Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-06-10
2001-05-08
Jones, W. Gary (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023100, C536S024300
Reexamination Certificate
active
06228582
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method of screening subjects for genetic markers associated with autism. The invention further relates to isolated nucleic acids having polymorphisms associated with autism, the polypeptide products of those nucleic acids, and antibodies specific to the polypeptides produced by the mutated genes.
BACKGROUND OF THE INVENTION
Autism is a behaviorally defined syndrome characterized by impairment of social interaction, deficiency or abnormality of speech development, and limited activities and interest (American Psychiatric Association, 1994). The last category includes such abnormal behaviors as fascination with spinning objects, repetitive stereotypic movements, obsessive interests, and abnormal aversion to change in the environment. Symptoms are present by 30 months of age. The prevalence rate in recent Canadian studies using total ascertainment is over 1/1,000 (Bryson, S. E. et al.,
J. Child Psychol. Psychiat
., 29, 433 (1988)).
Attempts to identify the cause of the disease have been difficult, in part, because the symptoms do not suggest a brain region or system where injury would result in the diagnostic set of behaviors. Further, the nature of the behaviors included in the criteria preclude an animal model of the diagnostic symptoms and make it difficult to relate much of the experimental literature on brain injuries to the symptoms of autism.
Several quantitative changes have been observed in autistic brains at autopsy. An elevation of about 100 g in brain weight has been reported (Bauman, M. L. and Kemper, T. L.,
Neurology
35, 866 (1985)). While attempts to find anatomical changes in the cerebral cortex have been unsuccessful (Williams, R. S. et al.,
Arch. Neurol.,
37, 749 (1980); Coleman P. D., et al.,
J. Autism Dev. Disord.,
15, 245 (1985)), several brains have been found to have elevated neuron packing density in structures of the limbic system (Bauman, M. L. and Kemper, T. L.,
Neurology
35, 866 (1985)), including the amygdala, hippocampus, septal nuclei and mammillary body. Multiple cases in multiple labs have been found to have abnormalities of the cerebellum. A deficiency of Purkinje cell and granule cell number, as well as reduced cell counts in the deep nuclei of the cerebellum and neuron shrinkage in the inferior olive, have been reported (Bauman, M. L. and Kemper, T. L.,
Neurology,
35, 866 (1985); Bauman, M. L. and Kemper, T. L.,
Neurology,
36 (suppl. 1), 190 (1986); Bauman, M. L. and Kemper, T. L.,
The Neurobiology of Autism
, Johns Hopkins University Press, 119 (1994); Ritvo, E. R. et al.,
Am. J. Psychiat.,
143, 862 (1986); Kemper, T. L. and Bauman M. L.,
Neurobiology of Infantile Autism
, Elsevier Science Publishers, 43 (1992)).
Imaging studies have allowed examination of some anatomical characteristics in living autistic patients, providing larger samples than those available for histologic evaluation. In general, these confirm that the size of the brain in autistic individuals is not reduced and that most regions are also normal in size (Piven, J. et al.,
Biol. Psychiat.,
31, 491 (1992)). Reports of size reductions in the brainstem have been inconsistent (Gaffney, G. R. et al.,
Biol. Psychiat.,
24, 578 (1988); Hsu, M. et al.,
Arch. Neurol.
48, 1160 (1991)), but a new, larger study suggests that the midbrain, pons, and medulla are smaller in autistic cases than in controls (Hashimoto, T. et al.,
J. Aut. Dev. Disord.,
25, 1 (1995)). In light of the histological effects reported for the cerebellum, it is interesting that the one region repeatedly identified as abnormal in imaging studies is the neocerebellar vermis (lobules VI and VII; Gaffney, G. R. et al.,
Am. J. Dis. Child.,
141, 1330 (1987); Courchesne E., et al.,
N. Engl. J. Med.,
318, 1349 (1988); Hashimoto, T. et al.,
J. Aut. Dev. Disord.,
25, 1 (1995)). Not all comparisons have found a difference in neocerebellar size (Piven, J. et al.,
Biol. Psychiat.,
31, 491 (1992); Kleiman, M. D. et al.,
Neurology,
42, 753 (1992)), but a recent reevaluation of positive and negative studies (Courchesne, E. et al,
Neurology,
44, 214 (1994)) indicates that a few autistic cases have hyperplasia of the neocerebellar vermis, while many have hypoplasia. Small samples of this heterogeneous population could explain disparate results regarding the size of the neocerebellum in autism. The proposal that the cerebellum in autistic cases can be either large or small is reasonable from an embryological standpoint, because injuries to the developing brain are sometimes followed by rebounds of neurogenesis (e.g., Andreoli, J. et al.,
Am. J. Anat.
137, 87 (1973); Bohn, M. C. and Lauder, J. M.,
Dev. Neurosci.,
1, 250 (1978); Bohn, M. C.,
Neuroscience,
5, 2003 (1980)), and it is possible that such rebounds could overshoot the normal cell number. Further, because increased cell density has been observed in the limbic system, the cerebellum is not the only brain region in which some form of overgrowth might account for the neuro-anatomy of autistic cases. It may well be that some autism-inducing injuries occur just prior to a period of rapid growth for the cerebellar lobules in question or the limbic system, leading to excess growth, while other injuries continue to be damaging during the period of rapid growth, leading to hypoplasia. However, the hypothesis that autism occurs with both hypoplastic and hyperplastic cerebella calls into question whether cerebellar anomalies play a major role in autistic symptoms.
A particularly instructive result has appeared in an MRI study on the cerebral cortex (Piven, J. et al.,
Am. J. Psychiat.,
14, 734 (1992)). Of a small sample of autistic cases, the majority showed gyral anomalies (e.g., patches of pachygyria). However, the abnormal areas were not located in the same regions from case to case. That is, while the functional symptoms were similar in all the subjects, the brain damage observed was not. The investigators argue convincingly that the cortical anomalies were not responsible for the functional abnormalities. This is a central problem in all attempts to screen for pathology in living patients or in autopsy cases. While abnormalities may be present, it is not necessarily true that they are related to the symptoms of autism.
To teratologists, the physical anomalies of a neonate, child, or adult can serve as a guide to when the embryo was injured. Years of research have amplified the details of that timetable for the nervous system (Rodier, P. M.,
Dev. Med. Child Neurol.,
22, 525 (1980); Bayer, S. A. et al.,
Neurotoxicology,
14, 83 (1993)). In the case of autism, lack of specific information on the neuroanatomy associated with the disease has made it difficult to estimate the stage of development when the disorder arises. However, in 1993, Miller and Strömland reported a finding that conclusively identified the time of origin for some cases. They observed that the rate of autism was 33% in people exposed to thalidomide between the 20th and 24th days of gestation, and 0% in cases exposed at other times (Strömland, K. et al.,
Devel. Med. Child. Neurol.,
36, 351 (1994)). Their deduction regarding the time of injury was not based on neuroanatomy, which was not known in their living subjects. Instead, it was based on the external stigmata of the cases.
Because thousands of thalidomide-exposed offspring have been evaluated for somatic malformations, the array of injuries associated with the drug is well-known, and the time when each arises has been carefully defined (Miller, M. T.,
Trans. Am. Ophthalmol. Soc.,
89, 623 (1991)). Of five cases of thalidomide-induced autism, four had malformations of the ears, without limb malformation, and the fifth had malformation of the ears, forelimb, and hindlimb. Thalidomide is not teratogenic before the 20th day of gestation. Starting on day 20 exposure causes ear malformation and abnormalities of the thumb. Limb malformations (other than those of the thumb) first appear with exposure on the 25th day, with effects moving from the forelimb to the hind
Figlewicz Denise A.
Hyman Susan L.
Ingram Jennifer L.
Rodier Patricia M
Stodgell Christopher J.
Jones W. Gary
Nixon & Peabody LLP
Souaya Jehanne
University of Rochester
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