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ScienceWeek
2004 4 June C3 3. MEDICAL BIOLOGY: ON RETT SYNDROME AND AUTISM
The following points are made by Huda Y. Zoghbi (Science 2004 302:827):
1) Both Rett syndrome and autism are childhood neurobehavioral disorders that become manifest after a period of apparently normal development. Both disrupt social and language development and are accompanied by unusual stereotypies. Despite the intellectual regression that marks the majority of Rett patients and approximately 30% of autistic patients (1,2), neither disease is neurodegenerative in nature. Many children can improve somewhat as they get older. The onset of both disorders after neurogenesis, neuronal migration, and maturation have occurred suggests that these disorders might affect synaptic maturation, connectivity, or stabilization.
2) Rett syndrome was first described by the Austrian pediatrician Andreas Rett (3), but skeptical clinicians doubted its identity as a distinct syndrome until 1983, when Hagberg et al (4) reported on 35 patients with an undeniably unique postnatal developmental disorder. One difficulty in diagnosis was (and is) that clinical and laboratory tests are nonspecific. The electroencephalogram (EEG) is typically normal the first 2 to 3 years of life (5), after which the background activity gradually slows, and repetitive high-amplitude spike and wave discharges appear in 60 to 70% of these patients. Imaging studies reveal changes in blood flow reminiscent of patterns seen in young infants, suggesting some arrest in development. Pathological studies show other changes, also nonspecific. Neurons are abnormally small and densely packed, and have markedly shortened and simplified dendritic arbors, although migration seems to be normal. A degenerative process is unlikely, because brains of Rett syndrome children weigh about 30% less than normal at any given age.
3) Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene cause the majority of Rett syndrome cases (1). Both mutation type and, in females, patterns of X chromosome inactivation (XCI) create a surprisingly wide range of phenotypes. Females with favorably skewed XCI can be asymptomatic or have mild learning disability, autism, or mild, later-onset versions of Rett. In males, the range is even wider: mutations that would cause classic Rett in females produce severe neonatal encephalopathy, motor abnormalities, respiratory dysfunction, and death by the second year. Mutations that cause little or no phenotype in female carriers cause male children to develop X-linked mental retardation with seizures, tremors, spasticity, macrocephaly, or bipolar disease. One boy with a receptive language disorder developed childhood-onset schizophrenia. This phenotypic diversity raises questions about the differential effects of the mutations, regional or neuronal vulnerability to MeCP2 dysfunction, effects of genetic modifiers, and the nature of MeCP2's role in the brain.
4) In summary: We often think of neurodevelopmental disorders as beginning before birth, and many certainly do. A handful, however, strike many months after birth, following a period of apparently normal growth and development. Autism and Rett syndrome are two such disorders. The author proposes that both disorders result from disruption of postnatal or experience-dependent synaptic plasticity.
References (abridged):
1. M. D. Shahbazian, H. Y. Zoghbi, Am. J. Hum. Genet. 71, 1259 (2002)
2. S. Wilson, A. Djukic, S. Shinnar, C. Dharmani, I. Rapin, Dev. Med. Child. Neurol. 45, 508 (2003)
3. A. Rett, Wien. Med. Wochenschr. 116, 723 (1966)
4. B. Hagberg, J. Aicardi, K. Dias, O. Ramos, Ann. Neurol. 14, 471 (1983)
5. N. P. Verma, R. L. Chheda, M. A. Nigro, Z. H. Hart, Electroencephal. Clin. Neurophysiol. 64, 394 (1986)
Science http://www.sciencemag.org
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ON AUTISM
The following points are made by Erik Stokstad (Science 2001 294:34):
1) First described in 1943, the primary manifestation of autism is an impaired ability to relate socially to other people, although this difficulty almost always occurs together with other debilitating symptoms. Autism is generally associated with language problems, and autistic patients who speak largely do so in monotone. Patients also seem to have trouble inferring what other people think and feel, with autistic patients described as child-like, sober-faced, incapable of lying, subject to toddler-like tantrums.
2) Up to 60 percent of people with autism are also mentally retarded, with some 20 percent having an IQ less than 35. However, a small fraction of autistic patients are gifted in some areas such as music, drawing, or calculations.
3) In general, the symptoms of autism can vary so greatly both in nature and severity and from person to person that diagnosis is sometimes difficult. The problems seen in autism apparently derive not from dysfunction of the senses but from faulty interpretation of the world. Autistic patients characteristically have difficulty interpreting faces, and research has demonstrated that when autistic patients interact with someone, they generally spend most of their time looking at the mouth of the person --not at the eyes, as most people do.
4) It has been shown that a part of the brain called the fusiform gyrus is not activated when autistic patients look at faces, whereas activation of this region occurs in other people when they look at faces. Currently, however, there is no consensus concerning brain anatomical differences or any typical brain pathology in autism.
5) Autism is usually diagnosed at 2 to 3 years of age, and although some drugs alleviate certain symptoms, there are no drugs that relieve the core problems. The most effective treatment is apparently intensive behavioral therapy involving up to 40 hours a week at a cost of tens of thousands of dollars a year.
Science http://www.sciencemag.org
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MEDICAL BIOLOGY: ON THE EARLY ORIGINS OF AUTISM
Autism is a behaviorally defined syndrome of unknown etiology associated with poor social interaction, disordered language, and atypical responses to people, objects, and events. The syndrome is classically manifested by severe disturbances in cognition, language, and behavior that appear before the age of 30 months. In some cases, there is an apparent hyperarousal state. Autistic children often exhibit ritualized body movements, repeated touching and sniffing of objects, ritualistic ordering, checking, and collecting, and insistence on precisely following routines. The ratio of male to female cases ranges from 2:1 to 4:1, and studies of monozygotic and dizygotic twins indicate an important role for genetic factors. There is presently a controversy over whether movement disorders play a central role in the phenomenon of autism and even whether such movement disorders exist in autism at all.
The following points are made by Patricia M. Rodier (Scientific American February 2000):
1) Autism is apparently associated with anatomical changes in the brainstem, the region immediately above the spinal cord. The brainstem of an individual with autism is shorter than a normal brainstem and lack certain structures. "It is almost as though a band of tissue were missing." The author suggests that such changes could occur only in early gestation.
2) Since autism was first identified in 1943, great strides have been made in describing symptoms, but the biological basis of autism has remained elusive. Studies of twins confirm that autism has a heritable component but suggest that environmental influences play a role as well. For example, if genetic factors alone were involved, identical twins (monozygotic twins), who share the same genes, should have a 100 percent chance of sharing the same diagnosis. Instead, when one twin has autism, the second twin has only a 60 percent chance of being diagnosed with the same disorder. That second twin also has an 86 percent chance of having at least some of the symptoms of autism. These results of twin studies indicate that other factors must modify the genetic predisposition to the disorder.
3) Several environmental risk factors for autism are known: In utero exposure to German measles (rubella), or to birth defect-causing substances such as ethanol and valproic acid, increases the chances that autism will develop. People with certain genetic diseases, such as phenylketonuria and tuberous sclerosis, also have a greater chance of developing autism. None of these factors, however, occurs frequently enough to be responsible for many cases of autism.
4) The author points out that even a minimal understanding of the genetic basis of autism would be of great value. But devising a genetic test for autism -- similar to the current tests for cystic fibrosis, sickle cell anemia, and other disorders -- would be a much more difficult task. "Because so many genes appear to be involved in the disorder, one cannot accurately predict the odds of having a child with autism by simply testing for one or two variant genes in the parents."
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