What Is Autism?

Although originally a medical diagnosis first used by Dr. Leo Kanner, today autism is a general term that is often used interchangeably with what health care providers refer to as “pervasive developmental disorders.” Individuals with a pervasive developmental disorder (PDD) have a unique set of symptoms that affect three areas or “domains”: communication, socialization (interaction with others), and behavior. Within this broad category, there are five currently accepted official diagnoses:

  • Autistic Disorder
  • Asperger Disorder
  • Pervasive Developmental Disorder Not Otherwise Specified (PDD/NOS)
  • Rett Disorder
  • Childhood Disintegrative Disorder

The distinctions between these diagnoses hinge on subtle differences in language development, severity, and age of onset (age at which symptoms first appeared), as well as other features that a health care provider can evaluate. For instance, the diagnosis of autistic disorder requires symptoms in all three of the areas described above, as well as a history of a delay in developing spoken language and onset of symptoms prior to 36 months of age. By contrast, Asperger disorder is an appropriate diagnosis for individuals who show many of the same features of Autistic disorder in all three areas, but who specifically do not have any delay in developing spoken language. Pervasive developmental disorder not otherwise specified (PDD/NOS) is a diagnosis assigned to children who have symptoms in all three areas, but who do not meet the specific diagnostic criteria for any of the other pervasive developmental disorders.

Parents often tell us their child has received several different PDD diagnoses, which may be due to changes in symptoms over time or variability in the methods of assessment. These diagnoses may include the five listed above, or others (not officially recognized medical diagnoses) such as “autism spectrum condition,” “high functioning autism,” or atypical autism.” The only way to diagnose someone with a PDD is through clinical means (such as observation and interviews) — there is no “medical test” that can give a clear diagnosis.

Genetic Conditions Associated with Autistic Disorder

Autistic disorder and other PDDs are due in large part to genetic factors. In some instances, autistic disorder is a feature of an identifiable genetic condition. More frequently, however, no underlying specific cause can be determined (this is called idiopathic autism, meaning autism of unknown cause). There is a great deal of evidence that idiopathic autism is caused by changes or “mutations” in genes. However, these genes have not yet been identified.

An estimated 10 to 15 percent of individuals with autistic disorder have an identifiable genetic condition (Gillberg et al 1996; Rutter et al 1994). Recognizing a genetic condition is vital because it may alter treatment or therapy options. Diagnosing a genetic condition also enables health care providers to both estimate the chance of recurrence in other family members and discuss the availability of diagnostic testing for other family members.

Chromosome Abnormalities

Numerous chromosome abnormalities have been reported in individuals with autism, most often involving chromosome 15 (specifically 15q11-q13, the Prader-Willi/Angelman syndrome region). Studies of individuals with idiopathic autism show the frequency of chromosome abnormalities to be less than 5 percent (Folstein et al 2001). Chromosome abnormalities may be passed from parent to child or can occur sporadically. A blood sample is all that is needed to create a karyotype for chromosome analysis. If a chromosome abnormality is identified, testing other family members is recommended. In some instances family members may be unaware that they have a chromosome abnormality because they carry a balanced rearrangement that produces no symptoms.

Isodicentric chromosome 15

Isodicentric chromosome 15 (idic(15)) is the most frequently identified chromosome abnormality in individuals with autism. There are now over 20 reports in the literature of individuals with both autism and idic(15). The frequency of these reports suggest that the co-occurrence of autism and idic(15) is not by chance. This chromosome abnormality is visible using standard methods of chromosome analysis but may need to be confirmed using chromosome 15 specific FISH probes.

Subtelomere abnormalities

Not all chromosome abnormalities are visible utilizing standard methods of chromosome analysis. Cytogenetic abnormalities involving the subtelomeres (the ends of the chromosomes) typically appear as normal karyotypes. Testing for subtelomere abnormalities is available using a complete set of subtelomeric FISH probes. Subtelomeric testing may be warranted in individuals with autism and dysmorphic features, cases of multiple affected siblings and a family history of recurrent pregnancy losses.

Fragile X Syndrome

There is a known association between autism and fragile X syndrome, a genetic condition transmitted via the X chromosome that causes mild to moderate mental retardation. Fragile x syndrome affects 1:4,000 to 1:6,000 males (Turner et al 1996; de Vries et al 1997). The prevalence of fragile x syndrome in females is approximately one-half the prevalence in males. Approximately 2-3 percent of individuals with autism have fragile x syndrome (Bailey et al 1993; Fombonne et al 1997).

Fragile x syndrome is caused by an increased number of CGG trinucleotide repeats (over 200) in the FMR1 gene located on the X chromosome. Women who are premutation carriers are at increased risk to have a child with fragile x syndrome and for premature ovarian failure. Genetic testing is available for this disorder. For a detailed review of fragile x syndrome or to locate a clinical testing laboratory, visit GeneTests (www.genetests.org), a genetic testing information resource targeted to health care providers and supported by the National Institutes of Health.. For family-friendly information about fragile x syndrome please contact the National Fragile X Foundation at www.nfxf.org.

Tuberous Sclerosis Complex

Between 0.4 and 2.9 percent of individuals with autism have tuberous sclerosis complex (Olsson et al 1988; Ritvo et al 1990). Up to 14 percent of individuals with autism and seizures have TSC (Gillberg 1991). The TSC phenotype may include seizures, mental retardation, and abnormalities of the skin and brain. There are two different genes that are known to cause tuberous sclerosis complex, one on chromosome 9 (TSC1) and the other on chromosome 16 (TSC2). An individual with TSC will have a mutation in only one of these genes.

Currently, TSC is most easily diagnosed by a physical examination that includes a Wood’s lamp examination of the skin. Molecular genetic testing for TSC is available but is complicated by the large size of the genes, the large number of mutations and the high rate of somatic mosaicism. For a detailed review of tuberous sclerosis complex or to locate a clinical testing laboratory, visit GeneTests (www.genetests.org). For family-friendly information contact the Tuberous Sclerosis Alliance (formerly National Tuberous Sclerosis Association) at www.tsalliance.org/.

Neurofibromatosis Type 1 (NF1)

Neurofibromatosis type 1 (NF1) has been reported in individuals with autism. The frequency of NF1 in individuals with autism varies from 0.2 to 14 percent in three studies (Gillberg et al 1984; Gaffney et al 1987; Mouridsen et al 1992). NF1 is an autosomal dominant neurological condition that may lead to unusual skin findings, tumors in the central nervous system, and learning disabilities. NF1 is caused by mutations in the NF1 gene on chromosome 17. DNA-based testing is available clinically but is usually not necessary for diagnosis.

Currently, NF1 is most easily diagnosed by a physical examination to look for characteristic café-au-lait spots and neurofibromas. For a detailed review of neurofibromatosis or to locate a clinical testing laboratory, visit GeneTests (www.genetests.org). For family-friendly information about NF1 contact the National Neurofibromatosis Foundation at www.nf.org.

Rett Disorder

Rett disorder is a neurological disorder and one of the PDDs. Rett disorder is caused by a mutation in the MECP2 gene on the X chromosome in approximately 80 percent of cases. Rett disorder primarily affects females and is characterized by a regression in language and motor skills, microcephaly and hang wringing. Researchers recently reported that several girls with autism were found to have mutations in the MECP2 gene (Carney et al 2003). The children in this study surprisingly did not have the typical symptoms of Rett disorder, causing researchers to wonder whether a significant number of additional children with autism might also have MECP2 mutations. DNA testing for Rett disorder is available clinically.

For a detailed review of Rett disorder, visit GeneTests (www.genetests.org). For family-friendly information please contact the International Rett Syndrome Association at www.rettsyndrome.org/.

Angelman Syndrome

Angelman syndrome should be considered in individuals with autism and severe mental retardation. A population-based study identified 4 children in almost 49,000 with Angelman syndrome (prevalence of 1:12,000) all of whom meet diagnostic criteria for autism (Steffenburg et al 1996). Angelman syndrome is characterized by severe mental retardation, ataxia, inappropriate laughter and a happy demeanor. Angelman syndrome is caused by loss of the maternally-inherited UBE3A gene in the Prader-Willi/Angelman syndrome region on chromosome 15 (15q11.2-q13). The etiology of Angelman syndrome is primarily maternal deletions of the 15q11.2-q13 region, paternal uniparental disomy (UPD) of chromosome 15, or mutations in the UBE3A gene. Clinical testing for Angelman syndrome is available.

For a detailed review of Angelman syndrome or to locate a clinical testing laboratory, visit GeneTests (www.genetests.org). For family-friendly information please contact the Angelman Syndrome Foundation at www.angelman.org.

Prader-Willi Syndrome

Several behavioral features of Prader-Willi syndrome including language, motor and developmental delays, overlap with features of autism. Prader-Willi syndrome is characterized by hypotonia, initial feeding difficulties followed by hyperphagia and excessive weight gain if not controlled, mental retardation, hypogonadism and short stature. Prader-Willi syndrome is caused by loss of the paternally-inherited Prader-Willi/Angelman syndrome region on chromosome 15 (15q11.2-q13). The etiology of Prader-Willi syndrome is primarily paternal deletions of the 15q11.2-q13 region, maternal uniparental disomy (UPD) and imprinting defects. Clinical testing for Prader-Willi syndrome is available.

For a detailed review of Prader-Willi syndrome or to locate a clinical testing laboratory, visit GeneTests (www.genetests.org). For family-friendly information please contact the Prader-Willi Syndrome Association at www.pwsausa.org/.

Smith-Lemli-Opitz Syndrome

Autism has been documented in a number of individuals with Smith-Lemli-Opitz syndrome (SLOS). A recent study of 26 individuals with SLOS found that 17 of them (53%) met criteria for autism (Tierney et al 2001). Clinical features of SLOS include microcephaly, 2-3 syndactyly of the toes, mental retardation, cleft palate, hypospadias in males and growth retardation. SLOS is an autosomal recessive condition, with carriers being unaffected. SLOS is caused by mutations in the DHCR7 gene on chromosome 11 (11q12-q13). DHCR7 produces 7-dehydrocholesterol reductase, which typically converts 7-dehydrocholesterol to cholesterol. Diagnosis is established by detection of elevated serum concentration of 7-dehydrocholesterol. Molecular genetic testing of the DHCR7 gene is clinically available for confirmation of diagnosis, carrier detection and prenatal testing.

For a detailed review of Smith-Lemli-Opitz syndrome or to locate a clinical testing laboratory, visit GeneTests (www.genetests.org). For family-friendly information please contact the Smith-Lemli-Opitz Advocacy and Exchange at members.aol.com/slo97/index.html.

Sotos Syndrome

Sotos syndrome is an overgrowth syndrome and should be considered in individuals with autism and macrocephaly. Individuals with Sotos syndrome usually have some degree of intellectual impairment, learning disabilities and language delay. Some individuals with Sotos have features of autism with others fulfilling full autism criteria (Zapella 1990). Clinical characteristics of Sotos syndrome include congenital macrocephaly, a prominent forehead with an apparently receding hairline, accelerated pre- and postnatal growth, advanced bone age and large hands and feet. In 2002 it was discovered that mutations in the NSD1 gene on chromosome 5 are responsible for a large number of Sotos cases (Kurotaki et al).

Other Related Conditions

Other genetic conditions reported in association with autism:

  • Aarskog syndrome
  • Cornelia de Lange syndrome
  • Hypomelanosis of Ito
  • Joubert syndrome
  • Moebius syndrome
  • Phenylketonuria (PKU)
  • Tourette syndrome
  • Williams syndrome
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