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Primary microcephaly is a specific form of microcephaly that is inherited in an autosomal recessive manner. Six loci have been mapped for this condition and the genes at two of these loci have recently been identified. These include the Microcephalin gene at the MCPH1 locus and the ASPM gene at the MCPH5 locus.
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Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder classically defined by hyperphagia and obesity. However, its profound psychiatric phenotype offers a unique genetic framework for understanding major mental illnesses. This review positions PWS as a potentially informative biological model for psychosis and obsessive-compulsive disorder (OCD), bridging the gap between 15q11-q13 imprinting defects and neural circuit dysfunction. We synthesize evidence demonstrating that psychosis in PWS is not a uniform trait but is disproportionately linked to the maternal uniparental disomy (mUPD) subtype. This genotype-phenotype correlation suggests that overexpression of maternally imprinted genes and loss of paternal expression disrupt cortical excitatory-inhibitory balance, resembling the "schizophrenia-bipolar" genomic architecture. Furthermore, synthesized evidence characterizes the repetitive, ritualistic behaviors in PWS not merely as behavioral challenges, but as a developmentally arrested OCD-spectrum phenotype driven by distinct serotonergic-oxytocinergic imbalances and hypothalamic-limbic dysconnectivity. Mechanistic insights from preclinical models of MAGEL2, SNORD116, and NDN deficiency are integrated with clinical findings to highlight shared neurobiological substrates. Finally, we outline a roadmap for precision psychiatry in PWS, emphasizing the necessity of pharmacogenomics in antipsychotic management and the potential of targeted circuit-based therapeutics. By deconstructing the psychiatric comorbidities of PWS, we provide a framework for translating genomic architecture into mechanistic understanding and targeted treatment for complex neuropsychiatric disorders.
A wide range of neuropathological abnormalities have been detected in schizophrenia sufferers, and emerging evidence points to neural substrates of connectivity as having a key role in the development of disease. This article reviews the available evidence for white matter pathology in schizophrenia, and examines its possible role as a substrate of impaired connectivity. Neuropathological data is suggestive of abnormalities in glial structure and function, and myelinated structures have also been implicated. A number of studies, particularly using gene array technology, are pointing towards significant disruption in expression of myelination genes. Magnetic resonance imaging has tended to focus on, and detect, more grey than white matter abnormalities, although non-volumetric techniques are suggestive of changes in the microstructure of white matter in schizophrenia. Myelinated structures are an attractive candidate for an anatomical substrate for disconnectivity, and may act synergistically with synaptic changes to result in functional disconnectivity although the relationship between white and grey matter changes in the illness remains unclear.
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The olfactory neuroepithelium exhibits neurogenesis throughout adult life, and in response to lesions, a phenomenon that distinguishes this neural tissue from the rest of the mammalian brain. The newly formed primary olfactory neurons elaborate axons into the olfactory bulb. Thus, denervation and subsequent reinnervation of olfactory bulb neurons may occur throughout life. This unique ability of the olfactory neuroepithelium to generate new neurons from a population of precursor cells present in the basal cell layer of this tissue makes it a valuable model in the study of neural development and regeneration. The molecular processes underlying the neurogenic properties of the olfactory neuroepithelium are poorly understood. Here we have reviewed our studies on the expression of B50/GAP43 during ontogeny of the olfactory system and following lesioning. This analysis includes the characterization of the expression of OMP, a protein expressed in mature olfactory neurons, as well as PKC and calmodulin. The latter two molecules are of particular interest to the function of B50/GAP43 since the degree of phosphorylation of B50/GAP43 appears to determine B50/GAP43's ability to bind calmodulin (see also Storm, chapter 4, this volume). In the mature olfactory epithelium B50/GAP43 expression is restricted to a subset of cells located in the basal region. Since the expression of B50/GAP43 is high in developing and regenerating nerve cells we are confident that the B50/GAP43 positive cells are new neurons derived from the stem cells in the basal region of the epithelium. B50/GAP43 is absent from the stem cells themselves and also from the mature OMP-expressing neurons. On the basis of the patterns of B50/GAP43 and OMP expression two stages could be discriminated in the regeneration of the olfactory epithelium. First, as an immediate response to lesioning a large population of B50/GAP43 positive, OMP negative neurons are formed. Subsequently, during the second stage, these newly formed differentiating neurons mature as evidenced by a decrease in B50/GAP43 and an increase in OMP expression. The second stage in the regeneration process is only manifested if the regenerating neurons can reach their target cells in the olfactory bulb. Hence, bulbectomy results in the arrest of the reconstituted olfactory epithelium in an immature state. The differential patterns of B50/GAP43 expression following peripheral lesioning and bulbectomy suggest the existence of a target derived signal molecule involved in the down-regulation of B50/GAP43 expression in olfactory neurons that have established synaptic contacts in the olfactory bulb (see also Willard, chapter 2, this volume, "the suppressor hypothesis").(ABSTRACT TRUNCATED AT 400 WORDS)
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The heteromodal association neocortex is believed to be a major site of involvement in schizophrenia. This system includes the prefrontal cortex and portions of the superior temporal and inferior parietal cortices, which are linked in cognitive networks observing complex executive functions. The heteromodal cortex is highly elaborated in humans and is believed to continue to develop past birth. The neuropathology of schizophrenia is likely to be heterogeneous and appears to involve developmental abnormalities, with a prominent genetic component. However, the genes involved in the development of the neocortex, and particularly the heteromodal cortex, are not well understood. A candidate-gene approach to schizophrenia using techniques of differential expression might now be feasible and could illuminate the basic neurobiology of the heteromodal cortical network.
Brain tissue of 50 patients with morphological confirmed Parkinson's disease (PD), blood samples from 149 patients with clinical parkinsonism and from 96 healthy control subjects were collected. Apolipoprotein-E (apo E) and cytochrome P450 2D6 (CYP2D6) genotyping were performed by PCR followed by restriction fragment analysis. A significantly higher allele frequency of CYP2D6*4 was found in patients with PD (35%) but not with parkinsonism (14.1%) compared to control subjects (19.8%). The combined alleles frequency of CYP2D6*3 + apoE4 was significantly higher not only in the PD group (33.3%) but also in patients with parkinsonism (22.3%) compared to control subjects (1.6%). These results suggest that there is a substantial overlap not only in the clinical manifestation but also in the genetic risk factors between Parkinson's and Alzheimer's diseases.
Hyperekplexia is primarily an autosomal dominant disease characterized by exaggerated startle reflex and neonatal hypertonia. It can be associated with, if untreated, sudden infant death from apnea or aspiration pneumonia and serious injuries and loss of ambulation from frequent falls. Different mutations in the alpha1 subunit of inhibitory glycine receptor (GLRA1) gene have been identified in many affected families. The most common mutation is Arg271 reported in at least 12 independent families. These mutations uncouple the ligand binding and chloride channel function of inhibitory glycine receptor and result in increased excitability in pontomedullary reticular neurons and abnormal spinal reciprocal inhibition. Three mouse models from spontaneous mutations in GLRA1 and beta subunit of inhibitory glycine receptor (GLRB) genes and two transgenic mouse models are valuable for the study of the pathophysiology and the genotype-phenotype correlation of the disease. The disease caused by mutation in GLRB in mice supports the notion that human hyperekplexia with no detectable mutations in GLRA1 may harbor mutations in GLRB. Clonazepam, a gamma aminobutyric acid (GABA) receptor agonist, is highly effective and is the drug of choice. It enhances the GABA-gated chloride channel function and presumably compensates for the defective glycine-gated chloride channel in hyperekplexia. Recognition of the disease will lead to appropriate treatment and genetic counseling.
Genetics has emphatically entered the practice of neurology. The last decade witnessed the discovery of the genetic basis of many diseases that primarily affect the nervous system. In areas such as neuromuscular and movement disorders, genetic testing has become a routine part of diagnostic testing. In areas like epilepsy, genetic advances likely will lead to new testing for certain patients. In dementia, the existence of a common predisposing genetic factor (apolipoprotein E) has already raised complex issues such as the appropriateness of genetic testing in specific clinical situations--issues that neurologists will confront more in the future. This article reviews basic principles of genetic testing, its application to neurology, and some limitations and ethical issues confronting the field.
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Explore the source record for details and available documents.
Dramatic advances in neuroscience are changing and enriching our understanding of brain and behaviour. But reductionist interpretations of these advances can cause great harm.
Rett syndrome (RTT) is unique among genetic, chromosomal and other developmental disorders because of its extreme female gender bias, early normal development, and subsequent developmental regression with loss of motor and language skills. RTT is caused by heterozygosity for mutations in the X-linked gene MECP2, which encodes methyl-CpG binding protein 2. MeCP2 is a multifunctional protein that can act as an architectural chromatin-binding protein, a function that is unrelated to its ability to bind methyl-CpG and to attract chromatin modification complexes. Inactivating mutations that cause RTT in females are not prenatally lethal in males, but lead to profound congenital encephalopathy. Molecular diagnoses of RTT, through demonstration of a MECP2 mutation, made at an early stage of the disorder, usually confirm the sporadic nature and very low recurrence risk of the condition. A positive DNA test result, however, also predicts the inevitable clinical course, given the lack of effective intervention. Initial hypotheses indicating that the MeCP2 protein acts as a genome-wide transcriptional repressor were not confirmed by global gene expression studies in various tissues of individuals with RTT and mouse models of MeCP2 deficiency. Rather, recent evidence points to low-magnitude effects of a small number of genes--including the brain--derived neurotrophic factor pathway and glucocorticoid response genes-that might affect formation and maturation of synapses or synaptic function in postmitotic neurons.