Autism and Comorbid Features: Autistic Regression

Autism Spectrum Disorder (ASD) has been associated with multiple syndromes of genetic etiologies. This poses the question of whether there is a direct correlation between ASD and these syndromes. The possible causes of ASD are due to genetic instability or genetic factors such as tuberous sclerosis complex, a neurocutaneous autosomal dominant disorder; fragile X syndrome, the most common inherited form of human mental retardation; Angelman Syndrome, characterized by developmental delays, mental retardation, speech impairment, gait ataxia and a “happy behavior,” marked by laughing, smiling, and excitability; Prader-Willi, characterized by hypotonia, developmental delay and mental retardation; Gilles de la Tourette, characterized by multiple motor and one or more vocal “tics”; Down’s syndrome, the most common chromosomal cause of mental retardation in United States; and Neurofibromatosis type 1, an autosomal dominant condition caused by decreased production of the protein neurofibromin. According to Zafeirious and colleagues (2007), autism is associated with another genetic syndrome more than 90% of the time. Although autism and genetic factors have been strongly correlated, the exact genetic background and epidemiological data of autism is unclear (Hrdlicka, 2008; Zafeirious, et al., 2007) [See table 1].

There are several medical conditions that have been recognized with relatively high frequency in individuals with Autistic Spectrum Disorder (ASD). About 30% of individuals with Autism Spectrum Disorder (ASD) also have seizure disorders; 2-5% has fragile X syndrome; and 1-3% has tuberous sclerosis. Rutter, Greenfield, and Lockyer (1967) reported that among 63 children with Infantile psychosis, 48% were hyperkinetic at the time of first hospitalization, 43% had morbid preoccupation, 37% had obsessive phenomena, 70% had stereotyped behaviors, 25% had self-injury, and 60% had anxiety or fear ( Strømme, et al. 2000.) In addition to these coexisting medical or psychiatric conditions, many autistic individuals also develop other behavioral and/or psychiatric symptoms in addition to the core autistic symptom domains (e.g. impairment in social interaction, impairment in communication, and restricted, repetitive and stereotyped patterns of behavior, interests, and activities), that may be considered clinical manifestations of comorbid psychiatric disorders.

Regression in individuals with Autism Spectrum Disorder defined as “a) loss of both language and social skills or b) loss of either language or social skills” associated with some neuro-psychopathologies – such as intellectual impairment, seizures, ADHD, gastrointestinal, sleep concerns, Anxiety Disorders, depression and psychosis (schizophrenia) – has been controversial, poorly understood and mistreated (Hansen, et al, 2008; Tuchman, 2006.) The prevalence of developmental regression in autism is one of the more puzzling features of this disorder due to problems in the definition used. Individuals with regression performed significantly less well on communication than those without regression. A study which examined the prevalence of regressive autism found that 15% of autistic individuals lost both language and social skills and 41% lost either language or social skills (Hansen, et al, 2008.)

It is believed that environmental factors may have relevance to the regression as well as progressive degenerative disease of the brain. There are several hypotheses to explain autistic regression such as a slow viral infection, an autoimmune phenomenon, an insufficiency of growth factors during the development, abnormalities of an excitatory neurotransmitter and recurrent seizures or abnormal electrical activity in the brain. For instance, recurrent seizures can cause specific cognitive, language, or behavioral abnormalities. Seizures or the interictal epileptiform activity are responsible for the deterioration of the individual (Hrdlicka, 2008; Oslejsková, et al., 2008; Engel, et al., 2001; Deonna, 1991). The age of regression is higher in autistic individuals with seizures when compared to individuals with regression without epileptic seizures. Moreover, it has been observed that autistic regression has different clinical implications than individual with epilepsy (Danielsson, et al., 2005).

According to Tuchman and Rapin (1996), developmental regression occurred greater in individuals with autism and epileptiform EEG than in individual without epileptiform EEG. The clinical implications of regression in individuals with epilepsy are different from the clinical implications of regression with autism (Danielsson, 2005) In addition, in a case-control study, autism is more prevalent in individuals with Down syndrome than it does in the general population, and when autism is comorbid with Down Syndrome, regression in language and other skills, as measured by the Autism Diagnostic interview-Revised (ADI-R), are reported to occur in up to 50% of the cases (Castillo, et al., 2008). Individuals with autism and comorbid Fragile X, were found to be significantly more impaired in overall imitation abilities, oral-facial imitation, and imitations of actions and joint attention than individual without Fragile X (Rogers, et al., 2003). Data from retrospective studies have suggested that the pathogenesis of autism with developmental regression differs from that of autism without regression (Ball, et al., 2007; Linda, et al., 2007).

Autism and regression represent a challenge from a pharmacological treatment point of view. The treatment should be designed accordingly with the features of regression. The pharmacological management would be different from the autism without regression. When autism with regression is suspected, clinicians should re-evaluate the comorbid conditions.

Table 1 1) Tuberous sclerosis complex 2) Fragile X syndrome 3) Down syndrome 4) Neurofibromatosis type 1 5) Angelman, Prader-Willi and isodicentric 15q chromosome syndromes 6) Anorexia nervosa 7) ARX syndrome 8) Charge, Goldenhar and Moebius syndromes 9) Chromosome 2q37 deletion syndrome 10) Chromosome 13 deletion syndrome 11) Cohen syndrome 12) Cole–Hughes macrocephaly 13) Cowden and other hamartoma syndromes 14) De Lange syndrome 15) Duchenne muscular dystrophy 16) Giles de la Tourette syndrome 17) Hypomelanosis of Ito 18) Lujan–Fryns syndrome (X-linked mental retardation with marfanoid habitus) 19) Mitochondrial disorders 20) Phenylketonuria 21) Smith–Lemli Opitz syndrome 22) Smith Magenis syndrome 23) Sotos syndrome 24) Steinert’s myotonic dystrophy 25) Timothy syndrome 26) Turner’s syndrome (monosomyX) 27) Velocardiofacial (catch 22) or 22q11 deletion or Di George syndrome 28) Williams syndrome 29) 47,XYY syndrome 30) Some other syndromes are: Ehlers Danlos, Joubert (which was strongly associated with autism, Leber’s congenital amaurosis, Coffin Siris, Biedl Bardet, Kleine Levin, Myhre, Apert, neuroaxonal dystrophy, HEADD, Klinefelter, San Filippo syndrome, Noonan, 10p deletion, etc. 31) Environmental factors [ e.g. see our previous blog] 32) ADHD 33) Seizure Disorders 34) Sensory Problems 35) Bowel Disorders Zafeiriou, D., Ververi, A. and Vargiami, E. (2007). Childhood autism and associated comorbidities. Brain and Development: Volume 29, Issue 5, Pages 257-272. (32-35 are not listed in Zafeiriou’s article).