1. Hagebeuk EE, Duran M, Abeling NG, Vyth A, Poll-The BT. {{S-adenosylmethionine and S-adenosylhomocysteine in plasma and cerebrospinal fluid in Rett syndrome and the effect of folinic acid supplementation}}. {J Inherit Metab Dis};2013 (Feb 8)
Rett syndrome is a neurodevelopmental disorder characterized by cognitive and locomotor regression and stereotypic hand movements. The disorder is caused by mutations in the X chromosomal MECP2 a gene encoding methyl CpG-binding protein. It has been associated with disturbances of cerebral folate homeostasis, as well as with speculations on a compromised DNA-methylation. Folinic acid is the stable form of folate. Its derived intermediate 5-MTHF supports the conversion of homocysteine to methionine, the precursor of S-adenosylmethionine (SAM). This in turn donates its methyl group to various acceptors, including DNA, thereby being converted to S-adenosylhomocysteine (SAH). The SAM/SAH ratio reflects the methylation potential. The goal of our study was to influence DNA methylation processes and ameliorate the clinical symptoms in Rett syndrome. Therefore we examined the hypothesis that folinic acid supplementation, besides increasing cerebrospinal fluid (CSF) 5-MTHF (p = 0.003), influences SAM and SAH and their ratio. In our randomized, double-blind crossover study on folinic acid supplementation, ten female Rett patients received both folinic acid and placebo for 1 year each. It was shown that both SAM and SAH levels in the CSF remained unchanged following folinic acid administration (p = 0.202 and p = 0.097, respectively) in spite of a rise of plasma SAM and SAH (p = 0.007; p = 0.009). There was no significant change in the SAM/SAH ratio either in plasma or CSF. The apparent inability of Rett patients to upregulate SAM and SAH levels in the CSF may contribute to the biochemical anomalies of the Rett syndrome. Our studies warrant further attempts to promote DNA methylation in the true region of interest, i.e. the brain.
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2. Jokiranta E, Brown AS, Heinimaa M, Cheslack-Postava K, Suominen A, Sourander A. {{Parental psychiatric disorders and autism spectrum disorders}}. {Psychiatry Res};2013 (Feb 4)
The present population-based, case-control study examines associations between specific parental psychiatric disorders and autism spectrum disorders (ASD) including childhood autism, Asperger’s syndrome and pervasive developmental disorder (PDD-NOS). The cohort includes 4713 children born between 1987 and 2005 with diagnoses of childhood autism, Asperger’s syndrome or PDD-NOS. Cases were ascertained from the Finnish Hospital Discharge Register, and each was matched to four controls by gender, date of birth, place of birth, and residence in Finland. Controls were selected from the Finnish Medical Birth Register. Parents were identified through the Finnish Medical Birth Register and Finnish Central Population Register. Parental psychiatric diagnoses from inpatient care were collected from the Finnish Hospital Discharge Register. Conditional logistic regression models were used to assess whether parents’ psychiatric disorders predicted ASD after controlling for parents’ age, smoking during pregnancy and weight for gestational age. In summary, parental schizophrenia spectrum disorders and affective disorders were associated with the risk of ASD regardless of the subgroup. PDD-NOS was associated with all parental psychiatric disorders investigated. Further studies are needed to replicate these findings. These results may facilitate the investigation of shared genetic and familial factors between ASD and other psychiatric disorders.
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3. Lionel AC, Vaags AK, Sato D, Gazzellone MJ, Mitchell EB, Chen HY, Costain G, Walker S, Egger G, Thiruvahindrapuram B, Merico D, Prasad A, Anagnostou E, Fombonne E, Zwaigenbaum L, Roberts W, Szatmari P, Fernandez BA, Georgieva L, Brzustowicz L, Rotzer K, Kaschnitz W, Vincent JB, Windpassinger C, Marshall CR, Trifiletti RR, Kirmani S, Kirov G, Petek E, Hodge JC, Bassett AS, Scherer SW. {{Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures}}. {Hum Mol Genet};2013 (Feb 7)
The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as Autism Spectrum Disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy arising due to cellular stress such as temperature and alkalosis associated with epileptogenesis has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein. Here we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses exons 3-5, corresponding to the G-domain of the gephyrin protein. These findings, together with previous reports of homozygous GPHN mutations in connection with autosomal recessive molybdenum cofactor deficiency, will aid in clinical genetic interpretation of the GPHN mutation spectrum. Our data also add to the accumulating evidence implicating neuronal synaptic gene products as key molecular factors underlying the etiologies of a diverse range of neurodevelopmental conditions.
