysis, we identified DBI as a novel candidate protein for ASD with severe language impairment. The mechanisms of this protein and its potential use as an ASD biomarker warrant further study.

The mis-wired language network in children with developmental language disorder: insights from DTI tractography.

This study aims to detect the neural substrate underlying the language impairment in children with developmental language disorder (DLD) using diffusion tensor imaging (DTI) tractography. Deterministic DTI tractography was performed in a group of right-handed children with DLD (N = 17; mean age 10;07 ± 2;01 years) and a typically developing control group matched for age, gender and handedness (N = 22; mean age 11;00 ± 1;11 years) to bilaterally identify the superior longitudinal fascicle, arcuate fascicle, anterior lateral segment and posterior lateral segment (also called dorsal language network) and the middle and inferior longitudinal fascicle, extreme capsule fiber system and uncinate fascicle (also called ventral language network). Language skills were assessed using an extensive, standardized test battery. Differences in language performance, white matter organization and structural lateralization of the language network were statistically analyzed. Children with DLD showed a higher overall volume and higher ADC values for the left-hemispheric language related WM tracts. In addition, in children with DLD, the majority (88%; 7/8) of the studied language related WM tracts did not show a significant left or right lateralization pattern. These structural alterations might underlie the language impairment in children with DLD.

Associations Between the 2D:4D Proxy Biomarker for Prenatal Hormone Exposures and Symptoms of Developmental Language Disorder.

Purpose: Relative lengths of the index (2D) and ring (4D) fingers in humans represent a retrospective biomarker of prenatal hormonal exposures. For this reason, the 2D:4D digit ratio can be used to investigate potential hormonal contributions to the etiology of neurodevelopmental disorders. This study tested potential group differences in 2D:4D digit ratios in a sample of boys with and without developmental language disorder (DLD) and examined the strength of associations between 2D:4D digit ratio and a battery of verbal and nonverbal measures. Method: A group of 29 boys affected by DLD and a group of 76 boys with typical language abilities participated (age range = 5;6-11;0 years). Scanned images were used to measure finger lengths. Language measures included the core language subtests from the Clinical Evaluation of Language Fundamentals-Fourth Edition (Semel, Wiig, & Secord, 2003), a nonword repetition task, a sentence recall task, and the Test of Early Grammatical Impairment (Rice & Wexler, 2001). Results: Significant group differences indicated lower 2D:4D digit ratios in the group with DLD. Modest associations were found between 2D:4D digit ratios and some Clinical Evaluation of Language Fundamentals-Fourth Edition subtests. Conclusions: Prenatal hormone exposures may play a role in the etiology of some language symptoms.

Guanidinoacetate methyltransferase (GAMT) deficiency: a rare but treatable epilepsy.

Epilepsy commonly presents in childhood as part of a syndrome, and some such children may reach adult services without an underlying syndromic diagnosis. For adult neurologists taking over their care, it is often unclear how hard to search for an underlying diagnosis. The diagnostic yield may be small and such a diagnosis may not change management. Young adults with learning difficulties are also challenging to investigate, as they may not tolerate standard epilepsy tests.We present such a case in which simple tests identified a unifying diagnosis. With the new diagnosis came a new treatment that had a significant impact on seizures and quality of life.

Una revisión sobre la aplicación de estrategias para aumentar el input de la comunicación aumentativa y alternativa asistida en personas con trastornos del desarrollo / A revision about the application of augmentative and alternative communication's augmented input strategies on people with developmental disabilities

Los niños y adultos que usan la comunicación aumentativa y alternativa (CAA) no obtienen la misma clase de input lingüístico con los sistemas de CAA que el que reciben los niños de desarrollo común. Entre las principales razones se encuentran la asimetría entre modalidades y la falta de modelos comunicativos en el entorno que enseñen cómo usar con eficacia los sistemas. Ahora bien, el input lingüístico se puede mejorar «aumentándolo» para facilitar el desarrollo del lenguaje y la comunicación mediante el empleo de estrategias de input aumentado (del inglés, augmented input), como el modelado del lenguaje asistido o la estimulación del lenguaje asistido, para enseñar los símbolos gráficos a los usuarios de CAA. El objetivo principal del input aumentado es proporcionar un modelo para el uso de los símbolos gráficos como modo de comunicación viable. En este artículo se tratarán aspectos cruciales para el aprendizaje y uso de sistemas de CAA como son la importancia de aumentar el input, las principales técnicas de intervención basadas en el aumento del input para la enseñanza de la comprensión y la expresión comunicativa, y los resultados más relevantes de la investigación en la aplicación de estas técnicas a niños y adultos con diferentes trastornos del desarrollo que necesitan aprender a usar un sistema de CAA (AU)

Children and adults who use Augmentative and Alternative Communication (AAC) do not acquire the same kind of linguistic input with their AAC systems as typical development children do. Asymmetry between communication modes and the lack of communication models in their environment that may teach them how to effectively use their systems are among the main reasons. Nevertheless, linguistic input may be enhanced by ‘augmenting’ it in order to facilitate language and communication development. This may be accomplished by using augmented input strategies, such as aided language modeling or aided language stimulation to teach graphic symbols to AAC users. The main goal of augmenting input is to provide a model for graphic symbols use as a viable communication mode. In this article some crucial aspects of learning and use of AAC systems such as the importance of augmenting input, the main intervention techniques based on augmenting input for receptive and expressive communication, as well as the most relevant research results in the application of this techniques for children and adults with different kind of developmental disabilities will be addressed (AU)

Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models?

While it has long been thought that most of cerebral creatine is of peripheral origin, the last 20 years has provided evidence that the creatine synthetic pathway (AGAT and GAMT enzymes) is expressed in the brain together with the creatine transporter (SLC6A8). It has also been shown that SLC6A8 is expressed by microcapillary endothelial cells at the blood-brain barrier, but is absent from surrounding astrocytes, raising the concept that the blood-brain barrier has a limited permeability for peripheral creatine. The first creatine deficiency syndrome in humans was also discovered 20 years ago (GAMT deficiency), followed later by AGAT and SLC6A8 deficiencies, all three diseases being characterized by creatine deficiency in the CNS and essentially affecting the brain. By reviewing the numerous and latest experimental studies addressing creatine transport and synthesis in the CNS, as well as the clinical and biochemical characteristics of creatine-deficient patients, our aim was to delineate a clearer view of the roles of the blood-brain and blood-cerebrospinal fluid barriers in the transport of creatine and guanidinoacetate between periphery and CNS, and on the intracerebral synthesis and transport of creatine. This review also addresses the question of guanidinoacetate toxicity for brain cells, as probably found under GAMT deficiency.

Systemic availability of guanidinoacetate affects GABAA receptor function and seizure threshold in GAMT deficient mice.

Deficiency of guanidinoacetate methyltransferase (GAMT) causes creatine depletion and guanidinoacetate accumulation in brain with the latter deemed to be responsible for the severe seizure disorder seen in affected patients. We studied electrical brain activity and GABAA mediated mechanisms of B6J.Cg-Gamt(tm1Isb) mice. Electrocorticographic (ECoG) monitoring of pharmacological treatments with ornithine (5 % in drinking water for 5-18 days) and/or Picrotoxin (PTX) (a GABAA receptor antagonist) (1.5 mg/kg, I.P.) in Gamt(MUT) and Gamt(WT) groups [n = 3, mean age (SEM) = 6.9 (0.2) weeks]. Mice were fitted with two frontal and two parietal epidural electrodes under ketamine/xylazine anesthesia. Baseline and test recordings were performed for determination of seizure activity over a 2 h period. The ECoG baseline of Gamt(MUT) exhibited an abnormal monotonous cortical rhythm (7-8 Hz) with little variability during awake and sleep states compared to wild type recordings. Ornithine treatment and also PTX administration led to a relative normalization of the Gamt(MUT) ECoG phenotype. Gamt(WT) on PTX exhibited electro-behavioral seizures, whereas the Gamt(MUT) did not have PTX induced seizures at the same PTX dose. Gamt(MUT) treated with both ornithine and PTX did not show electro-behavioral seizures while ornithine elevated the PTX seizure threshold of Gamt(MUT) mice even further. These data demonstrate: (1) that there is expression of electrical seizure activity in this Gamt-deficient transgenic mouse strain, and (2) that the systemic availability of guanidinoacetate affects GABAA receptor function and seizure thresholds. These findings are directly and clinically relevant for patients with a creatine-deficiency syndrome due to genetic defects in GAMT and provide a rational basis for a combined ornithine/picrotoxin therapeutic intervention.

Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.

De novo disruptions of the neural transcription factor FOXP1 are a recently discovered, rare cause of sporadic intellectual disability (ID). We report three new cases of FOXP1-related disorder identified through clinical whole-exome sequencing. Detailed phenotypic assessment confirmed that global developmental delay, autistic features, speech/language deficits, hypotonia and mild dysmorphic features are core features of the disorder. We expand the phenotypic spectrum to include sensory integration disorder and hypertelorism. Notably, the etiological variants in these cases include two missense variants within the DNA-binding domain of FOXP1. Only one such variant has been reported previously. The third patient carries a stop-gain variant. We performed functional characterization of the three missense variants alongside our stop-gain and two previously described truncating/frameshift variants. All variants severely disrupted multiple aspects of protein function. Strikingly, the missense variants had similarly severe effects on protein function as the truncating/frameshift variants. Our findings indicate that a loss of transcriptional repression activity of FOXP1 underlies the neurodevelopmental phenotype in FOXP1-related disorder. Interestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein. These variants also retained the ability to interact with FOXP2, a paralogous transcription factor disrupted in rare cases of speech and language disorder. Thus, speech/language deficits in these individuals might be worsened through deleterious effects on FOXP2 function. Our findings highlight that de novo FOXP1 variants are a cause of sporadic ID and emphasize the importance of this transcription factor in neurodevelopment.

De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome.

De novo truncating mutations in Additional sex combs-like 3 (ASXL3) have been identified in individuals with Bainbridge-Ropers syndrome (BRS), characterized by failure to thrive, global developmental delay, feeding problems, hypotonia, dysmorphic features, profound speech delays and intellectual disability. We identified three novel de novo heterozygous truncating variants distributed across ASXL3, outside the original cluster of ASXL3 mutations previously described for BRS. Primary skin fibroblasts established from a BRS patient were used to investigate the functional impact of pathogenic variants. ASXL3 mRNA transcripts from the mutated allele are prone to nonsense-mediated decay, and expression of ASXL3 is reduced. We found that ASXL3 interacts with BAP1, a hydrolase that removes mono-ubiquitin from histone H2A lysine 119 (H2AK119Ub1) as a component of the Polycomb repressive deubiquitination (PR-DUB) complex. A significant increase in H2AK119Ub1 was observed in ASXL3 patient fibroblasts, highlighting an important functional role for ASXL3 in PR-DUB mediated deubiquitination. Transcriptomes of ASXL3 patient and control fibroblasts were compared to investigate the impact of chromatin changes on transcriptional regulation. Out of 564 significantly differentially expressed genes (DEGs) in ASXL3 patient fibroblasts, 52% were upregulated and 48% downregulated. DEGs were enriched in molecular processes impacting transcriptional regulation, development and proliferation, consistent with the features of BRS. This is the first single gene disorder linked to defects in deubiquitination of H2AK119Ub1 and suggests an important role for dynamic regulation of H2A mono-ubiquitination in transcriptional regulation and the pathophysiology of BRS.

Creatine biosynthesis and transport in health and disease.

Creatine is physiologically provided equally by diet and by endogenous synthesis from arginine and glycine with successive involvements of arginine glycine amidinotransferase [AGAT] and guanidinoacetate methyl transferase [GAMT]. A specific plasma membrane transporter, creatine transporter [CRTR] (SLC6A8), further enables cells to incorporate creatine and through uptake of its precursor, guanidinoacetate, also directly contributes to creatine biosynthesis. Breakthrough in the role of creatine has arisen from studies on creatine deficiency disorders. Primary creatine disorders are inherited as autosomal recessive (mutations affecting GATM [for glycine-amidinotransferase, mitochondrial]) and GAMT genes) or X-linked (SLC6A8 gene) traits. They have highlighted the role of creatine in brain functions altered in patients (global developmental delay, intellectual disability, behavioral disorders). Creatine modulates GABAergic and glutamatergic cerebral pathways, presynaptic CRTR (SLC6A8) ensuring re-uptake of synaptic creatine. Secondary creatine disorders, addressing other genes, have stressed the extraordinary imbrication of creatine metabolism with many other cellular pathways. This high dependence on multiple pathways supports creatine as a cellular sensor, to cell methylation and energy status. Creatine biosynthesis consumes 40% of methyl groups produced as S-adenosylmethionine, and creatine uptake is controlled by AMP activated protein kinase, a ubiquitous sensor of energy depletion. Today, creatine is considered as a potential sensor of cell methylation and energy status, a neurotransmitter influencing key (GABAergic and glutamatergic) CNS neurotransmission, therapeutic agent with anaplerotic properties (towards creatine kinases [creatine-creatine phosphate cycle] and creatine neurotransmission), energetic and antioxidant compound (benefits in degenerative diseases through protection against energy depletion and oxidant species) with osmolyte behavior (retention of water by muscle). This review encompasses all these aspects by providing an illustrated metabolic account for brain and body creatine in health and disease, an algorithm to diagnose metabolic and gene bases of primary and secondary creatine deficiencies, and a metabolic exploration by (1)H-MRS assessment of cerebral creatine levels and response to therapeutic measures.

Moderna investigación educativa en el síndrome de Down / No disponible

Down Syndrome Education International ha publicado 21 breves artículos que describen los modernos avances realizados en la investigación educativa sobre el síndrome de Down, y las cuestiones que aún están por resolver. Ofrecemos los cinco primeros sobre lenguaje de signos, memoria operativa verbal, aprendizaje de la lectura, lenguaje y habla, y perfil de puntos fuertes y débiles

Down Syndrome Education International has edited short articles which describe modern advances in the field of educational research in Down syndrome, and face to the questions that remain unresolved. We offer the first five articles dealing on sign language, verbal working memory, reading as a tool to improve language, communication and speech, and the profile of strengths and weaknesses

Stable isotope dilution microquantification of creatine metabolites in plasma, whole blood and dried blood spots for pharmacological studies in mouse models of creatine deficiency.

BACKGROUND: To develop an accurate stable isotope dilution assay for simultaneous quantification of creatine metabolites ornithine, arginine, creatine, creatinine, and guanidinoacetate in very small blood sample volumes to study creatine metabolism in mice. METHODS: Liquid-chromatography (C18) tandem mass spectrometry with butylation was performed in positive ionization mode. Stable isotope dilution assay with external calibration was applied to three different specimen types, plasma, whole blood and dried blood spot (DBS). RESULTS: Analytical separation, sensitivity, accuracy, and linearity of the assay were adequate. The stable isotope dilution assay in plasma revealed no significant bias to gold standard methods for the respective analytes. Compared to plasma, we observed an overestimate of creatine and creatinine (2- to 5-fold and 1.2- to 2-fold, respectively) in whole-blood and DBS, and an underestimate of arginine (2.5-fold) in DBS. Validation of the assay in mouse models of creatine deficiency revealed plasma creatine metabolite pattern in good accordance with those observed in human GAMT and AGAT deficiency. Single dose intraperitoneal application of ornithine in wild-type mice lead to fast ornithine uptake (Tmax ≤ 10 min) and elimination (T1/2=24 min), and a decline of guanidinoacetate. CONCLUSION: The assay is fast and reliable to study creatine metabolism and pharmacokinetics in mouse models of creatine deficiency.

Feasibility of newborn screening for guanidinoacetate methyltransferase (GAMT) deficiency.

Guanidinoacetate methyltransferase (GAMT) deficiency causes brain creatine deficiency characterized by developmental delays, speech delay, seizures and autism-like behavior. Identification and therapy at birth because of a positive family history has prevented intellectual disability and seizures in all cases reported. The objective of this study was to develop a method to identify patients with GAMT deficiency from newborn screening blood spots. Creatine and guanidinoacetate were extracted from 10,000 deidentified blood spots using the same protocol routinely used for newborn screening and quantified by stable isotope dilution using deuterated creatine and guanidinoacetate as internal standards. Residual dried blood spots from three infants with GAMT deficiency were used to evaluate the sensitivity of the method. A second tier test using UPLC-MS/MS was performed to analyze samples with a concentration of guanidinoacetate >2.44 µmol/L (99.5th centile of the normal population). Fifty four blood spots required second tier testing in addition to seven blood spots from three patients with GAMT deficiency retrospectively analyzed. With second tier testing, only the samples from GAMT deficiency patients had elevated concentration of guanidinoacetate. Our results show that GAMT deficiency can be identified in newborns using routine extraction methods. The cost of this additional screening is minimal, as it does not require additional instrumentation, procedure, or sample collection. The use of a second tier test can reduce the false positive rate to a minimum. Summary Brain creatine deficiency syndromes cause mental retardation that can be prevented if therapy is initiated early in life. This manuscript reports that infants with GAMT deficiency (one of the brain creatine deficiency syndromes) can be identified from elevated guanidinoacetate in newborn blood spots with virtually absent false-positive results using a second tier test.

Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring.

We collected data on 48 patients from 38 families with guanidinoacetate methyltransferase (GAMT) deficiency. Global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems as the most affected domains was present in 44 participants, with additional epilepsy present in 35 and movement disorder in 13. Treatment regimens included various combinations/dosages of creatine-monohydrate, l-ornithine, sodium benzoate and protein/arginine restricted diets. The median age at treatment initiation was 25.5 and 39 months in patients with mild and moderate DD/ID, respectively, and 11 years in patients with severe DD/ID. Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate levels were achieved by supplementation with creatine-monohydrate combined with high dosages of l-ornithine and/or an arginine-restricted diet (250 mg/kg/d l-arginine). Therapy was associated with improvement or stabilization of symptoms in all of the symptomatic cases. The 4 patients treated younger than 9 months had normal or almost normal developmental outcomes. One with inconsistent compliance had a borderline IQ at age 8.6 years. An observational GAMT database will be essential to identify the best treatment to reduce plasma guanidinoacetate levels and improve long-term outcomes.

Evidence-based treatment of guanidinoacetate methyltransferase (GAMT) deficiency.

BACKGROUND: Guanidinoacetate methyltransferase (GAMT) deficiency causes cerebral creatine deficiency. Patients can have autistic behavior, seizures, intellectual disability, and severe speech delay. The goal of therapy is to increase creatine while reducing potentially neurotoxic guanidinoacetate concentrations. Here we evaluate how different therapies affect plasma guanidinoacetate levels in patients with GAMT deficiency. METHODS: Retrospective analysis of data from five new patients with GAMT deficiency (four with delays and seizures, one diagnosed at birth). RESULTS: The four symptomatic patients had decreased brain creatine by magnetic resonance spectroscopy and three also had abnormal globi pallidi by MRI. GAMT sequencing identified four previously reported mutations and one novel missense mutation (c.233T>A/p.V78E). Treatment with creatine (250-1000 mg/kg/day), ornithine (100-800 mg/kg/day), and sodium benzoate (50-135 mg/kg/day) supplements along with dietary protein restriction (0.8-1.5 g/kg/day) improved seizures and development with all patients becoming verbal. The patient treated at birth remains developmentally normal. Reduction in glycine and increase in ornithine levels significantly decreased plasma guanidinoacetate, with glycine levels being the best predictor of guanidinoacetate levels. In contrast, arginine levels were not significantly correlated with plasma guanidinoacetate. CONCLUSIONS: Our results show that supplements of creatine, sodium benzoate (to reduce glycine) and ornithine reduce guanidinoacetate levels in patients with GAMT deficiency (dietary therapy was not evaluated in our study). Normal development with early therapy renders GAMT deficiency an ideal candidate for inclusion in newborn screening panels.

Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes.

Cerebral creatine deficiency syndromes (CCDS) are a group of inborn errors of creatine metabolism that involve AGAT and GAMT for creatine biosynthesis disorders and SLC6A8 for creatine transporter (CT1) deficiency. Deficiencies in the three enzymes can be distinguished by intermediate metabolite levels, and a definitive diagnosis relies on the presence of deleterious mutations in the causative genes. Mutations and unclassified variants were identified in 41 unrelated patients, and 22 of these mutations were novel. Correlation of sequencing and biochemical data reveals that using plasma guanidinoacetate (GAA) as a biomarker has 100% specificity for both AGAT and GAMT deficiencies, but AGAT deficiency has decreased sensitivity in this assay. Furthermore, the urine creatine:creatinine ratio is an effective screening test with 100% specificity in males suspected of having creatine transporter deficiency. This test has a high false-positive rate due to dietary factors or dilute urine samples and lacks sensitivity in females. We conclude that biochemical screening for plasma GAA and measuring of the urine creatine:creatinine ratio should be performed for suspected CCDS patients prior to sequencing. Also, based on the results of this study, we feel that sequencing should only be considered if a patient has abnormal biochemical results on repeat testing.

Inborn errors of creatine metabolism and epilepsy.

Creatine metabolism disorders include guanidinoacetate methyltransferase (GAMT) deficiency, arginine:glycine amidinotransferase (AGAT) deficiency, and the creatine transporter (CT1-encoded by SLC6A8 gene) deficiency. Epilepsy is one of the main symptoms in GAMT and CT1 deficiency, whereas the occurrence of febrile convulsions in infancy is a relatively common presenting symptom in all the three above-mentioned diseases. GAMT deficiency results in a severe early onset epileptic encephalopathy with development arrest, neurologic deterioration, drug-resistant seizures, movement disorders, mental disability, and autistic-like behavior. In this disorder, epilepsy and associated abnormalities on electroencephalography (EEG) are more responsive to substitutive treatment with creatine monohydrate than to conventional antiepileptic drugs. AGAT deficiency is mainly characterized by mental retardation and severe language disorder without epilepsy. In CT1 deficiency epilepsy is generally less severe than in GAMT deficiency. All creatine disorders can be investigated through measurement of creatine metabolites in body fluids, brain proton magnetic resonance spectroscopy ((1) H-MRS), and molecular genetic techniques. Blood guanidinoacetic acid (GAA) assessment and brain H-MRS examination should be part of diagnostic workup for all patients presenting with epileptic encephalopathy of unknown origin. In girls with learning and/or intellectual disabilities with or without epilepsy, SLC6A8 gene assessment should be part of the diagnostic procedures. The aims of this review are the following: (1) to describe the electroclinical features of epilepsy occurring in inborn errors of creatine metabolism; and (2) to delineate the metabolic alterations associated with GAMT, AGAT, and CT1 deficiency and the role of a substitutive therapeutic approach on their clinical and electroencephalographic epileptic patterns.

Beyond DSM: the role of auditory processing in attention and its disorders.

This article reviews and synthesizes recent research regarding auditory processing, attention, and their roles in generating both adaptive and maladaptive behavioral responses. Research in these areas is beginning to converge on the role of polymorphisms associated with catecholamine metabolism and transport, particularly the neurotransmitter dopamine. The synthesis offered in this article appears to be the first to argue that genetic differences in dopamine metabolism may be the common factor in four disparate disorders that are often observed to be comorbid, i.e., attention-deficit hyperactivity disorder, auditory processing disorders, developmental language disorders, and reading disorders.