Metabolic shift toward ketosis in asocial cavefish increases social-like affinity.

BACKGROUND: Social affinity and collective behavior are nearly ubiquitous in the animal kingdom, but many lineages feature evolutionarily asocial species. These solitary species may have evolved to conserve energy in food-sparse environments. However, the mechanism by which metabolic shifts regulate social affinity is not well investigated. RESULTS: In this study, we used the Mexican tetra (Astyanax mexicanus), which features riverine sighted surface (surface fish) and cave-dwelling populations (cavefish), to address the impact of metabolic shifts on asociality and other cave-associated behaviors in cavefish, including repetitive turning, sleeplessness, swimming longer distances, and enhanced foraging behavior. After 1 month of ketosis-inducing ketogenic diet feeding, asocial cavefish exhibited significantly higher social affinity, whereas social affinity regressed in cavefish fed the standard diet. The ketogenic diet also reduced repetitive turning and swimming in cavefish. No major behavioral shifts were found regarding sleeplessness and foraging behavior, suggesting that other evolved behaviors are not largely regulated by ketosis. We further examined the effects of the ketogenic diet via supplementation with exogenous ketone bodies, revealing that ketone bodies are pivotal molecules positively associated with social affinity. CONCLUSIONS: Our study indicated that fish that evolved to be asocial remain capable of exhibiting social affinity under ketosis, possibly linking the seasonal food availability and sociality.

Metabolic Framework for the Improvement of Autism Spectrum Disorders by a Modified Ketogenic Diet: A Pilot Study.

The ketogenic diet (KD) can improve the core features of autism spectrum disorders (ASD) in some children, but the effects on the overall metabolism remain unclear. This pilot study investigated the behavioral parameters in relation to blood metabolites and trace elements in a cohort of 10 typically developed controls (TC) and 17 children with ASD at baseline and following 3 months of treatment with a modified KD regimen. A nontargeted, multiplatform metabolomic approach was employed, including gas chromatography-mass spectrometry, 1H nuclear magnetic resonance spectroscopy, and inductively coupled plasma-mass spectrometry. The associations among plasma metabolites, trace elements, and behavior scores were investigated. Employing a combination of metabolomic platforms, 118 named metabolites and 73 trace elements were assessed. Relative to TC, a combination of glutamate, galactonate, and glycerol discriminated ASD with 88% accuracy. ASD had higher concentrations of galactose intermediates, gut microbe-derived trimethylamine N-oxide and N-acetylserotonin, and lower concentrations of 3-hydroxybutyrate and selenium at baseline. Following 3 months of KD intervention, the levels of circulating ketones and acetylcarnitine were increased. KD restored lower selenium levels in ASD to that of controls, and correlation analysis identified a novel negative correlation between the changes in selenium and behavior scores. Based on the different behavior responses to KD, we found that high responders had greater concentrations of 3-hydroxybutyrate and ornithine, with lower galactose. These findings enhance our current understanding of the metabolic derangements present in ASD and may be of utility in predicting favorable responses to KD intervention.

Jitter Reduces Response-Time Variability in ADHD: An Ex-Gaussian Analysis.

OBJECTIVE: "Jitter" involves randomization of intervals between stimulus events. Compared with controls, individuals with ADHD demonstrate greater intrasubject variability (ISV) performing tasks with fixed interstimulus intervals (ISIs). Because Gaussian curves mask the effect of extremely slow or fast response times (RTs), ex-Gaussian approaches have been applied to study ISV. METHOD: This study applied ex-Gaussian analysis to examine the effects of jitter on RT variability in children with and without ADHD. A total of 75 children, aged 9 to 14 years (44 ADHD, 31 controls), completed a go/no-go test with two conditions: fixed ISI and jittered ISI. RESULTS: ADHD children showed greater variability, driven by elevations in exponential (tau), but not normal (sigma) components of the RT distribution. Jitter decreased tau in ADHD to levels not statistically different than controls, reducing lapses in performance characteristic of impaired response control. CONCLUSION: Jitter may provide a nonpharmacologic mechanism to facilitate readiness to respond and reduce lapses from sustained (controlled) performance.

Brain magnetic resonance imaging findings in Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a neurodevelopmental disorder caused by inborn errors of cholesterol metabolism resulting from mutations in 7-dehydrocholesterol reductase (DHCR7). There are only a few studies describing the brain imaging findings in SLOS. This study examines the prevalence of magnetic resonance imaging (MRI) abnormalities in the largest cohort of patients with SLOS to date. Fifty-five individuals with SLOS (27 M, 28 F) between age 0.17 years and 25.4 years (mean = 6.2, SD = 5.8) received a total of 173 brain MRI scans (mean = 3.1 per subject) on a 1.5T GE scanner between September 1998 and December 2003, or on a 3T Philips scanner between October 2010 and September 2012; all exams were performed at the Clinical Center of the National Institutes of Health. We performed a retrospective review of these imaging studies for both major and minor brain anomalies. Aberrant MRI findings were observed in 53 of 55 (96%) SLOS patients, with abnormalities of the septum pellucidum the most frequent (42/55, 76%) finding. Abnormalities of the corpus callosum were found in 38 of 55 (69%) patients. Other findings included cerebral atrophy, cerebellar atrophy, colpocephaly, white matter lesions, arachnoid cysts, Dandy-Walker variant, and type I Chiari malformation. Significant correlations were observed when comparing MRI findings with sterol levels and somatic malformations. Individuals with SLOS commonly have anomalies involving the midline and para-midline structures of the brain. Further studies are required to examine the relationship between structural brain abnormalities and neurodevelopmental disability in SLOS.

Corpus callosum measurements correlate with developmental delay in Smith-Lemli-Opitz syndrome.

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation, neurodevelopmental disorder of cholesterol metabolism caused by mutations in 7-dehydrocholesterol reductase. Corpus callosum (CC) malformations and developmental delay are common, but the relation between the two has not been evaluated. This study hypothesizes shorter callosal length and smaller area correlate with higher serum 7-dehydrocholesterol and increased severity of neurodevelopmental delay in SLOS. METHODS: Thirty-six individuals with SLOS (18M/18F) between 0.20 and 12.5 years (mean = 3.9, SD = 3.6) and 36 typically developing controls (18 boys and 18 girls) between 0.12 and 12.8 years (mean = 4.0, SD = 3.6) were each imaged once on a 1.5T scanner. One midsagittal image per study was selected for manual CC measurement. Gross motor, fine motor, and language developmental quotients; anatomical severity score; and serum sterol levels were assessed. RESULTS: Shorter CC length and smaller area correlated with a lower developmental quotient in gross motor and language domains. Furthermore, length and area negatively correlated with a serum sterol precursors and severity score, and positively correlated with total cholesterol. Degree of developmental delay ranged from mild to severe, involving all domains. CONCLUSIONS: For individuals with SLOS, smaller callosal area and length are associated with higher 7-dehydrocholesterol, severity scores, and developmental delay. The relationship between callosal development and biochemical abnormalities in this cohort may lead to further studies supporting imaging biomarkers.

Deletion 12p12 involving SOX5 in two children with developmental delay and dysmorphic features.

The SOX5 gene encodes a transcription factor involved in the regulation of nervous system development and chondrogenesis. This article reports on two cases of 12p12.1 deletion involving SOX5 presenting with global developmental delay, intellectual disability, expressive language delay, mild motor impairment, distinct features, and multiorgan involvement. The first case involves a 32-month-old boy with de novo 53-kilobase interstitial deletion at 12p12.1, representing the smallest deletion reported, and presents with severe symptomatology. The second case is a 31-month-old girl with 3.2-megabase deletion at 12p12.2 p12.1 with severe neurodevelopmental disability and minimal organ involvement. These patients bear many of the characteristics previously reported in patients with SOX5 mutations. We propose a neurodevelopmental approach to a novel syndrome with dose- and location-sensitive SOX5 gene expression.

Growth charts for individuals with Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a rare multiple congenital anomaly neurodevelopmental syndrome of impaired cholesterol synthesis. Growth restriction and developmental delay are very common clinical manifestations of SLOS. The degree, etiology, and consequences of growth restriction in SLOS remain an area of limited knowledge to the scientific community. There have been no studies describing the growth parameters and providing reference growth charts for individuals with SLOS. Our longitudinal data from 78 patients between the ages of 0.1 and 16 years with SLOS show a growth restriction of about two standard deviations below the Centers for Disease Control (CDC) norms for age. This study represents comprehensive anthropometric data from the largest cohort available, and proposes growth charts for widespread use in the management and study of individuals with SLOS.

Hypothesis: the role of sterols in autism spectrum disorder.

A possible role for sterols in the development of autism spectrum disorder (ASD) has not been proven, but studies in disorders of sterol biosynthesis, chiefly Smith-Lemli-Opitz syndrome (SLOS), enable hypotheses on a causal relationship to be discussed. Advances in genetic technology coupled with discoveries in membrane physiology have led to renewed interest for lipids in the nervous system. This paper hypothesizes on the role of sterol dysfunction in ASD through the framework of SLOS. Impaired sonic hedgehog patterning, alterations in membrane lipid rafts leading to abnormal synaptic plasticity, and impaired neurosteroid synthesis are discussed. Potential therapeutic agents include the development of neuroactive steroid-based agents and enzyme-specific drugs. Future investigations should reveal the specific mechanisms underlying sterol dysfunction in neurodevelopmental disorders by utilizing advanced imaging and molecular techniques.