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Several candidate gene studies support RELNas susceptibility gene for autism. Given the complex inheritance pattern of autism, it is expected that gene–gene interactions will exist. A logical starting point for examining potential gene–gene interactions is to evaluate the joint effects of genes involved in a common biological pathway. RELNshares a common biological pathway with APOE, and Persico et al.have observed transmission distortion of the APOE-2 allele in autism families.

One hundred and twenty-nine children, 2 to 8 years old, with idiopathic autistic spectrum disorder diagnosed by standard instruments (Childhood Austim Ratings Scale and Autism Diagnostic Observation Schedule) were treated with fluoxetine (0.15 to 0.5mg/kg) for 5 to 76 months (mean 32 to 36 months), with discontinuation trials. Response criteria are described. Family histories were obtained using the family history method in repeated interviews. Fluoxetine response, family history of major affective disorder, and unusual intellectual achievement, pretreatment language, and hyperlexia were used to define a coherent subgroup of autistic spectrum disorder. Statistical analyses were post hoc. Of the children, 22 (17%) had an excellent response, 67 (52%) good, and 40 (31%) fair/poor. Treatment age did not correlate with response. Fluoxetine response correlated robustly with familial major affective disorder and unusual intellectual achievement, and with hyperlexia in the child. Family history of bipolar disorder and of unusual intellectual achievement correlated strongly. Five children developed bipolar disorder during follow-up. Fluoxetine response, family history of major affective disorder (especially bipolar), unusual achievement, and hyperlexia in the children appear to define a homogeneous autistic subgroup. Bipolar disorder, unusual intellectual achievement, and autistic spectrum disorders cluster strongly in families and may share genetic determinants.

One hundred and twenty‐nine children, 2 to 8 years old, with idiopathic autistic spectrum disorder diagnosed by standard instruments (Childhood Austim Ratings Scale and Autism Diagnostic Observation Schedule) were treated with fluoxetine (0.15 to 0.5mg/kg) for 5 to 76 months (mean 32 to 36 months), with discontinuation trials. Response criteria are described. Family histories were obtained using the family history method in repeated interviews. Fluoxetine response, family history of major affective disorder, and unusual intellectual achievement, pretreatment language, and hyperlexia were used to define a coherent subgroup of autistic spectrum disorder. Statistical analyses were post hoc. Of the children, 22 (17%) had an excellent response, 67 (52%) good, and 40 (31%) fair/poor. Treatment age did not correlate with response. Fluoxetine response correlated robustly with familial major affective disorder and unusual intellectual achievement, and with hyperlexia in the child. Family history of bipolar disorder and of unusual intellectual achievement correlated strongly. Five children developed bipolar disorder during follow‐up. Fluoxetine response, family history of major affective disorder (especially bipolar), unusual achievement, and hyperlexia in the children appear to define a homogeneous autistic subgroup. Bipolar disorder, unusual intellectual achievement, and autistic spectrum disorders cluster strongly in families and may share genetic determinants.

To describe the neurobehavioral syndrome in two children with destruction of the right basal ganglia ostensibly from amniocentesis needle penetration at 17 weeks of gestation.

Growth and development of 207 children (49% males; mean age 5.4 years [SD 0.2], range 4 to 7.3 years whose mothers received iodine during pregnancy, and children who received iodine first in their 2nd year, were examined in 1996; 192 children(49% males; mean age 6.5 years[SD 0.2], range 5.8 to 6.9 years) whose mothers received iodine while pregnant were seen in 1998. Children were from the southern part of China's Xinjiang Province which has the lowest levels of iodine in water and soil ever recorded. Head circumference but not height was improved for those who received iodine during pregnancy (compared with those receiving iodine at age 2) and for those supplemented before the end of the 2nd trimester (relative to those supplemented during the 3rd trimester). Iodine before the 3rd trimester predicted higher psychomotor test scores for children relative to those provided iodine later in pregnancy or at 2 years. Results from the test for cognitive development resulted in trend only differences between those children supplemented during pregnancy versus later. The results address the question of when maternal iodine supplements should begin in public health programs world wide. Findings may be relevant to the treatment of maternal and newborn thyroid deficiency in industrialized countries, particularly for those infants delivered before the end of the second trimester.

Growth and development of 207 children (49% males; mean age 5.4 years [SD 0.2], range 4 to 7.3 years whose mothers received iodine during pregnancy, and children who received iodine first in their 2nd year, were examined in 1996; 192 children (49% males; mean age 6.5 years[SD 0.2], range 5.8 to 6.9 years) whose mothers received iodine while pregnant were seen in 1998. Children were from the southern part of China's Xinjiang Province which has the lowest levels of iodine in water and soil ever recorded. Head circumference but not height was improved for those who received iodine during pregnancy (compared with those receiving iodine at age 2) and for those supplemented before the end of the 2nd trimester (relative to those supplemented during the 3rd trimester). Iodine before the 3rd trimester predicted higher psychomotor test scores for children relative to those provided iodine later in pregnancy or at 2 years. Results from the test for cognitive development resulted in trend only differences between those children supplemented during pregnancy versus later. The results address the question of when maternal iodine supplements should begin in public health programs world wide. Findings may be relevant to the treatment of maternal and newborn thyroid deficiency in industrialized countries, particularly for those infants delivered before the end of the second trimester.

Autistic disorder is a pervasive neurodevelopmental disorder characterized by deficits in language and social communication, as well as stereotyped patterns of behavior. Peak LOD scores from several genomic screening efforts indicate the presence of an autistic disorder susceptibility locus within the distal long arm of human chromosome 7 (7q31-q35). Wassink et al. [2001: Am J Med Genet 105:406–413] reported that WNT2, located at 7q31, influences genetic risk in autistic disorder. These findings were enhanced when examined in a subset of families with severe language impairment. WNT genes encode secreted growth factor–like proteins that participate in growth regulation, differentiation, and tumorigenesis. We tested for genetic association of two WNT2 variants in an independent data set of 135 singleton and 82 multiplex families. No significant association was found between autistic disorder and the WNT2 genotypes in either the overall data set or in the language-impaired subset of families. However, differences in allele frequencies of the 3' UTR single nucleotide polymorphism between the present population and that of Wassink et al. may account for the inability to detect association between WNT2 and autistic disorder in the present data set. We also screened the two reported autistic disorder mutations previously detected by Wassink et al. We did not identify any activating mutation in the coding region of the WNT2 gene. Thus, we conclude that activating mutations of the WNT2 gene are not a major contributor to the development of autistic disorder in these data. © 2001 Wiley-Liss, Inc.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting via the GABAA receptors. The GABAA receptors are comprised of several different homologous subunits, forming a group of receptors that are both structurally and functionally diverse. Three of the GABAA receptor subunit genes (GABRB3, GABRA5 and GABRG3) form a cluster on chromosome 15q11-q13, in a region that has been genetically associated with autistic disorder (AutD). Based on these data, we examined 16 single nucleotide polymorphisms (SNPs) located within GABRB3, GABRA5 and GABRG3 for linkage disequilibrium (LD) in 226 AutD families (AutD patients and parents). Genotyping was performed using either OLA (oligonucleotide ligation assay), or SSCP (single strand conformation polymorphism) followed by DNA sequencing. We tested for LD using the Pedigree Disequilibrium Test (PDT). PDT results gave significant evidence that AutD is associated with two SNPs located within the GABRG3 gene (exon5_539T/C, p = 0.02 and intron5_687T/C, p = 0.03), suggesting that the GABRG3 gene or a gene nearby contributes to genetic risk in AutD.

Three children presented with a complex syndrome of atypical psychotic and extremely immature behavior, obesity and overgrowth, borderline retardation, and seizures (prominent in two). Weight overgrowth exceeded height overgrowth and was stratospheric (up to 8 SD above mean). Obesity seemed related to lack of satiety. The cases fit no known condition: hypothalamic damage, Sotos' syndrome, and Prader-Willi syndrome were excluded. Empirical treatment with anticonvulsants (carbamazepine and acetazolamide) together with psychotropic agents (selective serotonin reuptake inhibitors and risperidone) controlled seizures, improved behavior, and stopped weight gain in each patient. We have not found this syndrome previously described. The etiology is unknown: perinatal encephalopathy could be a factor in the two patients with prominent seizures; in the third, familial major affective disorder is implicated. Medication responses suggest a low-serotonin state underlying the lack of satiety, an imbalance of serotonin and noradrenergic modulation in the hypothalamus, and epileptogenic disorders (or affective disorder responsive to anticonvulsants in one case) involving these same systems. (J Child Neurol2000;15:518-528).

We have ascertained and examined a patient with autistic disorder (AD) and monosomy X (Turner syndrome). The patient met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)/International Classification of Diseases (ICD-10) criteria for AD verified by the Autism Diagnostic Interview—Revised. The patient exhibited both social and verbal deficits and manifested the classical physical features associated with monosomy X. Skuse et al. [1997: Nature 387:705–708] reported three such cases of AD and monosomy X in their study of Turner syndrome and social cognition. They observed that monosomy X females with a maternally inherited X chromosome had reduced social cognition when compared with monosomy X females with a paternally inherited X chromosome. All three cases of AD and monosomy X were maternally inherited. Based on their data, they suggested that there was a gene for social cognition on the X chromosome that is imprinted and not expressed when the X chromosome is of maternal origin. Thus, we conducted parent-of-origin studies in our AD/monosomy X patient by genotyping X chromosome markers in the patient and her family. We found that the patient's X chromosome was of maternal origin. These findings represent the fourth documented case of maternal inheritance of AD and monosomy X and provide further support for the hypothesis that parent-of-origin of the X chromosome influences social cognition. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:312–316, 2000. © 2000 Wiley-Liss, Inc.

ABSTRACT¶Autistic disorder (AD) is a developmental disorder affecting social interactions, communication, and behavior. AD is a disease of complex genetic architecture. It is postulated that several genes contribute to the underlying etiology of AD. Chromosome 15 is of particular interest due to numerous reports of AD in the presence of chromosomal abnormalities, located mainly in the 15q11-q13 region. There are also a number of plausible candidate genes in this area, including the gamma-aminobutyric acid: A(GABA: A) receptor gene complex. We have undertaken a study of this region of chromosome 15 in a data set of 63 multiplex families (with 2 or more AD affected individuals per family). We found evidence in support of linkage to the 15q11-q13 region, as well as evidence of increased recombination in this region. These findings provide further support for the involvement of chromosome 15q11-q13 in the genetic etiology of AD.:

Metabolic findings using [18F]fluorodeoxyglucose (FDG) with positron emission tomography (PET) and correlative anatomic findings with computed tomography (CT) or magnetic resonance imaging (MRI) were characterized in 13 children with infantile autism. Four of 13 patients had both an abnormal FDG-PET and an abnormal MRI, whereas seven of 13 patients had both a normal FDG-PET and a normal CT or MRI. Sixteen of a total of 195 brain areas qualitatively examined with FDG-PET had a hypometabolic abnormality on PET. Three of the five abnormal structural imaging studies revealed neuronal migrational anomalies (focal pachygyria). In two of the five patients with anatomic abnormalities, these were noted only after knowledge of the FDG-PET findings. Our experience reveals that anatomic and metabolic abnormalities can be found in children who exhibit autistic behavior. An FDG-PET study may provide evidence of metabolic dysfunction after an initially unremarkable MRI scan because subtle anatomic abnormalities (as those seen with neuronal migrational anomalies) may be found only after knowledge of a regional metabolic abnormality. (J Child Neurol1994;9:155-161).

We report an 11-year-old boy with continuous spike-wave discharges during sleep accompanied by partial motor and atypical absence seizures, psychomotor regression, and severe behavior problems. During wakefulness, epileptiform discharges occurred over the right parietal region, suggesting that the continuous spike-wave discharges during sleep were a manifestation of secondary bilateral synchrony. Bilateral suppression of the spike-and-wave activity was observed after right-sided intracarotid amobarbital injection, further supporting the impression of secondary bilateral synchrony. The right superior temporoparietal increase in metabolic activity during continuous spike-wave discharges and noncontinuous spike-wave discharges was seen on [18F]fluorodeoxyglucose positron emission tomography and supports a right temporoparietal focus in our case. The presence of a focal abnormality suggests that surgical therapy may be effective. (J Child Neurol1994;9:139-143).

Between 1969 and 1979 five children were found to have lumbar disc disease and were evaluated for clinically unsuspected thoracic spine abnormalities. Of these five children, two had Scheuermann's disease and one had disc space narrowing associated with Schmorl's nodes. One other had narrowed disc spaces without bony defects, and one had a normal thoracic spine. A unitary concept of childhood lumbar disc disease, Schmorl's nodes and Scheuermann's disease is suggested.

Extract: The basic biochemical defect of X-linked adrenoleukodystrophy (sudanophilic leukodystrophy, Schilder's disease) is unknown. To investigate reported abnormalities in cholesterol metabolism in vitro, we examined cultured skin fibroblasts of four patients and four normal control subjects. The kinetics of retention and accumulation of [14C]cholesterol by these cells was studied. After 3 days of exposure to tracer amounts of [14C]cholesterol, an apparent steady state between the medium and cellular cholesterol was established. The specific radioactivity expressed per mg of protein was similar for both Schilder and control fibroblasts. After labeling the pre-existing cellular cholesterol pool, the rate of loss of label was followed up for a 6-day period. About 23% and 14%, respectively, of the cellular radioactivity in both Schilder's disease and control cells were released into the medium after the consecutive change with fresh nonlabeled medium. No significant differences in [14C] cholesterol rates of uptake or release were observed between control and Schilder's disease fibroblasts. About 44% of the labeled cholesterol was present in an esterfied form after incubation in the presence of unheated serum in both Schilder's and control cultures.Speculation: These results do not confirm previously reported abnormalities in cholesterol metabolism in cultured fibroblasts. Nevertheless, accumulating evidence from studies of fatty acid composition of brain and adrenal tissues in Schilder's disease indicates the presence of an abnormal series of long chain fatty acids. Studies are now in progress to determine whether these possibly unique long chain fatty acids are evident in fibroblasts from patients with Schilder's disease.

Induction of cytochrome P-4501A protein and induction of related enzyme activity are hallmark physiological responses following exposure to planar halogenated aromatic hydro carbons (HAHs) such as 3,3',4,4',5-pentachlorobiphenyl (PCB 126; PeCB). Environments contaminated by HAHs are often contaminated by mixtures of anthropogenic contami nants, including organometallic compounds. Both HAHs and organometallics easily bio-concentrate and bioaccumulate in aquatic food chains that may ultimately be linked to humans through seafood consumption. Tributyltin (TBI), a marine biocide, has been detected in many aquatic environments due to its primary use as a marine antifoulant agent. Exposure to TBI, as well as several PCBs, has been associated with immunotoxicity, neurotoxicity, and endocrine disruption. Recently TBT has been shown to inhibit cyto chrome P-4501A activity in vitro, but information concerning these effects in vivo and in combination with classical inducers of P-4501A, such PeCB, is lacking. We exposed female B6C3F1 mice to 0.01, 0.1, and 1.0 mg/kg PeCB, TBI, or both in combination, with corn oil (CO) serving as a carrier control. Cytochrome P-4501A protein levels and related benzolalpyrene hydroxylation (BaP-OHase) activity were measured following a sin gle acute intraperitoneal dp) dose or seven daily injections. Body, thymus, and liver weights were used to monitor general physiological responses following exposure. P-4501A levels and BaP-OHase activity were significantly elevated in mice exposed to PeCB alone. This effect was enhanced by coexposure to low levels of TBT; PeCB-induced P-4501A-related activity was potentiated at the low range of each. The highest dose of TBT, however, inhibited these activities when given in combination with PeCB. Thymic atrophy was evident only in mice exposed daily to 0.1 and 1.0 mg/kg PeCB alone, or to a combi nation of the lowest and highest dose of PeCB and TBT, respectively. Because environ mental levels of TBT are not expected to be as high as the highest level used in our toxi-cological studies, we conclude that environmental exposure to TBT may potentiate, rather than inhibit, the activity of environmental levels of HAHs that are associated with P-4501A induction.

• Four persons who exhibited prominent autistic features throughout life died when 4,14, 27, and 33 years old. All were mentally retarded. One had documented phenylketonuria, but the cause of mental retardation and autistic behavior was undefined in three. At the time of autopsy, brain weights were within 2 SDs of the norm for age. Complete neuropathologic examination, including analysis of cortical neurons impregnated with the rapid Golgi method, failed to provide clues as to cause or the pathoanatomic substrate of autistic behavior in these cases.

• In seeking the neurologic substrate of the autistic syndrome of childhood, previous studies have implicated the medial temporal lobe or the ring of mesolimbic cortex located in the mesial frontal and temporal lobes. During an acute encephalopathic illness, a clinical picture developed in three children that was consistent with infantile autism. This development was reversible. It was differentiated from acquired epileptic aphasia, and the language disorder was differentiated from aphasia. One child had rises in serum herpes simplex titers, and a computerized tomographic (CT) scan revealed an extensive lesion of the temporal lobes, predominantly on the left. The other two, with similar clinical syndromes, had normal CT scans, and no etiologic agent was defined. These cases are examples of ah acquired and reversible autistic syndrome in childhood, emphasizing the clinical similarities to bilateral medial temporal lobe disease as described in man, including the Klüver-Bucy syndrome seen in postencephalitic as well as postsurgical states.

Hotien prefecture, Xinjiang Province, China, in the Taklamakan Desert, is an area of severe iodine deficiency. Because usual methods of iodine supplementation failed here, we began supplementation in 1992 with potassium iodate, which was added to irrigation water (Lancet 1994; 334:107–110). We report 4 y experience with this method in 3 townships that contained a total treated population of 37 000. Potassium iodate was dripped into irrigation water (to a concentration 10–80 μg/l) during a 2- to 4-wk period. During the 3 y that followed, no further supplementation was made, and iodine concentrations increased several fold in crops and plants, sheep and chicken thyroid glands, and meat and in urine of children 2–6 y of age and of women who were of childbearing age. Infant mortality decreased 50%, and sheep production increased 43%. Iodine repletion of soil through irrigation water is an effective and cost-efficient way of providing iodine in appropriate situations.

A behavior questionnaire was used retrospectively in 21 manic-depressive children to quantitate manic-depressive behaviors before and after treatment with lithium carbonate. The study children were matched with 21 control children for age, race, sex, and socioeconomic status. The study children had significantly more seizures, relatives with psychotic disorders, allergies, food sensitivities, headaches, and abnormal behaviors in all categories measured. During treatment, manic-depressive children had a statistically significant reduction in disturbed behavior. This behavior, however, was still significantly more disturbed than normal control children. (J Child Neurol1986;1:364-368)

The etiology of infantile autism is not known. To assess the possible role of familial psychopathology, we investigated a group of autistic subjects subgrouped by level of language functin. Family histories were obtained by the family history method. Neurological status was assessed by neurological diagnostic examination and prenatal and perinatal history. The results showed a high incidence of Asperger's syndrome in family members of high-functioning autistic subjects only. The rate of bipolar affective disorder in family members was 4.2%, higher than in the general population; it was significantly higher in families with Asperger's syndrome, suggesting an etiological link between Asperger's syndrome and manic depression. Positive neurological findings were concentrated in the low-functioning subgroup. These findings imply different etiologies for high- versus low-functioning autism, with high-functioning autism related to familial factors, especially Asperger's syndrome.

Temporary junctions were observed between developing optic fibers of the chick embryo and were distributed along the entire length of the axons from the cell body to the tip of the growth cone. These junctions were present in all material studied between days E-3 and E-18, the latter being the start of myelin formation of the optic tract. Junctions between adjacent axons were focal in nature and showed a decrease in the size of the intercellular space caused by a close apposition of the plasma membrane. With the experimental techniques used final identification of these junctions could not be made but are thought to be of two types - the gap and occludens junctions. Temporary fasciae adherentes junctions were observed at the end of the axon, between the growth cone and adjacent neural tissue. Speculation was made on the functional role of these temporary junctions.

Four infants had bilateral hippocampal sclerosis by magnetic resonance scans, including oblique coronal fast spin echo images of the temporal lobes; [18F]fluorodeoxyglucose–positron emission tomographic scans, done in 2 infants, showed isolated bilateral anterior temporal lobe hypometabolism. All had epilepsy with episodes of status epilepticus. Despite adequate motor and sensory functions, all failed to develop language (or lost attained language), social skills, and complex purposive or adaptive activity, even after epilepsy was controlled. Bilateral hippocampal dysfunction in early life appears to be associated with a profound failure of cognitive capacities, including language learning and learning of complex social and adaptive skills in general. The deficits correspond to the cognitive deficits of severe infantile autism. Hippocampal function, or more generally medial temporal lobe function, appears necessary for language learning in the infant, as well as for complex social and adaptive learning.

We treated four children with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with high-dose intravenous immunoglobulin (IVIG). All patients received 400 mg/kg of IVIG a day for 5 days during relapses, and one patient received additional periodic infusions of 400 mg/kg. All patients showed excellent recovery of motor strength following each relapse that was treated with IVIG. Compared with plasmapheresis (which was used to treat relapses earlier), recovery of function with IVIG treatments was similar, and in two patients it was superior, to plasmapheresis. There were no side effects with IVIG treatments as compared with plasmapheresis with which two children had infection of central lines with Staphylococcus epidermidis, one had profuse bleeding from accidental extrusion of a central line, and one had multiple episodes of major venous thromboses. High-dose IVIG was a safe and effective adjunctive therapy for childhood CIDP in these four patients.

Background: It is widely believed that the lesbian population is at a lower risk for sexually transmitted diseases. This myth has been perpetuated by misperception of lesbian patients and sexual practices associated with this lifestyle. Physician failure to identify lesbian patients and address issues confronting these patients is a confounding factor. We report two patients whose diagnosis was obscured by their sexual orientation.

Eight children (ages 5-15) with serious behavior disorders responded to lithium carbonate (Li) Rx with dramatic improvement. Aggressive hostile antisocial behavior, and hyperactivity and distractibility, were common to all. All had various Rx over years, including stimulants, tranquilizers, psychotherapy and environmental modification without satisfactory improvement. All were in stable homes (3 adoptive). One group (6 pts.) had cyclic behavior; 5 had family hx. consistent with manic-depressive disease (M-D); 4 met criteria for both mania and depression in childhood (Weinberg & Brumback, Am.J.Dis.Ch. 130:380, 1976). Five had disturbances of vegetative or homeostatic functions (hyperphagia, hyperdipsia, excess sweating, salt craving, sleep disorder, etc.) which improved during Li Rx. Work-up for other causes was negative. The second group (2 pts.) had no cyclic changes, no manic behavior, no vegetative disturbances, and no clear family history of affective disorder. In these, Li was synergistic with stimulants. Li serum levels were maintained in accepted range (0.4-1.0 mEq/L.); no toxicity was seen. Improvement, assessed from function in daily environment, has been maintained 7-25 months (ave. 15 mos.). In 6, Li was discontinued with reversion to previous behavior, which improved after restarting Li. Li Rx produces marked and sustained normalization of behavior in some children with severe disorders of mood and affect. It may help elucidate the relationships between childhood behavior disorders & familial psychiatric disease, esp. M-D and affective disorders.

TO THE EDITOR. —Ropper and Shahani1 described pain in 29 (mostly adult) patients with Guillain-Barré syndrome (GBS). Pain preceded weakness by one to five days in four of their 29 patients. We recently observed a girl 2 years 10 months of age who had pain that preceded the onset of clinically demonstrable weakness by 19 days. During this initial period, the patient carried the presumptive diagnosis of "toxic synovitis" and it was not until the 17th day of illness that the correct diagnosis was confirmed. REPORT OF A CASE. —One month prior to admission, a 2-year 10-month-old girl developed a viral respiratory tract infection with positive slide test for infectious mononucleosis heterophil antibodies (Monospot) and Epstein-Barr virus titers. Two weeks later, she complained of low back, buttock, and hip pain, resisted full movements of her hips, refused to walk because of pain, and was admitted to an outside hospital with