Paul R. Lee

Lack of an association between a dopamine-4 receptor polymorphism and attention-deficit/hyperactivity disorder: genetic and brain morphometric analyses

Although the etiology of attention-deficit/hyperactivity disorder (ADHD) is likely multifactorial, family,1 adoption,2 and twin studies3 suggest that genetic factors contribute significantly. Polymorphisms of the dopamine 4 receptor (DRD4) affect receptor binding,4 and one allele with seven tandem repeats in exon 3 (DRD4*7R) has been associated with ADHD.5,6 We examined this putative association in 41 children with severe ADHD and 56 healthy controls who were group matched for ethnicity and sex. The frequency of the DRD4*7R allele did not vary by diagnosis (0.220 vs 0.205 in patients and controls, respectively). Behavioral and brain anatomic MRI measures, previously found to discriminate patients from controls,7 did not differ significantly between subjects having and those lacking a DRD4*7R allele. These data do not support the reported association between DRD4*7R and the behavioral or brain morphometric phenotype associated with ADHD.

Temperature-Acclimated Brown Adipose Tissue Modulates Insulin Sensitivity in Humans

In rodents, brown adipose tissue (BAT) regulates cold- and diet-induced thermogenesis (CIT; DIT). Whether BAT recruitment is reversible and how it impacts on energy metabolism have not been investigated in humans. We examined the effects of temperature acclimation on BAT, energy balance, and substrate metabolism in a prospective crossover study of 4-month duration, consisting of four consecutive blocks of 1-month overnight temperature acclimation (24°C [month 1] → 19°C [month 2] → 24°C [month 3] → 27°C [month 4]) of five healthy men in a temperature-controlled research facility. Sequential monthly acclimation modulated BAT reversibly, boosting and suppressing its abundance and activity in mild cold and warm conditions (P < 0.05), respectively, independent of seasonal fluctuations (P < 0.01). BAT acclimation did not alter CIT but was accompanied by DIT (P < 0.05) and postprandial insulin sensitivity enhancement (P < 0.05), evident only after cold acclimation. Circulating and adipose tissue, but not skeletal muscle, expression levels of leptin and adiponectin displayed reciprocal changes concordant with cold-acclimated insulin sensitization. These results suggest regulatory links between BAT thermal plasticity and glucose metabolism in humans, opening avenues to harnessing BAT for metabolic benefits.

Nodding syndrome may be an autoimmune reaction to the parasitic worm Onchocerca volvulus

Patients with nodding syndrome have autoantibodies to leiomodin-1 that are neurotoxic and cross-react with proteins of the parasitic worm Onchocerca volvulus. Linking parasitic infection to autoimmune epilepsy Nodding syndrome is a unique seizure disorder affecting children in parts of East Africa. The cause of nodding syndrome has been an enigma, although an epidemiological association with the parasite Onchocerca volvulus has been established. Johnson et al. demonstrate that patients with nodding syndrome have autoantibodies to leiomodin-1 that are neurotoxic in vitro and that leiomodin-1 is expressed in regions of the brain affected during disease. Leiomodin-1 antibodies cross-react with O. volvulus proteins, linking the parasite to the autoantibody. Thus, nodding syndrome may be an autoimmune epilepsy initiated by a parasitic infection and may be preventable by treatment with antiparasitic strategies such as the drug ivermectin. Nodding syndrome is an epileptic disorder of unknown etiology that occurs in children in East Africa. There is an epidemiological association with Onchocerca volvulus, the parasitic worm that causes onchocerciasis (river blindness), but there is limited evidence that the parasite itself is neuroinvasive. We hypothesized that nodding syndrome may be an autoimmune-mediated disease. Using protein chip methodology, we detected autoantibodies to leiomodin-1 more abundantly in patients with nodding syndrome compared to unaffected controls from the same village. Leiomodin-1 autoantibodies were found in both the sera and cerebrospinal fluid of patients with nodding syndrome. Leiomodin-1 was found to be expressed in mature and developing human neurons in vitro and was localized in mouse brain to the CA3 region of the hippocampus, Purkinje cells in the cerebellum, and cortical neurons, structures that also appear to be affected in patients with nodding syndrome. Antibodies targeting leiomodin-1 were neurotoxic in vitro, and leiomodin-1 antibodies purified from patients with nodding syndrome were cross-reactive with O. volvulus antigens. This study provides initial evidence supporting the hypothesis that nodding syndrome is an autoimmune epileptic disorder caused by molecular mimicry with O. volvulus antigens and suggests that patients may benefit from immunomodulatory therapies.

Large CAG/CTG repeats are associated with childhood-onset schizophrenia

Recent studies have shown an association between trinucleotide repeat expansions (TREs) and adult-onset schizophrenia (AOS). Childhood-onset schizophrenia (COS) is a severe variant of schizophrenia with onset of symptoms before age 12 years. We have used the repeat expansion detection (RED) method to investigate the occurrence of repeat expansions in a group of well-characterized COS patients as well as a set of clinically related childhood-onset psychosis cases labeled ‘multidimensionally impaired‘ (MDI). The difference observed in the CAG/CTG RED product distribution between normal (n = 44) and COS (n = 36) samples was only marginally significant (P = 0.036). However, male COS samples (n = 20) had a significantly different RED product distribution compared to male controls (n = 25, P = 0.002) with longer RED products in COS. No such difference was seen in females (ncont = 19; nCOS = 16; P = 0.236). The difference remained significant between male COS (n = 12) and male controls (n = 24) when only Caucasian samples were used (P = 0.003). Similarly, the RED product distribution in male MDI samples (n = 18) was significantly different compared to male controls (P = 0.018). Some of the detected TREs in all three populations (COS, MDI and control) correlated with expanded alleles found at the CTG18.1 locus on chromosome 18. In conclusion, we have found an association between TREs and COS. This association is specifically significant in the male population. Thus, the occurrence of an expanded trinucleotide repeat may contribute to the genetic risk of COS, possibly in combination with other factors.

Child Neurology: Zellweger syndrome

Zellweger syndrome (ZS) is a severe manifestation of disease within the spectrum of peroxisome biogenesis disorders that includes neonatal adrenoleukodystrophy, infantile Refsum disease, and rhizomelic chondroplasia punctata. Patients with ZS present in the neonatal period with a characteristic phenotype of distinctive facial stigmata, pronounced hypotonia, poor feeding, hepatic dysfunction, and often seizures and boney abnormalities. In patients with ZS, a mutation in one of the PEX genes coding for a peroxin (a peroxisome assembly protein) creates functionally incompetent organelles causing an accumulation of very long chain fatty acids (VLCFA), among other complications. Despite an absence of treatment options, prompt diagnosis of ZS is important for providing appropriate symptomatic care, definitive genetic testing, and counseling regarding family planning.

HLA antigens in childhood onset schizophrenia

Evidence of immune system abnormalities in adult schizophrenia has prompted examination of the human leukocyte antigen (HLA) system. Childhood onset schizophrenia offers a unique opportunity to test neurodevelopmental hypotheses of schizophrenia, including those which implicate components of the immune system. In the present study, class I and II HLA antigens were typed using sequence-specific primers and the polymerase chain reaction in 28 childhood onset schizophrenics and 51 ethnically matched healthy subjects. Groups were compared for frequencies of HLA antigens reported to be associated with schizophrenia and/or autoimmune disorders. We hypothesized that antigen frequencies would differ between schizophrenic and healthy children, suggesting that some dimension of the neurodevelopmental disturbance experienced by these children may be mediated by subtle abnormalities of immune function. There were no significant differences between schizophrenic and healthy subjects in the frequency of any antigen tested. These findings do not support HLA-associated pathology in childhood onset schizophrenia.

Detection of auto-antibodies to leiomodin-1 in patients with nodding syndrome

NINDS, National Institutes of Health, Bethesda, MD, United States; NIAID, National Institutes of Health, Bethesda, MD, United States; National Center for Emerging and Zoonotic Infectious Diseases, Center for Disease Control and Prevention, Atlanta, GA, United States; Ministry of Health, Uganda, Kampala, Uganda; Center for Global Health, Center for Disease Control and Prevention, Atlanta, GA, United States

Aberrant splicing induced by the most common EPG5 mutation in an individual with Vici syndrome

Sir, Recently, a study describing the clinical and genetic data of 50 patients (30 families) with Vici syndrome (OMIM 242840) was published in Brain (Byrne et al. , 2016 b ). Vici syndrome is a severe autosomal recessive condition recently found to be caused by mutations in the EPG5 gene (NG_042838.1) (Cullup et al. , 2013). Principal features of Vici syndrome include neurological sequelae (agenesis of the corpus callosum, profound developmental delay, and progressive microcephaly), neonatal cataracts, hypopigmentation involving both skin and hair, progressive dilated or hypertrophic cardiomyopathy, and both B and T cell-related immunodeficiency (Byrne et al. , 2016 a , b ). The most common mutation identified in Vici syndrome patients is EPG5 NM_020964.2; c.1007A>G p.Gln336Arg. Based on the two large cohorts of patients recently studied (Cullup et al. , 2013; Byrne et al. , 2016 b ), this mutation accounts for >10% (9/86) of mutations. Ancestry data from previous studies show that this mutation may be associated with Ashkenazi descent (Byrne et al. , 2016 a , b ). This variant was not detected in whole genome sequencing data from our cohort of 4456 unrelated adults seen at the Inova Translational Medicine Institute (Bodian et al. , 2014, 2016). This variant is seen with a frequency of 3.129 ×10−5 in the European (non-Finnish) population of Exome Aggregation Consortium (ExAC) and has thus far never been reported in other ExAC populations (ExAC, 2016; http://exac.broadinstitute.org). The EGP5 c.1007A>G mutation has been suggested to affect splicing through in silico prediction models, though multiple predictions are contradictory [Human Splicing Finder (Desmet et al. , 2009; http://www.umd.be/HSF3/HSF.html: −6%) and NNSPLICE (Reese et al. , 1997; http://www.fruitfly.org/seq_tools/splice.html: −100%)]. Likewise, in silico predictions of the missense mutation are in disagreement with regards to its pathogenicity [PolyPhen-2 (Adzhubei et al. , …

MED23‐associated intellectual disability in a non‐consanguineous family

Intellectual disability (ID) is a heterogeneous condition arising from a variety of environmental and genetic factors. Among these causes are defects in transcriptional regulators. Herein, we report on two brothers in a nonconsanguineous family with novel compound heterozygous, disease‐segregating mutations (NM_015979.3: [3656A > G];[4006C > T], NP_057063.2: [H1219R];[R1336X]) in MED23. This gene encodes a subunit of the Mediator complex that modulates the expression of RNA polymerase II‐dependent genes. These brothers, who had profound ID, spasticity, congenital heart disease, brain abnormalities, and atypical electroencephalography, represent the first case of MED23‐associated ID in a non‐consanguineous family. They also expand upon the clinical features previously reported for mutations in this gene.

Protease-activated receptor-1 activation by granzyme B causes neurotoxicity that is augmented by interleukin-1β

BackgroundThe cause of neurodegeneration in progressive forms of multiple sclerosis is unknown. We investigated the impact of specific neuroinflammatory markers on human neurons to identify potential therapeutic targets for neuroprotection against chronic inflammation.MethodsSurface immunocytochemistry directly visualized protease-activated receptor-1 (PAR1) and interleukin-1 (IL-1) receptors on neurons in human postmortem cortex in patients with and without neuroinflammatory lesions. Viability of cultured neurons was determined after exposure to cerebrospinal fluid from patients with progressive multiple sclerosis or purified granzyme B and IL-1β. Inhibitors of PAR1 activation and of PAR1-associated second messenger signaling were used to elucidate a mechanism of neurotoxicity.ResultsImmunohistochemistry of human post-mortem brain tissue demonstrated cells expressing higher amounts of PAR1 near and within subcortical lesions in patients with multiple sclerosis compared to control tissue. Human cerebrospinal fluid samples containing granzyme B and IL-1β were toxic to human neuronal cultures. Granzyme B was neurotoxic through activation of PAR1 and subsequently the phospholipase Cβ-IP3 second messenger system. Inhibition of PAR1 or IP3 prevented granzyme B toxicity. IL-1β enhanced granzyme B-mediated neurotoxicity by increasing PAR1 expression.ConclusionsNeurons within the inflamed central nervous system are imperiled because they express more PAR1 and are exposed to a neurotoxic combination of both granzyme B and IL-1β. The effects of these inflammatory mediators may be a contributing factor in the progressive brain atrophy associated with neuroinflammatory diseases. Knowledge of how exposure to IL-1β and granzyme B act synergistically to cause neuronal death yields potential novel neuroprotective treatments for neuroinflammatory diseases.