Susan E. Folstein

Genetics of austim: complex aetiology for a heterogeneous disorder

Since autism was first recognized as a disorder in 1943, speculation about its aetiology has ranged from biological to psychological and back again. After twin studies during the 1970s and 1980s yielded unequivocal evidence for a genetic component, aetiological research in autism began to focus primarily on uncovering the genetic mechanisms involved. The identification of chromosomal abnormalities and Mendelian syndromes among individuals with autism, in conjunction with data from genome screens and candidate-gene studies, has helped to refine the view of the complex genetics that underlies autism spectrum conditions.

Macrocephaly in children and adults with autism

OBJECTIVE To explore the frequency and onset of macrocephaly in autism and its relationship to clinical features. METHOD Head circumferences at birth, during early childhood, and at the time of examination were studied in a community-based sample of autistic children and adults. The authors investigated whether head circumference at the time of examination was associated with clinical features. RESULTS Fourteen percent of the autistic subjects had macrocephaly: 11% of males and 24% of females. In most, the macrocephaly was not present at birth; in some it became apparent in early and middle childhood as a result of increased rate of head growth. A small relationship was noted between head circumference percentile and less severe core features of autism. Neither macrocephaly nor head circumference percentile was associated with nonverbal IQ, verbal status, seizure disorder, neurological soft signs or minor physical anomalies in the autistic subjects. CONCLUSION Macrocephaly is common in autism and usually is not present at birth. Rates of head growth may be abnormal in early and middle childhood in some (37%) children with autism. Macrocephaly does not define a homogeneous subgroup of autistic individuals according to clinical features.

An autosomal genomic screen for autism

Autism is a severe neurodevelopmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors that are detectable in early childhood. The etiology of idiopathic autism is strongly genetic, and oligogenic transmission is likely. The first stage of a two-stage genomic screen for autism was carried out by the Collaborative Linkage Study of Autism on individuals affected with autism from 75 families ascertained through an affected sib-pair. The strongest multipoint results were for regions on chromosomes 13 and 7. The highest maximum multipoint heterogeneity LOD (MMLS/het) score is 3.0 at D13S800 (approximately 55 cM from the telomere) under the recessive model, with an estimated 35% of families linked to this locus. The next highest peak is an MMLS/het score of 2.3 at 19 cM, between D13S217 and D13S1229. Our third highest MMLS/het score of 2.2 is on chromosome 7 and is consistent with the International Molecular Genetic Study of Autism Consortium report of a possible susceptibility locus somewhere within 7q31-33. These regions and others will be followed up in the second stage of our study by typing additional markers in both the original and a second set of identically ascertained autism families, which are currently being collected. By comparing results across a number of studies, we expect to be able to narrow our search for autism susceptibility genes to a small number of genomic regions.

Early Loss of Neostriatal Striosome Neurons in Huntington's Disease

During the first years of symptomatic Huntingtons disease (HD), no readily apparent pathology is seen in the neostriatum at autopsy. To investigate the pathological correlates of chorea and other early clinical signs, we examined the evolution of neuronal loss and accompanying astrocytosis in neostriatal tissue from autopsy cases of early HD. We found scattered islands of astrocytosis and neuronal loss that were present before the previously described ventrally progressive wave of generalized neuronal loss. Histological demonstration of these islands, which are apparently specific to HD, is very helpful in the pathological differential diagnosis of this disease. Immunocytochemical stains for glial fibrillary acidic protein and for markers of the neostriatal striosome-matrix system showed that these islands correspond to the striosome compartment. Striosomal neuronal loss was present throughout the dorsoventral extent of the caudate nucleus and putamen during the early phase of symptomatic disease, and this loss extended to the most ventral region of the nucleus accumbens in later stages. Analysis of the functional circuitry of the basal ganglia suggests that early degeneration of striosomal neurons may produce hyperactivity of the nigrostriatal dopaminergic pathway, causing chorea and other early clinical manifestations of HD.

Head circumference and height in autism : A study by the collaborative program of excellence in autism

Data from 10 sites of the NICHD/NIDCD Collaborative Programs of Excellence in Autism were combined to study the distribution of head circumference and relationship to demographic and clinical variables. Three hundred thirty‐eight probands with autism‐spectrum disorder (ASD) including 208 probands with autism were studied along with 147 parents, 149 siblings, and typically developing controls. ASDs were diagnosed, and head circumference and clinical variables measured in a standardized manner across all sites. All subjects with autism met ADI‐R, ADOS‐G, DSM‐IV, and ICD‐10 criteria. The results show the distribution of standardized head circumference in autism is normal in shape, and the mean, variance, and rate of macrocephaly but not microcephaly are increased. Head circumference tends to be large relative to height in autism. No site, gender, age, SES, verbal, or non‐verbal IQ effects were present in the autism sample. In addition to autism itself, standardized height and average parental head circumference were the most important factors predicting head circumference in individuals with autism. Mean standardized head circumference and rates of macrocephaly were similar in probands with autism and their parents. Increased head circumference was associated with a higher (more severe) ADI‐R social algorithm score. Macrocephaly is associated with delayed onset of language. Although mean head circumference and rates of macrocephaly are increased in autism, a high degree of variability is present, underscoring the complex clinical heterogeneity of the disorder. The wide distribution of head circumference in autism has major implications for genetic, neuroimaging, and other neurobiological research.

Neuronal loss in layers V and VI of cerebral cortex in Huntington's disease.

Neuronal loss in the cerebral cortex in Huntingtons disease (HD) has not been well documented, nor has its laminar pattern been definitively established. We therefore counted neurons in individual cortical laminae in the dorsal frontal cortex of 5 HD and 5 control autopsy brains. Significant neuronal loss (to 57% of control, P = 0.002) was found in layer VI of HD brains. These cells project principally to the thalamus, the claustrum and other regions of cerebral cortex; thus their loss is unlikely to be the result of retrograde degeneration secondary to striatal pathology. Layer V neurons were also decreased (to 71% of control, P = 0.034). Degeneration of cerebral cortical neurons may be at least partly responsible for some of the non-choreic symptoms of HD, such as dementia, irritability, apathy, and depression.

Social language use in parents of autistic individuals

Social language use (pragmatics) in parents of autistic individuals and controls was compared. Autism parents displayed atypical pragmatic behaviours more often than controls. Preliminary factor analysis suggested three parsimonious groupings of pragmatic abnormalities: Disinhibited Social Communication, Awkward/Inadequate Expression, and Odd Verbal Interaction. The pragmatic features observed in some autism parents are milder but conceptually similar to the social language deficits of autism. Possible reasons for familial aggregation of pragmatic language deficits are discussed.

Magnetic Resonance Imaging in Autism: Measurement of the Cerebellum, Pons, and Fourth Ventricle

Magnetic resonance imaging (MRI) research has suggested that autistic individuals have hypoplasia of cerebellar lobules VI and VII, the pons, and enlargement of the fourth ventricle. Using MRI we measured the mid-sagittal area of these structures in 15 high-functioning autistic males; 15 age- and IQ-comparable male volunteers (control group I); and 15 male volunteers comparable to cases on age and parental socioeconomic status (SES) (control group II). Using ratio measures, cerebellar lobules VI-VII were found to be smaller in autistic subjects than controls in group II but not those in group I. No differences were found after multivariate analysis adjusting for mid-sagittal brain area (MSBA), age, and IQ. The size of the pons and fourth ventricle did not differ between cases and controls, although autistic subjects were noted to have a significantly larger MSBA than subjects in either control group.

Saccades in Huntington's disease: Initiation defects and distractibility

We recorded saccadic eye movements in patients mildly affected with Huntingtons disease. Most showed an increase in saccade latencies that was greater for saccades made on command than to the sudden appearance of a visual target. All patients showed excessive distractibility during attempted fixation. They had particular difficulty suppressing a saccade to a suddenly appearing visual target when simultaneously trying to initiate a saccade in the opposite direction. Our results are compatible with a posited role of the basal ganglia in both the initiation of volitional saccades and in the maintenance of fixation. Saccade abnormalitie—especially distractibility—are sensitive but probably not specific indicators of Huntingtons disease.

A Family History Study of Neuropsychiatric Disorders in the Adult Siblings of Autistic Individuals

The family history method was used to obtain developmental, social, and psychiatric histories on the 67 adult siblings of 37 autistic probands. Two of 67 siblings (3.0%) were autistic, three siblings (4.4%) had severe social dysfunction and isolation, 10 (15%) had cognitive disorders, and 10 (15%) had received treatment for affective disorder. This study is the first to investigate the frequency of disorders in the adult siblings of autistic probands. These results suggest aggregation of a variety of neuropsychiatric disorders in the siblings of autistic individuals.