Rubella Virus Infection, the Congenital Rubella Syndrome, and the Link to Autism

Abstract

Rubella is a systemic virus infection that is usually mild. It can, however, cause severe birth defects known as the congenital rubella syndrome (CRS) when infection occurs early in pregnancy. As many as 8%–13% of children with CRS developed autism during the rubella epidemic of the 1960s compared to the background rate of about 1 new case per 5000 children. Rubella infection and CRS are now rare in the U.S. and in Europe due to widespread vaccination. However, autism rates have risen dramatically in recent decades to about 3% of children today, with many cases appearing after a period of normal development (‘regressive autism’). Evidence is reviewed here suggesting that the signs and symptoms of rubella may be due to alterations in the hepatic metabolism of vitamin A (retinoids), precipitated by the acute phase of the infection. The infection causes mild liver dysfunction and the spillage of stored vitamin A compounds into the circulation, resulting in an endogenous form of hypervitaminosis A. Given that vitamin A is a known teratogen, it is suggested that rubella infection occurring in the early weeks of pregnancy causes CRS through maternal liver dysfunction and exposure of the developing fetus to excessive vitamin A. On this view, the multiple manifestations of CRS and associated autism represent endogenous forms of hypervitaminosis A. It is further proposed that regressive autism results primarily from post-natal influences of a liver-damaging nature and exposure to excess vitamin A, inducing CRS-like features as a function of vitamin A toxicity, but without the associated dysmorphogenesis. A number of environmental factors are discussed that may plausibly be candidates for this role, and suggestions are offered for testing the model. The model also suggests a number of measures that may be effective both in reducing the risk of fetal CRS in women who acquire rubella in their first trimester and in reversing or minimizing regressive autism among children in whom the diagnosis is suspected or confirmed.

Molecules, Mechanisms, and Disorders of Self-Domestication: Keys for Understanding Emotional and Social Communication from an Evolutionary Perspective

“…In addition to mutations and changes in genes associated with non-syndromic ASD and mutations and changes in genes that in themselves cause a pathology that may or may not be associated with ASD, some of the presumed risk factors for autism also include: (1) low birth weight (head circumference at birth is lower than average, see later), (2) exposure to heavy metals and environmental toxins and pollutants in the air [ 184 , 185 ], which can lead to decreased expression of RELN gene and consequently to abnormal positioning of cortical neurons (the product of RELN gene – protein reelin serves as signal for stopping radially migrating neurons into the cortical plate [ 186 , 187 ], whereas RELN gene promoter is hypermethylated in persons with schizophrenia in comparison to controls – together with concomitantly increased expression of DNA methyltransferase 1 ( DNMT1 ) [ 188 ], so some authors suggested reelin measurement in blood as a possible biological marker of autism [ 189 ]), (3) maternal exposure to xenobiotics and endocrine disruptors during pregnancy [ 190 , 191 ], (4) viral infections such as rubella [ 192 ], (5) fetal exposure to some drugs such as valproic acid and thalidomide, (6) various metabolic disorders including vitamin D deficiency [ 193 , 194 ], maternal thyroid dysfunction (especially hypothyroidism) [ 195 ], as well as many others.…”

Selective postnatal excitation of neocortical pyramidal neurons results in distinctive behavioral and circuit deficits in adulthood

“…The sufficiency of brief hyperexcitability to derail circuit formation in an otherwise normal brain highlights an underappreciated vulnerability of developing neural circuits where seemingly innocuous events can have lifelong behavioral consequences. This finding may provide an explanation for the large variety of potential etiologies reported for symptoms of ASD and other neurodevelopmental disorders, with infections, autoimmune processes, and environmental causes acting in concert with genetic and epigenetic susceptibilities ( Amaral, 2017 ; Grandjean and Landrigan, 2006 ; Jones and Van de Water, 2019 ; Landrigan, 2010 ; Mawson and Croft, 2019 ; Roberts et al., 2019 ; Tartaglione et al., 2019 ).…”

Prevention in Autism Spectrum Disorder: A Lifelong Focused Approach

“…These factors should be the focus of the prevention in high-risk cases. Immune reactions during pregnancy represent additive risk factors, whether these were the results of infections [ 42 ]—with congenital rubella being the historical paradigm [ 43 ]—or maternal autoimmune conditions [ 44 ]. Maternal influenza, other viral infections in the first trimester and bacterial infections, as well as prolonged fever in the second trimester, were found to increase the risk of ASD up to three-fold [ 45 , 46 ].…”