Structured neurological soft signs examination reveals motor coordination deficits in adults diagnosed with high-functioning autism.

Neurological soft signs (NSS), discrete deficits in motor coordination and sensory integration, have shown promise as markers in autism diagnosis. While motor impairments, partly associated with core behavioral features, are frequently found in children with autism, there is limited evidence in adults. In this study, NSS were assessed in adults undergoing initial diagnosis of high-functioning autism (HFA), a subgroup difficult to diagnose due to social adaptation and psychiatric comorbidity. Adults with HFA (n = 34) and 1:1 sex-, age-, and intelligence-matched neurotypical controls were administered a structured NSS examination including motor, sensory, and visuospatial tasks. We showed that adults with HFA have significantly increased motor coordination deficits compared with controls. Using hierarchical cluster analysis within the HFA group, we also identified a subgroup that was particularly highly affected by NSS. This subgroup differed from the less affected by intelligence level, but not severity of autism behavioral features nor global psychological distress. It remains questionable whether motor impairment represents a genuinely autistic trait or is more a consequence of factors such as intelligence. Nevertheless, we conclude that examining NSS in terms of motor coordination may help diagnose adults with HFA and identify HFA individuals who might benefit from motor skills interventions.

Psychiatric care for people with Prader-Willi syndrome-characteristics, needs and barriers.

BACKGROUND: Prader-Willi syndrome (PWS) is commonly associated with intellectual disability, but also with a specific behavioural phenotype and a high predisposition to psychiatric comorbidity. This study examines the psychiatric care situation of people with PWS. METHOD: A structured online questionnaire was administered to carers of people with PWS living in Germany, asking about demographic, diagnostic and treatment parameters as well as personal experiences. RESULTS: Of 77 people with PWS, 44.2% had at least one psychiatric comorbid diagnosis. The main reasons for seeking psychiatric care were emotional outbursts and aggressive behaviour. 34.9% reported that they were currently seeking psychiatric care without success. However, 32.5% of PWS had been treated with psychotropic medication, mainly antipsychotics. CONCLUSIONS: Psychiatric comorbidity appears to be undertreated in PWS, especially in the ambulatory setting. Uncertainty among mental health care providers may also lead to frequent off-label use of psychotropic medications.

A targeted long-read sequencing approach questions the association of OXTR methylation with high-functioning autism.

BACKGROUND: DNA sequence variation and altered epigenetic regulation of the oxytocin receptor gene (OXTR) have been implicated in autism and autistic-like behaviors. While previous studies have examined subsegments of OXTR, nanopore Cas9-targeted sequencing (nCATS) allows deep characterization of entire genes with simultaneous assessment of epigenetic 5-methylcytosine (5mC) modification and without the need for prior DNA amplification or bisulfite conversion. This pilot study uses an nCATS approach to sequence the entire OXTR gene and its regulatory construct and screen for 5mC modification to compare results between individuals with high-functioning autism (HFA) and neurotypical controls (NC). METHODS: Using DNA extracted from peripheral blood, OXTR (Hg38, chr3: 8750381-8770434, 20,054 base pairs) was analyzed by nCATS. 5mC modification probabilities were calculated and visualized across the gene and differential methylation analysis was performed. RESULTS: Twenty adults with HFA (10 males, 10 females) and 20 age- and sex-matched NC (± 5 years) were included. There were no apparent group differences in the entire OXTR gene sequence, except for the intron variant rs918316, which was clustered in the HFA group. However, differential methylation analysis did not reveal a single significant group-dependent differentially methylated site among the 412 CpG sites captured. LIMITATIONS: Limitations of this study include the small number of samples due to the pilot nature of the study, which particularly limits the relevance of the sequence variants found. It should also be noted that the use of peripheral blood material limits the ability to draw conclusions about central processes. CONCLUSIONS: Previous findings of autism-associated OXTR epigenetic alterations were not reproducible with our method. In our opinion, this may lead to a reconsideration of the relevance of altered methylation at individual OXTR CpG positions in autism research. However, given the pilot nature of the study, these results need to be replicated in independent cohorts and with larger sample sizes.

Hypomethylation of the dopamine transporter (DAT) gene promoter is associated with hyperphagia-related behavior in Prader-Willi syndrome: A case-control study.

Prader-Willi syndrome (PWS), a neurodevelopmental disorder based on the loss of paternally derived but maternally imprinted genes on chromosome 15q11-13, is typically associated with hyperphagia-related behavior leading to massive obesity. Recently, there has been increasing evidence for dysregulated expression patterns of genes outside the PWS locus that influence the behavioral phenotype and for alterations in the dopaminergic system associated with weight regulation in PWS. In this study, we investigated the epigenetic regulation of the promoter regions of the dopamine transporter (DAT) and dopamine receptor D2 (DRD2) genes and their association with hyperphagia-related behavior in PWS. Methylation of the DAT and DRD2 promoter regions was examined by DNA bisulfite sequencing in 32 individuals with PWS and compared with a control group matched for sex, age, and body mass index (BMI). Hyperphagia-related behavior was assessed using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Analysis by linear mixed models revealed a significant effect of factor group on mean DAT promoter methylation rate with decreased mean methylation in PWS (7.3 ± 0.4%) compared to controls (18.8 ± 0.6%), p < 0.001. In the PWS group, we further identified effects of HQ-CT score and BMI on DAT promoter methylation. Although also statistically significantly different (8.4 ± 0.2 in PWS, 10.5 ± 0.3 in controls, p < 0.001), DRD2 promoter methylation visually appeared to be evenly distributed between groups, raising concerns regarding a biological effect. Here, we provide evidence for altered epigenetic regulation of the DAT gene in PWS, which is associated with PWS-typical hyperphagia-related behaviors.

Aripiprazole treatment for temper outbursts in Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed genes in chromosome segment 15q11-13. Behavioral traits such as temper outbursts, stereotypic, and ritualistic behavior, as well as an increased risk of psychosis accompany the syndrome, representing a major issue in the treatment of adults with PWS. Up to now, no treatment guideline for these conditions in PWS exist. This study aimed to retrospectively analyze the effect and adverse effects of treatment with aripiprazole for temper outbursts in 10 adults with PWS. RESULTS: Aripiprazole was prescribed for temper outbursts (n = 10). Treatment outcome was assessed using the Clinical Global Impression-Severity (CGI-S) and -Improvement Scale (CGI-I). Treatment success (CGI-I < 3) was observed in 70% of cases, with adverse effects from mild to partly serious extent in 60% of cases. The major adverse effect observed was increased daytime sleepiness. In total, 50% of the individuals were treated successfully for temper outbursts. The BMI did not change significantly in the successfully treated group after 6 months of treatment. CONCLUSIONS: Aripiprazole can be a treatment option for temper outbursts in people with PWS. Although a high rate of side effects was detected, their severity led to discontinuation in only 20% of the cases. Furthermore, the absence of weight gain makes aripiprazole interesting especially for the PWS population.

Alteration of serum leptin and LEP/LEPR promoter methylation in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed but maternally imprinted genes in chromosome region 15q11-13. PWS individuals typically show insatiable appetite with subsequent obesity representing the major mortality factor unless food intake is inhibited. The neurobiological basis of PWS-typical hyperphagia has remained poorly understood. Many PWS-typical abnormalities are based on hypothalamic dysregulation, a region in which hunger and satiety are hormonally regulated, with the hormone leptin being a main long-term regulator of satiety. Previous studies in PWS have inconsistently shown leptin alterations solely in early childhood, without investigating the leptin system on an epigenetic level. The present study investigates serum leptin levels (S-leptin) and DNA methylation of the leptin (LEP) and leptin receptor gene (LEPR) promoter in 24 individuals with PWS compared to 13 healthy controls matched for sex, age, and body mass index (BMI) and relates the results to the extent of hyperphagia in PWS. S-Leptin levels were obtained by Enzyme-linked Immunosorbent Assay. LEP/LEPR-promoter DNA methylation was assessed by bisulfite-sequencing, hyperphagia by Hyperphagia Questionnaire for Clinical Trials (HQ-CT). PWS and control groups differed significantly in S-leptin levels with higher S-leptin in PWS. Methylation analysis showed significant differences in mean promoter methylation rate both for LEP and LEPR with a lower methylation rate in PWS. LEPR, but not LEP methylation correlated significantly with S-leptin levels. S-leptin and both LEP and LEPR methylation did not correlate with HQ-CT scores in PWS. The present study is the first to show significantly elevated S-leptin levels in an adult PWS cohort combined with an altered, downregulated LEP and LEPR promoter methylation status compared to sex-, age- and BMI-matched controls. Analogous to previous studies, no link to the behavioral dimension could be drawn. Overall, the results suggest an increased leptin dysregulation in PWS, whereby the findings partly mirror those seen in non-syndromic obesity.

Distinct promoter regions of the oxytocin receptor gene are hypomethylated in Prader-Willi syndrome and in Prader-Willi syndrome associated psychosis.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder caused by a loss of usually paternally expressed, maternally imprinted genes located on chromosome 15q11-q13. Individuals with PWS display a specific behavioral phenotype and have a higher susceptibility than the general population for certain psychiatric conditions, especially psychosis. An impairment of the oxytocin system has been described in Prader-Willi syndrome, but has not yet been investigated in detail on the epigenetic level. Recent studies have pointed out altered methylation patterns of the oxytocin receptor gene (OXTR) in various psychiatric disorders, including psychosis. In this study, we investigated methylation rates of CpG dinucleotides in the promoter region of the oxytocin receptor gene via bisulfite-sequencing using DNA extracted from peripheral blood samples of 31 individuals with PWS and 14 controls matched for age, sex, and BMI. Individuals with PWS show significantly lower methylation in the intron 1 region of the OXTR than neurotypical controls (p = 0.012). Furthermore, male PWS subjects with psychosis show significantly lower methylation of the OXTR exon 1 region than those without psychosis (p = 0.002). Transcription factor binding site analysis revealed E2F1 as a transcription factor potentially binding to the exon 1 region. E2F1 is physiologically regulated by Necdin, an anti-apoptotic protein whose corresponding gene is located within the PWS locus. This study provides evidence of a disruption of the Oxytocin system on an epigenetic level in PWS in general and in individuals with PWS and psychosis.

N-Acetylcysteine provides limited efficacy as treatment option for skin picking in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed genes in chromosome region 15q11-13. In addition to typical characteristics such as hyperphagia, PWS is evidenced by a certain behavioral phenotype. Common indicators are repetitive behaviors, temper tantrums, and self-injurious behaviors such as skin- and/or rectal picking. N-Acetylcysteine (NAC) was previously described as a promising therapeutic option for skin picking in PWS. In this case series, we retrospectively investigated the effect of pharmacotherapy with NAC in 14 individuals with PWS suffering from skin- and/or rectal picking. Treatment success was determined using the Clinical Global Impression-Improvement scale (CGI-I). The Clinical Global Impression-Efficacy index (CGI-EI) was used to put treatment success and side effects into perspective. Six of fourteen patients, all of which were female, showed improvement in symptoms (dosage 1800-2400 mg/day), whereas six patients did not show any change during treatment. Moreover, two male patients treated for solitary rectal picking showed new onset of skin picking. Across all cases, a CGI-I of 3 (corresponding to minimal improvement) was seen after 3 months of treatment, with a CGI-EI of 1.6 (corresponding to moderate efficacy). NAC remains a reasonable therapeutic option in certain cases of skin picking in PWS but provides only limited efficacy compared to previous studies on the topic. There was a higher rate of adverse drug reactions than previously reported. The results particularly suggest caution in future treatment in individuals with solitary rectal picking and reduced efficacy when coadministered with neuroleptics.

DNA Methylation of the Leptin Gene Promoter is Altered by Chronic Alcohol Exposure in an Animal Model for Alcohol Dependence.

Appetite-regulating peptides, such as leptin, are linked to craving and have been in the focus of alcohol dependence research for years. The objective of our study was to investigate the dynamics of leptin gene promoter methylation during alcohol withdrawal and specific treatment in a rodent (rat) model for alcohol dependence. DNA methylation was measured using direct bisulfite sequencing at 0 h, 24 h, and 6 days of alcohol withdrawal as well as after treatment with alpha-melanocyte-stimulating hormone (alpha-MSH), Beta-Endorphin, or saline. We found significantly lower methylation levels in alcohol-consuming animals compared to alcohol-naïve animals. During 6 days of alcohol deprivation, this difference in methylation vanished. Leptin methylation of the alpha-MSH-treated group and 6 days alcohol-deprived animals was significantly higher than that in saline-treated animals, possibly indicating compensatory effects of the treatment. Our results further expand on previous findings from human studies that explain leptin's role in bridging the gap between alcohol consumption and appetite regulation.