Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics.

Disclaimer: These ACMG Standards and Guidelines are intended as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of others that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinical laboratory geneticists should apply their professional judgment to the specific circumstances presented by the patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Cerebral creatine deficiency syndromes are neurometabolic conditions characterized by intellectual disability, seizures, speech delay, and behavioral abnormalities. Several laboratory methods are available for preliminary and confirmatory diagnosis of these conditions, including measurement of creatine and related metabolites in biofluids using liquid chromatography-tandem mass spectrometry or gas chromatography-mass spectrometry, enzyme activity assays in cultured cells, and DNA sequence analysis. These guidelines are intended to standardize these procedures to help optimize the diagnosis of creatine deficiency syndromes. While biochemical methods are emphasized, considerations for confirmatory molecular testing are also discussed, along with variables that influence test results and interpretation.Genet Med 19 2, 256-263.

Case study for the evaluation of current treatment recommendations of guanidinoacetate methyltransferase deficiency: ineffectiveness of sodium benzoate.

BACKGROUND: Guanidinoacetate methyltransferase deficiency is an autosomal recessively inherited disorder of creatine biosynthesis. We report a new patient with guanidinoacetate methyltransferase deficiency and her >3-year treatment outcome. PATIENT: This is a 6-year-old girl who was diagnosed with guanidinoacetate methyltransferase deficiency at the age of 28 months. She presented with moderate global developmental delay, one afebrile seizure, and hypotonia between 6 and 18 months of life. She was treated with creatine and ornithine supplementation and a strict arginine-restricted diet for 42 months. RESULTS: Mutation analysis (compound heterozygous mutations, a known c.327G>A and a novel c.58dupT [p.Trp20LeufsX65]) and enzyme studies in primary fibroblasts confirmed the diagnosis. After 33 months of therapy, her cerebrospinal fluid guanidinoacetate level decreased from 47 to 5.3 times the normal level. Brain creatine by proton magnetic resonance spectroscopy increased by >75% but did not normalize in the basal ganglia and white matter after 3 years of therapy. Additional treatment with sodium benzoate for 17 months did not further improve plasma guanidinoacetate levels, which questions the relevance of this therapy. CONCLUSION: Treatment did not improve moderate intellectual disability or normalize guanidinoacetate accumulation in the central nervous system.

Gray-white matter and cerebrospinal fluid volume differences in children with Specific Language Impairment and/or Reading Disability.

We studied gray-white matter and cerebrospinal fluid (CSF) alterations that may be critical for language, through an optimized voxel-based morphometry evaluation in children with Specific Language Impairment (SLI), compared to Typical Language Development (TLD). Ten children with SLI (8;5-10;9) and 14 children with TLD (8;2-11;8) participated. They received a comprehensive language and reading test battery. We also analyzed a subgroup of six children with SLI+RD (Reading Disability). Brain images from 3-Tesla MRIs were analyzed with intelligence, age, gender, and total intracranial volume as covariates. Children with SLI or SLI+RD exhibited a significant lower overall gray matter volume than children with TLD. Particularly, children with SLI showed a significantly lower volume of gray matter compared to children with TLD in the right postcentral parietal gyrus (BA4), and left and right medial occipital gyri (BA19). The group with SLI also exhibited a significantly greater volume of gray matter in the right superior occipital gyrus (BA19), which may reflect a brain reorganization to compensate for their lower volumes at medial occipital gyri. Children with SLI+RD, compared to children with TLD, showed a significantly lower volume of: (a) gray matter in the right postcentral parietal gyrus; and (b) white matter in the right inferior longitudinal fasciculus (RILF), which interconnects the temporal and occipital lobes. Children with TLD exhibited a significantly lower CSF volume than children with SLI and children with SLI+RD respectively, who had somewhat smaller volumes of gray matter allowing for more CSF volume. The significant lower gray matter volume at the right postcentral parietal gyrus and greater cerebrospinal fluid volume may prove to be unique markers for SLI. We discuss the association of poor knowledge/visual representations and language input to brain development. Our comorbid study showed that a significant lower volume of white matter in the right inferior longitudinal fasciculus may be unique to children with SLI and Reading Disability. It was significantly associated to reading comprehension of sentences and receptive language composite z-score, especially receptive vocabulary and oral comprehension of stories.

Glial fibrillary acidic protein in the cerebrospinal fluid of children with autism and other neuropsychiatric disorders.

The cerebrospinal fluid (CSF) of 47 children and adolescents with autism was analyzed for the contents of two astroglial proteins, the glial fibrillary acidic protein (GFA) and S 100. The results were contrasted with those obtained in similarly aged cases with other neuropsychiatric disorders (n = 25) and in normal children (n = 10). S-100 did not discriminate the groups from each other. However, GFA in autism and autistic-like conditions was at a level almost three times that in the normal group. The results could implicate gliosis and unspecific brain damage in autism. An alternative model would be increased synapse turnover regardless of underlying cause.