A family study of symbolic learning and synaptic plasticity in autism spectrum disorder.

The current study presents a male with autism spectrum disorder (ASD) and a 3q29 deletion, and three healthy first-degree relatives. Our magnetic resonance imaging (MRI) dataset included a healthy control subset. We describe a comprehensive multimodal approach, including equivalence class formation, neurocognitive testing, MRI, and electroencephalography (EEG)-based cortical plasticity, which can provide new insights into socio-communicative and learning impairments and neural underpinnings in ASD. On neurocognitive testing, the proband showed reduced processing speed, attending behavior, and executive function. He required more training trials in equivalence class training compared with family members and exhibited impaired priming of words compared with priming with images. The proband had smaller intracranial volume and surface area and a larger visual evoked potential (VEP) C1 amplitude than family members and intact long-term potentiation (LTP)-like visual cortex plasticity. Together, these results suggest that 3q29 deletion-related ASD is associated with impaired problem-solving strategies in complex socio-communicative and learning tasks, smaller intracranial and surface area, altered VEP amplitude, and normal LTP-like visual cortex plasticity. Further studies are needed to clarify whether this multimodal approach can be used to identify ASD subgroups with distinct neurobiological alterations and to uncover mechanisms underlying socio-communicative and learning impairments. Lay Summary: We studied learning, brain activity, and brain structure in a person with autism and a genetic aberration, and his close relatives. Compared with relatives, the person with autism required more training for learning, and visual learning was better than verbal learning. This person had some changes in the activity of the visual cortex, and the size and the surface area of the brain were reduced. Knowledge about learning and brain mechanisms is valuable for the development of training programs for individuals with autism.

Neuropsychiatric phenotype in relation to gene variants in the hemizygous allele in 3q29 deletion carriers: A case series.

BACKGROUND: Genetic risk variants in the hemizygous allele may influence neuropsychiatric manifestations and clinical course in 3q29 deletion carriers. METHODS: In-depth phenotypic assessment in two deletion carriers included medical records, medical, genetic, psychiatric and neuropsychological evaluations, brain MRI scan and EEG. Blood samples were analyzed for copy number variations, and deep sequencing of the affected 3q29 region was performed in patients and seven first-degree relatives. Risk variants were identified through bioinformatic analysis. RESULTS: One deletion carrier was diagnosed with learning difficulties and childhood autism, the other with mild intellectual disability and schizophrenia. EEG abnormalities in childhood normalized in adulthood in both. Cognitive abilities improved during adolescence in one deletion carrier. Both had microcytic, hypochromic erythrocytes and suffered from chronic pain and fatigue. Molecular and bioinformatic analyses identified risk variants in the hemizygous allele that were not present in the homozygous state in relatives in genes involved in cilia function and insulin action in the autistic individual and in synaptic function and neurosteroid transport in the subject with schizophrenia. CONCLUSION: 3q29 deletion carriers may undergo developmental phenotypic transition and need regular medical follow-up. Identified risk variants in the remaining hemizygous allele should be explored further in autism and schizophrenia research.

A Role for the Transcription Factor Nk2 Homeobox 1 in Schizophrenia: Convergent Evidence from Animal and Human Studies.

Schizophrenia is a highly heritable disorder with diverse mental and somatic symptoms. The molecular mechanisms leading from genes to disease pathology in schizophrenia remain largely unknown. Genome-wide association studies (GWASs) have shown that common single-nucleotide polymorphisms associated with specific diseases are enriched in the recognition sequences of transcription factors that regulate physiological processes relevant to the disease. We have used a "bottom-up" approach and tracked a developmental trajectory from embryology to physiological processes and behavior and recognized that the transcription factor NK2 homeobox 1 (NKX2-1) possesses properties of particular interest for schizophrenia. NKX2-1 is selectively expressed from prenatal development to adulthood in the brain, thyroid gland, parathyroid gland, lungs, skin, and enteric ganglia, and has key functions at the interface of the brain, the endocrine-, and the immune system. In the developing brain, NKX2-1-expressing progenitor cells differentiate into distinct subclasses of forebrain GABAergic and cholinergic neurons, astrocytes, and oligodendrocytes. The transcription factor is highly expressed in mature limbic circuits related to context-dependent goal-directed patterns of behavior, social interaction and reproduction, fear responses, responses to light, and other homeostatic processes. It is essential for development and mature function of the thyroid gland and the respiratory system, and is involved in calcium metabolism and immune responses. NKX2-1 interacts with a number of genes identified as susceptibility genes for schizophrenia. We suggest that NKX2-1 may lie at the core of several dose dependent pathways that are dysregulated in schizophrenia. We correlate the symptoms seen in schizophrenia with the temporal and spatial activities of NKX2-1 in order to highlight promising future research areas.

Flagellate dermatitis as a bleomycin-specific adverse effect of cytostatic therapy: a clinical-histopathologic correlation.

In oncology, bleomycin is a frequently used drug for the treatment of several malignancies. In particular, it is part of chemotherapy protocols in testicular cancer. We report on two patients with testicular cancer who received bleomycin-including chemotherapy and developed flagellate dermatitis. This is a typical adverse effect of bleomycin therapy; however, its pathophysiology has not yet been clarified. We discuss possible pathophysiologic mechanisms for this reaction. In general, it has been postulated that histopathologic findings in flagellate dermatitis share similarities with those observed in fixed drug eruptions. In fact, published cases in the literature have shown a broad variety of histologic changes and the histopathologic investigation of our two patients was not indicative of fixed drug eruption-like changes. Histology of one patient showed a superficial and deep, perivascular and periadnexal infiltrate of lymphocytes and eosinophils with a prominent perisudoral distribution, whereas the other patient was remarkable only for the presence of a rather sparse, superficial, perivascular lymphocytic infiltrate with occasional eosinophils and a few melanophages. Epidermal changes, in particular necrotic keratinocytes, were not present in either patient. We provide an overview of all reported histologic changes in bleomycin-induced flagellate dermatitis, including our experience with two patients. Based on these data, we present a summary of the clinical and histologic features.

Familiar ochronotic arthropathy-caused by a gene mutation traced three hundred years.

Authors trace an ochronotic Hungarian family, which moved from Slovakia to Hungary 300 years ago. As the family members lived in a relatively close village community the gene mutation had been survived silently for ages before the clinical symptoms developed. Family tree analysis could detect with the use of allele specific PCR amplification-the p.G161R mutation of the homogentisic acid 1,2-dioxygenase (HGD) gene, which resulted in a specific genotype appearing in the Slovak population. We found a heterozygote member of this family who has children with an alkaptonuria-homozygote and known-heterozygote genotypes so there would be a high risk of alkaptonuria in their offsprings. Therefore genetic counselling is highly recommended to minimize the risk factors.

Motor neuron disease presenting with slow saccades and dementia.

A 46-year-old man with a 2-year history of dementia presented with very slow saccades and tongue fasciculations. The diagnosis of amyotrophic lateral sclerosis (ALS) was established by electrophysiologic studies and ultimately on autopsy. Rarely, slowed saccades may be present in ALS, and slow saccades in a relatively young demented patient should prompt consideration of ALS.