Genetic factors

There are presently two identified genetically inherited disorders of mutations in calcium channels with high incidence of autism. Timothy syndrome is caused by mutations in CACNA1C, the gene encoding Ca(V)1.2 calcium channel, causing loss of channel inactivation and suspected intracellular calcium overload. This dysfunction causes a multisystem disorder including congenital heart disease, webbing of fingers and toes, immune deficiency, intermittent hypoglycemia and cognitive abnormalities. Frequent seizures, irregular sleep patterns, dysmorphic facial features, myopia, motor abnormalities and small and decaying teeth have also been recorded in affected individuals [15454078]. The exact incidence of autism is unknown but could be as high as 80 percent.

A mutation in a calcium channel gene CACNA1F, encoding for Cav1.4 L-type calcium channel, that results in retinal disorder and visual impairments has been observed in a New Zealand familiy. Although female members of the family display visual impairments, the symptoms are more severe in male family members. Five of the affected males exibit intellectual disability, with autism being present in three of those five individuals [15807819]. (see Motor/Sensory and Gender).

A study looking at mutations in genes encoding for calcium channels in a broader sample of 461 individuals with autism found that 6 of them expressed a CACNA1H mutation, relating to Cav3.2 T-type calcium channel. Although it was clear that the identified mutation was not solely responsible for the condition, as some of the nonaffected familiy members were found to carry the same mutation, it was suggested that it could contribute to the development of the ASD phenotype or influence its expression [16754686]. CACNA1H chromosomal location 16p13.3 is shared with with tuberous sclerosis 2 gene (see below).

Similarly, a mutation in the gene encoding for Shank3, a scaffolding protein that forms signalling complexes with at least two of the voltage gated calcium channels, was recently identified on chromosome 22q13 in a small number of affected individuals [avaiting publication]. Shank proteins are involved in calcium-mediated activation of gene transcription factor CREB. (see Brain). The haploinsufficiency of Shank3 is thought to be the responsible for the neurological deficits of 22q13 Deletion Syndrome, in which an estimated 50 percent of affected individuals exibit autism-like symptoms [15286229]. Of note in this context that chromosome 22q13 has been identified as one of the preferred location for integration of human herpesvirus 6 DNA [9753061] (see Viruses).

Calmodulin is another cellular protein that binds to LTCC in neurons and other excitable cells and plays an important role in regulating their activities and signalling in CREB activation pathway [11598293, 16685765]. Caldmodulin binds to tuberin, and its binding site is altered by mutations linked to tuberous sclerosis [11811958, 17114346]. Tuberin is encoded by tuberous sclerosis 2 gene, located on chromosome 16p13.3 (see above). Mutations in tuberous sclerosis genes 1 and 2 lead to a rare genetic disorder characterized by seizures, mental retardation, skin lesions and impaired functioning of many organs, including brain, kidneys, heart, eyes and lungs. About half of affected individuals have learning difficulties and a reported 16% meet the diagnostic criteria for autism [16901420].

22q11.2 Deletion syndrome (DiGeorge/velocardiofacial syndrome) is characterized by congenital cardiovascular disease, dysfunction of parathyroid gland, immunodeficiency, neurodevelopmental and psychiatric disorders. Autism spectrum disorders as well as related Attention Deficit Hyperactivity Disorder and sometimes Obsessive Compulsive Disorder are common in children with the syndrome [16926618]. Affected children show hypoparathyroidism and abnormal calcium homeostasis and, because of depressed cell-mediated immunity, serious bacterial, viral and fungal infections [6973633, 16995575]. Behavioral manifestations of this syndrome has been hypothesised to result in part from haploinsufficiency of the catechol-O-methyltransferase (COMT) gene, located within the 22q11 region [10643919].

Individuals with Cowden Syndrome, caused by mutations in PTEN tumour suppressor gene, sometimes exibit neurobehavioural symptoms similar to autism. Germline mutations in the gene have been identified in a small subset of individuals with non-syndromatic autism, as well as some non-affected family members [15805158, 11496368]. It has been suggested that inactivation of PTEN leads to behavioral abnormalities seen in this disorder. It is of interest that inactivation of PTEN has been observed to result in enhancement of LTCC current in cardiac tissue [16627784].

Autism often co-occurs with phenylketonuria (PKU), a genetic disorder in which the body lacks phenylalanine hydroxylase, the enzyme necessary to metabolize phenylalanine to tyrosine. A recent study has found that amongst the genes upregulated by phenylalanine, and thus likely to be affected in PKU disease, were L-type calcium channels, calcium/calmodulin-dependent protein kinase (CaMK II), several genes related to transmitter release, some glutamate receptor subunits and glutamate transporters [15127128].

(also see Membrane for Smith-Lemli-Opitz Syndrome).

Several polymorphisms in the genes encoding proteins whose activity is directly modulated by calcium have been suggeste to play a possible role to autism [17275285]. Although no firm genetic linkage has been established, it has also been hypothesised that mutations in genes encoding sodium channels SCN1A and SCN2A, and those encoding potassium channels, such as CASPR2, may play a role [12610651, 10673544]. On the other hand, physical disruption in the gene KCNMA1 encoding BKCa channels and decreased activity of these channels in autism have been observed recently [16946189]. Recent findings have pointed to functional coupling of BKCa and LTCC channels on plasma membrane, and in additon excessive calcium levels as result from either extracellular space or intracellular store-released, are known to modulate functioning of potassium channels [15141163, 16828974, 15486093] (see also Epilepsy). It may be worth noting that KCNMA1 gene location on chromosome 10q22 has been implicated in preeclampsia [15208369] and also that this chromosomal location has been identified as a preferred integration site for hepatitis B virus [9519839].

Equally important are the findings of increased frequency of polymorphisms in the genes related to the immune system in autism, possibly indicating weakened defenses against and elimination of pathogens such as viruses and bacteria from the body, leaving a developing nervous system especially vulnerable to direct and indirect pathogenic influences (see Immune and Viruses). In addition to several mutations in genes belonging to major histocompatibility complex (MHC) region, related to immune function, being associated with autism, the involvement of CREB-mediated events in regulation and expression of these genes should be also be of interest [16730065] (see above, also see Brain).

One very interesting finding in recent times was the association of genetic polymorphisms related to macrophage migration inhibitory factor (MIF) in individuals with autism [18676531]. MIF is central in host immune reactions/viral clearance and inflammatory responses. MIF favours viral neuroinvasion by compromising the integrity of the blood-brain barrier (see Infectious Agents re viral/bacterial aetiology in autism). It is very closely linked to MCP-1 (elevated manifold in autism) and other proinflammatory chemokines/cytokines, and its levels are inversely related to regulatory cytokine IL-10 (low in autism). MIF also plays a central part in gastrointestinal inflammation (see Gastrointestinal), as well as cellular oxidative stress pathways - cysteine mediated redox mechanisms (impaired in autism, see Oxidative Stress). It is also appears to be directly involved in neuronal function via at least one pathway, that of Angiotensin II. Levels of MIF are often suppressed in fever. The expression levels of MIF gene are partly regulated by calcium-dependent CREB.

In addition, autism has been link to some genetic mutations and polymorphisms that raise suceptibility to oxidative stress (see Oxidative_Stress).