Vitamin D and autism, what’s new?
An increasing amount of evidence points to the
possibility that gestational and early childhood vitamin D deficiency
[25(OH)D < 40 ng/ml] cause some cases of autism.
Vitamin D is metabolized into a seco-steroid hormone that
regulates about 3% of the 26,000 genes in the coding human
genome. It is also a neurosteroid that is active in brain development,
having effects on cellular proliferation, differentiation,
calcium signaling, neurotrophic and neuroprotective actions;
it also appears to have an effect on neurotransmission
and synaptic plasticity. Children who are, or who are destined
to become, autistic have lower 25(OH)D levels at 3 months of
gestation, at birth and at age 8 compared to their unaffected
siblings. Two open label trials found high dose vitamin D
improves the core symptoms of autism in about 75% of autistic
children. A few of the improvements were remarkable. The
vitamin D doses used in these children were 300 IU/KG/day
up to a maximum of 5000 IU/day (highest final 25(OH)D
level reached was 45 ng/ml). The other study used
150,000 IU/month IM as well as 400 IU/day [highest final
25(OH)D level was 52 ng/ml]. These two open label trials
were recently confirmed with a randomized controlled trial
(RCT) using 300 IU/kg/day with a maximum of 5000 IU/
day and resulted in effects similar to the two open label studies.
In terms of prevention, a recent small study showed vitamin
D supplementation during pregnancy (5000 IU/day) and
during infancy and early childhood (1000 IU/day) significantly
reduced the expected incidence of autism in mothers who
already had one autistic child from 20% to 5%. Vitamin D is
safe; for example, over the last 15 years, Poison Control reports
there have been approximately 15,000 cases of vitamin
D overdose. However only three of these 15,000 people developed
clinical toxicity and no one died. Given those facts,
practitioners might consider treating autism with 300 IU/kg/
day, and seek to prevent autism by supplementing pregnant
and lactating women (5000 IU/day) and infants and young
children (150 IU/kg/day) checking 25(OH)D levels every
3 months. These doses will increase 25(OH)D blood levels
to those recommended by the Endocrine Society. As the
American Academy of Pediatrics recommends vitamin D supplementation
during infancy and childhood, pediatricians and
family practitioners should evaluate the current evidence on
autism and vitamin D and act accordingly.
Vitamin D-related genes are subjected to significant de novo mutation burdens in autism spectrum disorder
Vitamin D deficiency is a putative environmental risk factor for autism spectrum disorder (ASD).
Besides, de novo mutations (DNMs) play essential roles in ASD. However, it remains unclear
whether vitamin D-related genes (VDRGs) carry a strong DNM burden. For the 943 reported
VDRGs, we analyzed publicly-available DNMs from 4,327 ASD probands and 3,191 controls.
We identified 126 and 44 loss-of-function or deleterious missense mutations in the probands
and the controls, respectively, representing a significantly higher DNM burden (p = 1.06 × 10−5;
odds ratio = 2.11). Specifically, 18 of the VDRGs were found to harbor recurrent functional
DNMs in the probands, compared with only one in the controls. In addition, we found that 108
VDRGs with functional DNMs in the probands were significantly more likely to exhibit
haploinsufficiency and genic intolerance (p < 0.0078). These VDRGs were also significantly
interconnected and co-expressed, and also with other known ASD-risk genes (p < 0.0014),
thereby forming a functional network enriched in chromatin modification, transcriptional
regulation, and neuronal function. We provide straightforward genetic evidences for the first
time that VDRGs with a strong degree of DNM burden in ASD and DNMs of VDRGs could be
involved in the mechanism underlying in ASD pathogenesis.