Autistic Patient Research Articles

Diagnostic Testing for Rett Syndrome by DHPLC and Direct Sequencing Analysis of the MECP2 Gene: Identification of Several Novel Mutations and Polymorphisms

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder affecting 1/10,000-15,000 girls. The disease-causing gene was identified as MECP2 on chromosome Xq28, and mutations have been found in approximately 80% of patients diagnosed with RTT. Numerous mutations have been identified in de novo and rare familial cases, and they occur primarily in the methyl-CpG-binding and transcriptional-repression domains of MeCP2. Our first diagnostic strategy used bidirectional sequencing of the entire MECP2 coding region. Subsequently, we implemented a two-tiered strategy that used denaturing high-performance liquid chromatography (DHPLC) for initial screening of nucleotide variants, followed by confirmatory sequencing analysis. If a definite mutation was not identified, then the entire MECP2 coding region was sequenced, to reduce the risk of false negatives. Collectively, we tested 228 unrelated female patients with a diagnosis of possible (209) or classic (19) RTT and found MECP2 mutations in 83 (40%) of 209 and 16 (84%) of 19 of the patients, respectively. Thirty-two different mutations were identified (8 missense, 9 nonsense, 1 splice site, and 14 frameshifts), of which 12 are novel and 9 recurrent in unrelated patients. Seven unclassified variants and eight polymorphisms were detected in 228 probands. Interestingly, we found that T203M, previously reported as a missense mutation in an autistic patient, is actually a benign polymorphism, according to parental analysis performed in a second case identified in this study. These findings highlight the complexities of missense variant interpretation and emphasize the importance of parental DNA analysis for establishing an etiologic relation between a possible mutation and disease. Overall, we found a 98.8% concordance rate between DHPLC and sequence analyses. One mutation initially missed by the DHPLC screening was identified by sequencing. Modified conditions subsequently enabled its detection, underscoring the need for multiple optimized conditions for DHPLC analysis. We conclude that this two-tiered approach provides a sensitive, robust, and efficient strategy for RTT molecular diagnosis.

Red blood cell fatty acid compositions in a patient with autistic spectrum disorder: a characteristic abnormality in neurodevelopmental disorders?

The fatty acid compositions of red blood cell (RBC) phospholipids from a patient with autistic spectrum disorder (ASD) had reduced percentages of highly unsaturated fatty acids (HUFA) compared to control samples. The percentage of HUFA in the RBC from the autistic patient was dramatically reduced (up to 70%) when the sample was stored for 6 weeks at −20°C. However, only minor HUFA reductions were recorded in control samples stored similarly, or when the autistic sample was stored at −80°C. A similar instability in RBC HUFA compositions upon storage at −20°C has been recorded in schizophrenic patients. In a number of other neurodevelopmental conditions, including attention deficit hyperactivity disorder (ADHD) and dyslexia, reduced concentrations of RBC HUFA have been recorded. The extent and nature of these aberrations require further assessment to determine a possible common biochemical origin of neurodevelopmental disorders in general. To facilitate this, a large scale assessment of RBC fatty acid compositions in patients with ASD, and related disorders, should be performed as a matter of urgency. Supplementing cells in culture with the tryptophan metabolite indole acrylic acid (IAA) affected the levels of cellular HUFA and prostaglandin production. Indole acroyl glycine (IAG), a metabolite of IAA excreted in urine, is found in high concentrations in patients with neurodevelopmental disorders including ASD, ADHD, dyslexia, Asperger's syndrome and obsessive compulsive disorder.

5-12-01 Diabetes insipidus and polydipsia in an autistic patient with an empty sella

5-12-01 Diabetes insipidus and polydipsia in an autistic patient with an empty sella

Perspective production in a savant autistic draughtsman

This study examines perspective construction in an autistic patient (E.C.) with quasinormal intelligence who exhibits exceptional ability when performing three-dimensional drawings of inanimate objects. Examination of E.C.'s spontaneous graphic productions showed that although his drawings approximate the 'linear perspective' system, the subject does not use vanishing points in his productions. Nevertheless, a formal computational analysis of E.C.'s accuracy in an experimental task showed that he was able to draw objects rotated in three-dimensional space more accurately than over-trained controls. This accuracy was not modified by suppressing graphic cues that permitted the construction of a vanishing point. E.C. was also able to detect a perspective incongruency between an object and a landscape at a level superior to that of control subjects. Since E.C. does not construct vanishing points in his drawings, it is proposed that his production of a precise realistic perspective is reached without the use of explicit or implicit perspective rules. 'Special abilities' in perspective are examined in relation to existing theoretical models of the cognitive deficit in autism and are compared to other special abilities in autism.

Effect of naltrexone upon self-injurious behavior, learning and activity: a case study

Naltrexone significantly attenuated self-injurious behavior in a 20-year-old mildly retarded autistic male patient. The patient was videotaped daily and behavior was evaluated with a time-sampling procedure. Behavioral ratings of SIB frequency, SIB severity, and activity were collected automatically with a computerized system. Learning and memory were tested on a weekly basis with a modification of a paired associate learning test (PALT). Treatment with naltrexone resulted in (a) attenuation of SIB in the unstructured setting and (b) improvements in learning and memory without influencing activity levels.

Microscopic Neuroanatomic Abnormalities in Autism

Since its initial description in 1943,1 autism has been primarily conceptualized as a behavioral disorder, and for many years it was believed to be the result of parental and environmental influences. With heightened clinical interest in the disorder, coincident with advances in medical technology, however, evidence for an underlying neurologic basis for autism has become increasingly apparent. HISTORICAL NEUROPATHOLOGIC PERSPECTIVE Based largely on the constellation of symptoms that characterize the disorder, various anatomical sites within the brain have been suggested as a possible primary source of pathology in autism. Suspected regions have included the medial temporal lobe,2-5 the thalamic nuclei,6 the basal ganglia,7 and the vestibular system.8 Computed tomographic imaging studies have shown inconsistent findings.9-14 More recently, however, magnetic resonance imaging studies have described abnormalities in portions of the cerebellum and posterior fossa.15-17 Direct microscopic examination of the autistic brain has, until recently, yielded little information. Aarkrog18 reported "slight thickening of the arterioles, slight connective tissue increase in the leptomeninges, and some cell increase" in a frontal lobe biopsy performed on an autistic patient. Later, in 1976, 33 cases of childhood psychosis were reviewed by Darby.19 Although he suggested a possible correlation between limbic system lesions and the affective symptomatology of autism, no consistent neuropathologic findings were found. In 1980, Williams et al20 studied sections of brain from four patients with autistic-like behavior; looking primarily for cell loss and gliosis, they failed to find any consistent abnormalities. MICROSCOPIC NEUROANATOMIC OBSERVATIONS In 1984, anatomic abnormalities were reported in the brain of a 29-year-old man with well-documented autism; the technique of whole brain serial section was used, and the patient was studied in comparison with an identically processed age- and sex-matched control subject.21,22

Neuropsychiatric Testing in an Autistic Mathematical Idiot-Savant: Evidence for Nonverbal Abstract Capacity

A 29-year-old autistic male patient with developmental delay due to perinatal asphyxia developed mathematical skills superior to his language and social skills. Detailed neuropsychiatric testing reveals preservation of capacity to reason using mathematical but not linguistic symbols. Testing implicates the frontal lobe regions as areas of specific difficulty with better preserved posterior, especially right posterior, functions. This autistic idiot-savant illustrates the extreme in a spectrum of developmentally abnormal persons with preservation of isolated skills.

An operant procedure to teach an echolalic, autistic child to answer questions appropriately.

An operant conditioning procedure to teach an autistic patient with rapid immediate echolalia to answer questions correctly was devised. The procedure involved positively reinforcing the patient immediately after a correct response and preventing incorrect responses. It is simple to implement and eliminates some of the structure and constraints inherent in previously described operant methods. This allows the procedure to be administered by a variety of therapeutic personnel and parents and in a variety of living situations.